1. Name Of The Medicinal Product
Single Dose Syringes
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2. Qualitative And Quantitative Composition
Active ingredient
Dalteparin sodium (INN)
Quality according to Ph Eur and in-house specification
1. Fragmin 5,000 IU : Single dose syringe containing dalteparin sodium 5,000IU (anti-Factor Xa*) in 0.2ml solution for injection equivalent to 25,000IU/ml.
2. Fragmin 7,500 IU : Single dose syringe containing dalteparin sodium 7,500IU (anti-Factor Xa*) in 0.3ml solution for injection equivalent to 25,000 IU/ml.
3. Fragmin 10,000 IU : Single dose syringe containing dalteparin sodium 10,000IU (anti-Factor Xa*) in 0.4ml solution for injection equivalent to 25,000 IU/ml.
4. Fragmin 12,500 IU : Single dose syringe containing dalteparin sodium 12,500IU (anti-Factor Xa*) in 0.5ml solution for injection equivalent to 25,000 IU/ml.
5. Fragmin 15,000 IU : Single dose syringe containing dalteparin sodium 15,000IU (anti-Factor Xa*) in 0.6ml solution for injection equivalent to 25,000 IU/ml.
6. Fragmin 18,000 IU : Single dose syringe containing dalteparin sodium 18,000IU (anti-Factor Xa*) in 0.72ml solution for injection equivalent to 25,000 IU/ml.
For excipients see section 6.1.
1 – 6 : Fragmin does not contain preservatives
*Potency is described in International anti-Factor Xa units (IU) of the 1st International Standard for Low Molecular Weight Heparin.
3. Pharmaceutical Form
Solution for injection for subcutaneous administration.
4. Clinical Particulars
4.1 Therapeutic Indications
Patients with solid tumours: Extended treatment of symptomatic venous thromboembolism (VTE) and prevention of its recurrence.
4.2 Posology And Method Of Administration
Recommended dosage for adults : Single Dose Syringes
Patients with solid tumours: Extended treatment of symptomatic venous thromboembolism (VTE) and prevention of its recurrence.
Month 1
Administer Fragmin 200 IU/kg total body weight subcutaneously (SC) once daily for the first 30 days of treatment. The total daily dose should not exceed 18,000 IU daily.
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Maximum dose of 18, 000 IU was used in patient weighing up to 132 kg in the CLOT study.
In the case of chemotherapy-induced thrombocytopenia, Fragmin dose should be adopted as follows:
- In patients receiving Fragmin who experience platelet counts between 50,000 and 100,000/mm3, the daily dose of Fragmin should be reduced by 2,500 IU until the platelet count recovers to 3.
- In patients receiving Fragmin who experience platelet counts <50,000/mm3, Fragmin should be discontinued until the platelet count recovers above 50,000/mm3.
Months 2-6
Fragmin should be administered at a dose of approximately 150 IU/kg, subcutaneously, once daily using fixed dose syringes and the table shown below.
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Recommended duration of treatment is 6 months (first month of Fragmin treatment is included). Relevance of continuing treatment beyond this period will be evaluated according to individual risk/benefit ratio, taking into account particularly the progression of cancer. No data is available with dalteparin beyond 6 months of treatment in the CLOT study.
In the case of chemotherapy-induced thrombocytopenia, Fragmin dose should be adopted as follows:
- With platelet counts <50,000/mm3, Fragmin dosing should be interrupted until the platelet count recovers above 50,000/mm3
- For platelet counts between 50,000 and 100,000/mm3, Fragmin should be reduced as illustrated in the table below depending on the patient's weight. Once the platelet count has recovered to 3, Fragmin should be re-instituted at full dose.
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Renal failure:
In the case of significant renal failure, defined as a creatinine clearance <30 ml/min, the dose of Fragmin should be adjusted based on anti-Factor Xa activity. If the anti-Factor Xa level is below or above the desired range, the dose of Fragmin should be increased or reduced respectively, and the anti-Factor Xa measurement should be repeated after 3-4 new doses. This dose adjustment should be repeated until the desired anti-Factor Xa level is achieved.
As an indication, on the basis of the data available in CLOT, the observed mean levels (min, max) between 4 and 6 hours after administration in patients without severe renal insufficiency were 1.11 IU anti-Factor Xa/ml (0.6; 1.88) and 1.03 IU anti-Factor Xa/ml (0.54; 1.70), respectively, on week 1 and 4 of dalteparin 200 IU/kg OD. Anti-Factor Xa activity determinations were conducted by the chromogenic method.
For patients with an increased risk of bleeding, it is recommended that Fragmin be administered according to the twice daily regimen detailed for Fragmin 10,000 IU/ml ampoules or Fragmin Multidose Vial.
Children
Not recommended for children.
Elderly
Fragmin has been used safely in elderly patients without the need for dosage adjustment.
Method of Administration
By subcutaneous injection, preferably into the abdominal subcutaneous tissue anterolaterally or posterolaterally, or into the lateral part of the thigh. Patients should be supine and the total length of the needle should be introduced vertically, not at an angle, into the thick part of a skin fold, produced by squeezing the skin between thumb and forefinger; the skin fold should be held throughout the injection.
4.3 Contraindications
Known hypersensitivity to Fragmin or other low molecular weight heparins and/or heparins e.g. history of confirmed or suspected immunologically mediated heparin induced thrombocytopenia (type II), acute gastroduodenal ulcer; cerebral haemorrhage; known haemorrhagic diathesis; serious coagulation disorders; septic endocarditis; haemorrhagic pericardial effusion and haemorrhagic pleural effusion; injuries to and operations on the central nervous system, eyes and ears.
In patients receiving Fragmin for treatment rather than prophylaxis, local and/or regional anaesthesia in elective surgical procedures is contra-indicated with high doses of dalteparin (such as those needed to treat acute deep-vein thrombosis, pulmonary embolism, and unstable coronary artery disease).
In cancer patients with body weight < 40kg at time of venous thromboembolic event, Fragmin should not be used for extended treatment of symptomatic VTE and prevention of its recurrences due to lack of data.
Dalteparin should not be used in patients who have suffered a recent (within 3 months) stroke
Unless due to systemic emboli.
4.4 Special Warnings And Precautions For Use
Do not administer by the intramuscular route. Due to the risk of haematoma, intramuscular injection of other medical preparations should be avoided when the twenty-four hour dose of dalteparin exceeds 5,000 IU.
Caution should be exercised in patients in whom there is an increased risk of bleeding complications, e.g. following surgery or trauma, haemorrhagic stroke, severe liver or renal failure, thrombocytopenia or defective platelet function, uncontrolled hypertension, hypertensive or diabetic retinopathy, patients receiving concurrent anticoagulant/antiplatelet agents (see interactions section). Caution shall also be observed at high-dose treatment with dalteparin (such as those needed to treat acute deep-vein thrombosis, pulmonary embolism, and unstable coronary artery disease).
Limited data are available regarding the safety and efficacy of antithrombotic therapy in patients with primary or metastatic tumours of the brain who develop concurrent thromboembolic events. There is a risk of fatal intracranial bleeding with use of anticoagulation in this category of patients. Therefore, if the treatment with Fragmin was considered, it should be monitored closely with regular re-assessment of the status of tumour involvement of the brain and other individual risks.
Thrombocytopenia, should it occur, usually appears within three weeks following the beginning of therapy. Therefore, it is recommended that the platelet counts are measured before starting treatment with Fragmin and monitored closely in first three weeks and regularly thereafter during treatment. Special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (<100,000/µl) associated with positive or unknown results of in-vitro tests for anti-platelet antibody in the presence of Fragmin or other low molecular weight (mass) heparins and/or heparin.
Fragmin induces only a moderate prolongation of the APTT and thrombin time. Accordingly, dosage increments based upon prolongation of the APTT may cause overdosage and bleeding. Therefore, prolongation of the APTT should only be used as a test of overdosage.
Monitoring Anti-Xa Levels
Monitoring ofAnti-Xa Levels in patients using Fragmin is not usually required but should be considered for specific patient populations such as paediatrics, those with renal failure, those who are very thin or morbidly obese, pregnant or at increased risk for bleeding or rethrombosis
Where monitoring is necessary, laboratory assays using a chromogenic substrate are considered the method of choice for measuring anti-Xa levels. Activated partial thromboplastin time (APTT) or thrombin time should not be used because these tests are relatively insensitive to the activity of dalteparin. Increasing the dose of dalteparin in an attempt to prolong APTT may result in bleeding (see section 4.9 Overdosage).
Patients under chronic haemodialysis with dalteparin need as a rule fewer dosage adjustments and as a result fewer controls of anti-Xa levels. Patients undergoing acute haemodialysis may be more unstable and should have a more comprehensive monitoring of anti-Xa levels (See Section 5.2 Pharmacokinetic properties).
Patients with severely disturbed hepatic function, significant renal failure or chemotherapy induced thrombocytopenia may need a reduction in dosage and should be monitored accordingly.
If a transmural myocardial infarction occurs in patients where thrombolytic treatment might be appropriate, this does not necessitate discontinuation of treatment with Fragmin but might increase the risk of bleeding.
As individual low molecular weight (mass) heparins have differing characteristics, switching to an alternative low molecular weight heparin should be avoided. The directions for use relating to each specific product must be observed as different dosages may be required.
Interchangeability with other anticoagulants
Dalteparin cannot be used interchangeably (unit for unit) with unfractionated heparin, other low molecular weight heparins, or synthetic polysaccharides. Each of these medicines differ in their starting raw materials, manufacturing process, physico-chemical, biological, and clinical properties, leading to differences in biochemical identity, dosing and possibly clinical efficacy and safety. Each of these medicines is unique and has its own instructions for use.
Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium or taking potassium sparing drugs. The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days.
In patients undergoing spinal or epidural anaesthesia, the prophylactic use of heparin may be very rarely associated with spinal haematomas resulting in prolonged or permanent paralysis. The risk is increased by use of an epidural or spinal catheter for anaesthesia, by the concomitant use of drugs (NSAIDs), platelet inhibitors or anti-coagulants and by traumatic or repeated epidural or spinal puncture.
In decision-making on the interval between the last administration of Fragmin at prophylactic doses and the placement or removal of a peridural or spinal catheter for anaesthesia, the product characteristics and the patient profile should be taken into account. Readministration should be delayed until at least four hours after the surgical procedure is completed.
Should a physician, as a clinical judgement, decide to administer anticoagulation in the context of peridual spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment such as back pain, sensory or motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction. Nurses should be trained to detect such signs and symptoms. Patients should be instructed to inform immediately a nurse or a clinician if they experience any of these.
If signs or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment may include spinal cord decompression.
There have been no adequate studies to assess the safe and effective use of Fragmin in preventing valve thrombosis in patients with prosthetic heart valves. Prophylactic doses of Fragmin are not sufficient to prevent valve thrombosis in patients with prosthetic heart valves. The use of Fragmin cannot be recommended for this purpose.
Paediatric Patients:
Clinical experience of treatment of children is limited. If dalteparin is used in children the anti-Xa levels should be monitored.
The administration of medications containing benzyl alcohol as a preservative to premature neonates has been associated with a fatal “Gasping Syndrome” (see section 4.6 pregnancy and lactation).
Elderly patients (especially patients aged eighty years and above) may be at an increased risk for bleeding complications within the therapeutic dosage ranges. Careful clinical monitoring is advised.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The possibility of the following interactions with Fragmin should be considered:
(i) An enhancement of the anticoagulant effect by anticoagulant/antiplatelet agents e.g. aspirin/ dipyridamole, GP IIb/IIIa receptor antagonists, vitamin K antagonists, NSAIDs e.g. indometacin, cytostatics, dextran, thrombolytics, sulfinpyrazone, probenecid, and etacrynic acid.
(ii) A reduction of the anticoagulant effect may occur with concomitant administration of antihistamines, cardiac glycosides, tetracycline and ascorbic acid.
Because NSAIDs and ASA analgesic/anti-inflammatory doses reduce production of vasodilatatory prostaglandins, and thereby renal blood flow and the renal excretion, particular care should be taken when administering dalteparin concomitantly with NSAIDs or high dose ASA in patients with renal failure.
However, if there are no specific contraindications, patients with unstable coronary artery disease (unstable angina and non-Q-wave infarction) can be treated with low doses of acetylsalicylic acid.
As heparin has been shown to interact with intravenous nitroglycerine, high dose penicillin, quinine and tobacco smoking interaction cannot be ruled out for dalteparin.
4.6 Pregnancy And Lactation
Pregnancy
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal developments, parturition or postnatal development (see Section 5.3 Preclinical Safety Data).
Only very limited controlled studies are so far available on the use of low molecular heparins in pregnancy. Dalteparin does not pass the placenta.
If dalteparin is used during pregnancy, the possibility of foetal harm appears remote. However, because the possibility of harm cannot be completely ruled out, dalteparin should be used during pregnancy only if clearly needed (see Section 5.3 Preclinical Safety Data).
Therefore, caution should be exercised when prescribing to pregnant women.
Epidural anaesthesia during childbirth is absolutely contraindicated in women who are being treated with high-dose anticoagulants (see section 4.3). In pregnant women during the last trimester, dalteparin anti-Xa half-lives of 4 to 5 hours were measured.
Fragmin 25000 IU/ml, solution for injection, solution, contain benzyl alcohol as a preservative. As benzyl alcohol may cross the placenta, Fragmin without preservative should therefore be used during pregnancy (see section 4.4 warnings and precautions).
Therapeutic failures have been reported in pregnant women with prosthetic heart valves on full anti-coagulant doses of low molecular weight heparin. In the absence of clear dosing, efficacy and safety information in this circumstance, Fragmin is not recommended for use in pregnant women with prosthetic heart valves.
Lactation
Limited data are available for excretion of dalteparin in human milk. One study in 15 women(between day 3 and 5 of lactation and 2 to 3 hours after receiving prophylactic doses of dalteparin) detected small amounts of anti-factor Xa levels of 2 to 8% of plasma levels in breast milk, equivalent to a milk/plasma ratio of <0.025-0.224. As oral absorption of low molecular weight heparin is extremely low the clinical implications, if any, of this small amount of anticoagulant activity on the nursing infant are unknown.
A risk to the suckling child cannot be excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Fragmin should be made taking into account the benefit of breast-feeding to the child and the benefit of Fragmin therapy to the woman.
4.7 Effects On Ability To Drive And Use Machines
Fragmin does not affect the ability to drive or operate machinery.
4.8 Undesirable Effects
About 3% of the patients having had prophylactic treatment reported side-effects.
The reported adverse reactions, which may possibly be associated to dalteparin sodium, are listed in the following table by system organ class and frequency group: common (1/100, <1/10), uncommon (1/1000, <1/100), rare (1/10 000).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse events associated with dalteparin therapy, in patients participating in controlled clinical studies were:
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In post-marketing experience, the following additional undesirable effects have been reported:
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The risk of bleeding is depending on dose. Most bleedings are mild. Severe bleedings have been reported, some cases with fatal outcome.
Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium. Rarely, clinically significant hyperkalaemia may occur particularly in patients with chronic renal failure and diabetes mellitus (see section 4.4 Special warnings and precautions for use).
Long term treatment with heparin has been associated with a risk of osteoporosis. Although this has not been observed with dalteparin, the risk of osteoporosis cannot be excluded.
4.9 Overdose
The anticoagulant effect (i.e. prolongation of the APTT) induced by Fragmin is inhibited by protamine. Since protamine itself has an inhibiting effect on primary haemostasis it should be used only in an emergency.
The prolongation of the clotting time induced by Fragmin may be fully neutralised by protamine, but the anti-Factor Xa activity is only neutralised to about 25-50%. 1 mg of protamine inhibits the effect of 100 IU (anti-Factor Xa) of Fragmin.
Protamine should be given by intravenous injection over approximately 10 minutes.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC Code BO1 AB 04: Antithrombotics
Dalteparin sodium is a low molecular weight heparin fraction (average molecular weight 4000-6000 Daltons) produced from porcine-derived sodium heparin.
Dalteparin sodium is an antithrombotic agent, which acts mainly through its ability to potentiate the inhibition of Factor Xa and thrombin by antithrombin. It has a relatively higher ability to potentiate Factor Xa inhibition than to prolong plasma clotting time (APTT).
Compared with standard, unfractionated heparin, dalteparin sodium has a reduced adverse effect on platelet function and platelet adhesion, and thus has only a minimal effect on primary haemostasis. Some of the antithrombotic properties of dalteparin sodium are thought to be mediated through the effects on vessel walls or the fibrinolytic system.
The randomized, open-label, controlled, multicenter CLOT study (Randomized Comparison of Low-Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer patients with Venous Thomboembolism) compared dalteparin to standard oral anticoagulant (OAC) therapy in the long term treatment of venous thromboembolism (VTE) in 676 patients with active malignancy who had experienced an acute symptomatic VTE (deep venous thrombosis (DVT) and/or a pulmonary embolism (PE)).
Patients were randomized to one of two groups:
- dalteparin arm prescribed at 200 IU/kg/day administered by subcutaneous (SC) injections (maximum 18,000 IU/day) during 1 month, then approximately 150 IU/kg/day from 2nd– 6th month, or
- VKA arm prescribed during 6 months (target INR 2-3), preceded by SC dalteparin 200 IU/kg/day OD (maximum 18,000 IU/day) during 5 to 7 days.
The most frequent diagnoses were: tumors of the gastrointestinal tract and pancreas (23.7%), genitourinary tumors (prostate, testicle, cervix, uterus, ovary and bladder) (21.5%), breast (16.0%), lung (13.3%). 10.4% of patients had haematological malignancies ; 75.1% of patients had metastatic disease.
The index VTE event was DVT alone in nearly 70% and PE with or without DVT in 30% of patients.
The primary endpoint was the time to first recurrence of symptomatic VTE (DVT and/or PE) during 6 months.
A total of 27 patients of 338 (8.0%) in the dalteparin arm and 53 patients of 338 (15.7%) in the VKA arm experienced at least one of the events of the composite primary endpoint. A significant 52% risk reduction in VTE recurrence at 6 months was seen with dalteparin (RR= 0.48, 95% CI [0.30-0.77], p=0.0016).
In the dalteparin arm, 19 patients (5.6%) experienced at least one episode of major bleeding compared to 12 patients (3.6%) in the VKA arm. The cumulative probability of experiencing a major bleeding at 6 months was respectively 6.5% and 4.9%, respectively. Any bleeding occurred with a higher frequency in the VKA arm (18.5% VKA vs 13.6% dalteparin). The comparison of the cumulative probability of first bleeding episode for the 2 treatments was of statistical significance in favour of dalteparin treatment (p=0.0487).
There was no significant difference in mortality between the two groups in deaths at 6 and 12 months (131 vs. 137 and 190 vs. 194 in the dalteparin and VKA arms, respectively).
There was no significant difference in the assessment of Quality of Life between the two groups of treatment.
5.2 Pharmacokinetic Properties
The half life following iv and sc. administration is 2 hours and 3.5-4 hours respectively, twice that of unfractionated heparin.
The bioavailability following sc. injection is approximately 87 per cent and the pharmacokinetics are not dose dependent. The half life is prolonged in uraemic patients as dalteparin sodium is eliminated primarily through the kidneys.
Special Populations
Haemodialysis:
In patients with chronic renal insufficiency requiring haemodialysis, the mean terminal hal-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU 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.
5.3 Preclinical Safety Data
The acute toxicity of dalteparin sodium is considerably lower than that of heparin. The only significant finding, which occurred consistently throughout the toxicity studies after subcutaneous administration of the higher dose levels was local haemorrhage at the injection site, dose-related in incidence and severity. There was no cumulative effect on injection site haemorrhages.
The haemorrhagic reaction was reflected in dose related changes in the anticoagulant effects as measured by APTT and anti-Factor Xa activities.
It was concluded that dalteparin sodium may have an osteopenic effect at very high concentrations, and that this effect is less than that of unfractionated heparin at equivalent doses.
The results revealed no organ toxicity irrespective of the route of administration, doses or the duration of treatment. No mutagenic effect was found. No embryotoxic or teratogenic effects and no effect on fertility reproductive capacity or peri- and postnatal development was shown.
6. Pharmaceutical Particulars
6.1 List Of Excipients
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6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
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6.4 Special Precautions For Storage
1 – 6 : Store below 25oC
6.5 Nature And Contents Of Container
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6.6 Special Precautions For Disposal And Other Handling
Not applicable
7. Marketing Authorisation Holder
Pfizer Limited
Ramsgate Road
Sandwich KENT
CT13 9NJ
United Kingdom
8. Marketing Authorisation Number(S)
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9. Date Of First Authorisation/Renewal Of The Authorisation
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10. Date Of Revision Of The Text
June 2011
LEGAL CATEGORY
POM
Ref: FR 6_1
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