Eurimolan may be available in the countries listed below.
Ingredient matches for Eurimolan
Brotizolam
Brotizolam is reported as an ingredient of Eurimolan in the following countries:
- Japan
International Drug Name Search
Thursday, 29 September 2016
Apidra
Generic Name: Insulin Glulisine
Class: Insulins
Chemical Name: [3B-L-Lysine,29B-L-glutamic acid] insulin (human)
Molecular Formula: C258H384N64O78S6
CAS Number: 207748-29-6
Introduction
Antidiabetic agent; rapid-acting human insulin analog prepared using recombinant DNA technology and special laboratory strain of nonpathogenic Escherichia coli (K12).1 2 7
Uses for Apidra
Diabetes Mellitus
Treatment of type 1 or type 2 diabetes mellitus in adults who require a rapid-acting insulin for control of hyperglycemia.1 2 3 4
Used in conjunction with a longer-acting insulin (e.g., isophane [NPH] insulin human, insulin glargine), except when administered via an external controlled-infusion device (pump).1 2 4 6 7
At least as effective for glycemic control as insulin human (regular) or insulin lispro.1 3 4 6
May provide greater convenience compared with insulin human (regular) in timing of insulin injections in relation to meals; clinical relevance of this difference remains to be established.3 4 6
Used by IV infusion in appropriately monitored patients;1 American Diabetes Association (ADA) states that insulin glulisine offers no advantage over regular crystalline insulin in patients who require IV insulin.
Apidra Dosage and Administration
Administration
Administer by sub-Q injection, continuous sub-Q infusion, or IV infusion.1 2 8
Sub-Q Injection
For solution and drug compatibility information, see Compatibility under Stability.
When used as a mealtime insulin to control postprandial hyperglycemia, administer within 15 minutes before a meal or 20 minutes after starting a meal.1 2 6 8
Administer by sub-Q injection using a conventional insulin syringe or an insulin injection pen (e.g., OptiClik) using BD ultra-fine needles.1 2 Apidra 3-mL cartridges are intended for use with the OptiClik injection pen; use of other injection pens with the cartridge may lead to inaccurate dosing.1 2 9
Consult accompanying labeling for proper assembly, administration, and care of the injection pen.2 If the OptiClik device malfunctions, may withdraw insulin glulisine from the cartridge system into a U-100 insulin syringe and inject.1
Inject into abdominal wall, thigh, or upper arm.1 2 6 8 Follow a planned rotation of injection sites within an injection area.1 2 8
Sub-Q Infusion
For solution and drug compatibility information, see Compatibility under Stability.
Administer by continuous sub-Q infusion into the abdominal wall using an external controlled-infusion device (e.g., Disetronic H-Tron plus V100; D-Tron; MiniMed models 506, 507, 507c, and 508).1 2 8
Replace infusion set (reservoir, tubing, and catheter) at least every 48 hours; replace insulin glulisine in the reservoir and select new infusion site.1
Consult manufacturer’s labeling for specialized administration techniques (e.g., length of infusion, frequency of changing infusion sets) or other details specific to insulin glulisine.1 Consult manual provided by manufacturer of sub-Q infusion device for additional information on general use of the pump.1
IV Administration
For solution and drug compatibility information, see Compatibility under Stability.
Administer by IV infusion in a setting that allows appropriate clinical and laboratory monitoring.1 (See Hypoglycemia and Hypokalemia under Cautions.)
Dilution
For IV infusion, dilute in 0.9% sodium chloride injection to a concentration of 1 unit/mL.1
Dosage
Dosage of insulin glulisine is expressed in terms of USP units.1 a
Insulin glulisine and insulin human are equipotent on a unit-for-unit basis with regard to glucose-lowering activity.1 6 7 8 (See Pharmacokinetics.)
More rapid onset and shorter duration of action than insulin human (regular).1 2 7 8 May require a longer-acting insulin or insulin infusion therapy to maintain adequate glycemic control.1 7 8
Individualize dosage based on blood glucose determinations to obtain optimum therapeutic effect.1 8 No specific dosage recommendations by the manufacturer.1
Whenever possible, patients should self-monitor blood glucose concentrations.1 2 8
Glucose monitoring is particularly important for patients receiving insulin via an external infusion pump.
Make any dosage change cautiously and only under medical supervision.1 2 a Changes in insulin therapy (e.g., strength, timing of dosing, manufacturer, type, method of administration, or species [animal insulins no longer commercially available in US]) may necessitate adjustments in dosage of insulin glulisine or concomitant antidiabetic agents.1 2 a
Insulin dosage adjustment may be necessary if patient changes usual physical activity or meal plan, or during times of illness, emotional disturbances, or stress.1 2
Adults
Diabetes Mellitus
Type 1
Sub-Q Injection
Usually, initial total insulin dosages range from 0.2–1 units/kg daily.
As part of a meal-related regimen, basal insulin requirements (e.g., using insulin detemir, insulin glargine) usually comprise 40–60% of the total daily insulin dosage, with the remainder given preprandially as rapid- or short-acting insulin.
Sub-Q Infusion
When used in external infusion pumps, a portion of the total dosage is given as meal-related injections, with the remainder as a basal infusion.8 Individualize dosage; adjust dosage regularly based on blood glucose determinations.1
Type 2
Sub-Q Injection
In patients not controlled on intermediate-acting or long-acting insulin, some clinicians suggest initiating preprandial therapy with a rapid-acting insulin (e.g., insulin glulisine), with the preprandial injection comprising 40–50% of the total insulin dosage and the remainder (50–60%) given as a basal insulin.5
Sub-Q Infusion
When used in external infusion pumps, a portion of the total dosage is given as meal-related injections, with the remainder as a basal infusion.8 Individualize dosage; adjust dosage regularly based on blood glucose determinations.1
Special Populations
Hepatic Impairment
Dosage reduction may be required; carefully monitor blood glucose concentrations and adjust dosage as necessary.1 (See Elimination: Special Populations, under Pharmacokinetics.)
Renal Impairment
Dosage reduction may be required; carefully monitor blood glucose concentrations and adjust dosage as necessary.1 (See Elimination: Special Populations, under Pharmacokinetics.)
Geriatric Patients
No specific dosage recommendations.1 (See Geriatric Use under Cautions.)
Lactation
Dosage adjustments may be required.1
Cautions for Apidra
Contraindications
Known hypersensitivity to insulin glulisine or any ingredient in the formulation.1 2
Hypoglycemic episodes.1 7
Warnings/Precautions
Warnings
Hypoglycemia
Most common adverse effect of insulins.1 Blood glucose concentration monitoring is recommended for all diabetic patients.1 Hypoglycemic timing may differ among various insulin formulations and may change when the treatment regimen or timing of dosing of the insulins is changed.b
Rapid changes in serum glucose concentrations may precipitate manifestations of hypoglycemia, regardless of glucose concentrations.1 Early warning signs of hypoglycemia may be diminished or absent in patients with long-standing diabetes mellitus, diabetic neuropathy, intensified diabetes control, and/or those receiving drugs such as β-adrenergic blocking agents that mask catecholamine-induced manifestations of hypoglycemia.1 a Severe hypoglycemia (including loss of consciousness) may occur prior to patient’s awareness.1
Use intensive insulin therapy with caution in patients with a history of hypoglycemic unawareness or recurrent, severe hypoglycemic episodes. Higher target blood glucose concentrations (e.g., fasting blood glucose concentrations of 140 mg/dL and 2-hour postprandial concentrations of 200–250 mg/dL) are advisable in these patients.
Insulin Pumps
For solution and drug compatibility information, see Compatibility under Stability. For pump compatibility, see Sub-Q Infusion under Administration in Dosage and Administration.
Because of rapid onset and shorter duration of action of insulin glulisine compared to insulin human, risk of hyperglycemia and ketosis in a shorter time period if pump or infusion set malfunctions or if insulin degradation occurs.1
Prompt identification and correction of hyperglycemia or ketosis is necessary; may require interim therapy with sub-Q injections until problems with pump are corrected.1
Sensitivity Reactions
Hypersensitivity Reactions
Possible localized allergic reactions (e.g., pruritus, erythema, swelling) at injection site; usually resolve within a few days to a few weeks.1 a In some patients, may be related to other factors (e.g., irritants in skin cleaning agent, poor injection technique).1
Generalized hypersensitivity reactions (e.g., rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, diaphoresis, anaphylaxis) reported less frequently than localized reactions, but may be life-threatening.1 2
Localized reactions and generalized myalgias reported with use of m-cresol, an excipient in the formulation.1
Antibody Formation
Can stimulate transient formation of antibodies to insulin that may cross-react with insulin glulisine or HbA1c insulin human.1 No correlation found between antibody concentration and changes in HbA1c, insulin doses, or incidence of hypoglycemia.1 8
General Precautions
Hypoglycemia and Hypokalemia
Following IV administration, closely monitor glucose and potassium concentrations to avoid potentially fatal hypoglycemia or hypokalemia.1 (See Hypoglycemia under Cautions.)
Lipodystrophy
Atrophy or hypertrophy of subcutaneous fat tissue may occur at injection sites and may delay insulin absorption;1 injection site rotation may reduce or prevent these effects.2
Specific Populations
Pregnancy
Category C.1
Lactation
Not known whether insulin glulisine is distributed into milk; use caution in nursing women.1
Pediatric Use
Safety and efficacy not established in children <18 years of age.1 9 (See Absorption: Special Populations, under Pharmacokinetics.)
Geriatric Use
No substantial differences in safety and efficacy in those ≥65 years of age relative to younger adults; however, possibility exists of greater sensitivity in some geriatric individuals.1
Common Adverse Effects
Hypoglycemia,1 7 8 systemic hypersensitivity,1 4 7 8 injection site reaction.1 3 4 7 8
Interactions for Apidra
Many drugs affect glucose metabolism; if such drugs are used concomitantly, may require insulin dosage adjustment and careful monitoring.1
Specific Drugs
ACE inhibitors |
|---|
Disopyramide |
Fibrate derivatives |
Fluoxetine |
MAO inhibitors |
Oral antidiabetic agents |
Pentoxifylline |
Propoxyphene |
Salicylates |
Sulfa anti-infectives |
Antipsychotics, atypical (e.g., clozapine, olanzapine) |
Corticosteroids |
Danazol |
Diazoxide |
Diuretics |
Estrogens and progestins (e.g., oral contraceptives) |
Glucagon |
HIV protease inhibitors |
Isoniazid |
Phenothiazines |
Somatropin |
Sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline) |
Thyroid hormones |
β-Adrenergic blocking agents |
Alcohol |
Clonidine |
Lithium salts |
Pentamidine |
β-Adrenergic blocking agents |
Clonidine |
Guanethidine |
Reserpine |
Apidra Pharmacokinetics
Absorption
Bioavailability
Following sub-Q injection, absorption is rapid; faster than that of insulin human (regular).1 7 8
Following sub-Q injection, absolute bioavailability is approximately 70%.1
Substantial interindividual and intraindividual variation may occur based on site of injection, method of administration, tissue blood supply, temperature, and physical activity.1 8
Atrophy or hypertrophy of subcutaneous fat tissue at the injection site1 2 may delay absorption.1
Onset
Following sub-Q injection, insulin glulisine has shorter onset of action than insulin human (regular).1
Duration
Following sub-Q injection, duration is shorter than that of insulin human insulin (regular).1 3 7 8
Special Populations
Relative differences in pharmacokinetics between insulin glulisine and insulin human (regular) in type 1 diabetic children 7–16 years of age similar to the relative differences observed in adults.1 (See Pediatric Use under Cautions.)
Distribution
Extent
Following IV administration, distribution similar to that of insulin human (regular).1
Not known whether insulin glulisine is distributed into milk.1
Elimination
Following sub-Q injection, elimination more rapid than that of insulin human (regular).1 8
Following IV administration, elimination similar to that of human insulin (regular).1
Half-life
Sub-Q administration: 42 minutes.1 7 8
IV administration: 13 minutes.1 7 8
Special Populations
Reduced clearance reported in nondiabetic patients with moderate or severe renal impairment.1 (See Renal Impairment under Dosage and Administration.)
Effects of hepatic impairment not evaluated; however, possible increased circulating concentrations of insulin, reduced capacity for gluconeogenesis, and reduced insulin metabolism, based on observations with other insulins in patients with hepatic dysfunction.1 (See Hepatic Impairment under Dosage and Administration.)
Stability
Storage
Parenteral
Injection
Unopened vials and cartridges: 2–8°C.1 2 Protect from light.1 2 Do not freeze; discard if solution has been frozen.1 2
Opened (in-use) vials: <25°C for ≤28 days.1 Protect from direct heat and light.1
When diluted for IV administration, stable at room temperature for 48 hours.1
OptiClik opened cartridges: <25°C away from direct heat and light.1 Discard opened cartridge system after 28 days.1 Do not refrigerate OptiClik system, with or without cartridges.1
Infusion sets (reservoirs, tubing, and catheters): Discard infusion set and any insulin glulisine in the reservoir after 48 hours (or less) of use.1 Discard if exposed to >37°C.1
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
When used in an external infusion pump, do not mix insulin glulisine with other insulins or diluents.1
Manufacturer recommends use of polyvinyl chloride Viaflex infusion bags and polyvinyl chloride tubing with a dedicated infusion line; compatibility with other bags or tubing has not been established.1
Solution Compatibility
Compatible with 0.9% sodium chloride injection.1
Incompatible with dextrose or Ringer’s injection; other IV diluents not studied and not recommended.1
Drug Compatibility
Compatible with isophane insulin human; incompatible with other insulin preparations.1 2
If mixed with isophane insulin human for sub-Q injection, draw insulin glulisine into the syringe first.1 8 Administer immediately after mixing; do not administer such mixtures IV.1
ActionsActions
Pharmacologic effects comparable to those of insulin human;1 8 stimulates peripheral glucose uptake by tissues (e.g., skeletal muscle, fat), inhibits hepatic glucose production, inhibits lipolysis, and enhances protein synthesis.1
More rapid onset and shorter duration of action than insulin human (regular) following sub-Q administration.1 3 7 8
Advice to Patients
Provide copy of manufacturer’s information for patients.1
Importance of strict adherence to manufacturer’s instructions regarding assembly, administration, and care of specialized delivery systems, such as insulin pens or pumps.1 2
Provide instructions regarding self-monitoring of blood glucose, insulin storage and injection technique, adherence to meal planning, physical exercise, blood glucose monitoring, and management of hypoglycemia or hyperglycemia.1 2
Importance of not mixing insulin glulisine for sub-Q injection with insulin preparations other than isophane insulin human.1 2 When mixing with isophane insulin human, importance of drawing insulin glulisine into the syringe first.1 2 8 Importance of using insulin glulisine only if solution is clear and colorless with no visible particles.1 2
Importance of not mixing insulin glulisine with other insulins or diluents when used in external sub-Q infusion pumps.1 2
Importance of administering insulin glulisine ≤15 minutes before a meal or ≤20 minutes after the start of a meal.1 2 8
Importance of changing insulin dosage with caution and only under medical supervision.1 2 Discuss potential for alterations in insulin requirements in special situations (e.g., illness, emotional disturbances or other stresses, concomitant agents that alter glycemic control).1 2 Discuss potential for alterations in insulin requirements as a result of changes in physical activity, inadequate or missed doses, inadvertent administration of incorrect doses, inadequate food intake, or skipped meals.1 2 8
Importance of providing instructions on safe disposal of needles.2
Importance of informing clinicians of recurrent or persistent skin reactions (erythema, pruritus, thickened skin, skin depression or atrophy) at injection or infusion sites.1 2 Importance of selecting a new infusion or injection site if such reactions occur.1 2
Importance of informing clinicians of the development of generalized hypersensitivity reactions (shortness of breath, low BP, wheezing, whole body rash, fast pulse, sweating).2
Importance of wearing a medical alert identification bracelet or pendant, carrying ample insulin and supplies when traveling, and having carbohydrates (sugar or candy) on hand for emergencies.2
Importance of resumption of sub-Q injections of insulin glulisine with a syringe and of contacting a clinician if pump malfunctions occur and cannot be corrected promptly.1 2
Importance of contacting a clinician if self-monitored blood glucose concentrations are consistently high.2
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements, as well as concomitant alcohol ingestion.1 2
Importance of informing clinicians of concomitant illnesses, including hepatic or renal disease.2
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection | 100 units/mL | Apidra (with m-cresol; available as 3-mL cartridges, OptiClik prefilled pen, and 10-mL vials) | Sanofi-Aventis |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Apidra 100UNIT/ML Solution (SANOFI-AVENTIS U.S.): 10/$109.99 or 30/$307.98
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 01, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
1. Sanofi-Aventis. Apidra (insulin glulisine [rDNA origin]) injection prescribing information. Bridgewater, NJ; 2007 Apr.
2. Sanofi-Aventis. Apidra (insulin glulisine [rDNA]) injection patient information. Bridgewater, NJ; 2007 Apr.
3. Dailey G, Rosenstock J, Moses RG et al. Insulin glulisine provides improved glycemic control in patients with type 2 diabetes. Diabetes Care. 2004; 27:2363-8. [PubMed 15451901]
4. Dreyer M, Prager R, Robinson A et al. Efficacy and safety of insulin glulisine in patients with type 1 diabetes. Horm Metab Res. 2005; 37:702-7. [PubMed 16308840]
5. Mayfield JA, White RD. Insulin therapy for type 2 diabetes: rescue, augmentation, and replacement of beta-cell function. Am Fam Physician. 2004; 70:489-500, 511-2. [IDIS 519852] [PubMed 15317436]
6. Garg SK, Rosenstock J, Ways K . Optimized basal-bolus insulin requirements in type 1 diabetes: insulin glulisine versus regular human insulin in combination with basal insulin glargine. Endocr Pract. 2005; 11:11-7. [PubMed 16033730]
7. Robinson DM, Wellington K. Insulin glulisine. Drugs. 2006; 66:861-9. [PubMed 16706558]
8. Gabry KE. Insulin glulisine injection, Apidra. Summary basis of approval: medical review. NDA number: 21-629. Rockville, MD: US Food and Drug Administration; 2004 Apr 16.
9. Sanofi-Aventis, Bridgewater, NJ: Personal communication.
10. Sanofi-Aventis. Getting to know your Opticlik pen: Opticlik and its parts. Bridgewater, NJ; 2006 Feb. Available from website. Accessed 2008 Mar 17.
a. AHFS drug information 2008. McEvoy GK, ed. Insulins general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2008:3196-3207.
b. Novo Nordisk. Levemir (insulin detemir [rDNA origin] injection prescribing information. Princeton, NJ; 2007 May 16.
More Apidra resources
- Apidra Side Effects (in more detail)
- Apidra Use in Pregnancy & Breastfeeding
- Apidra Drug Interactions
- Apidra Support Group
- 0 Reviews for Apidra - Add your own review/rating
- Apidra Prescribing Information (FDA)
- Apidra Advanced Consumer (Micromedex) - Includes Dosage Information
- Apidra Cartridges MedFacts Consumer Leaflet (Wolters Kluwer)
- Apidra Consumer Overview
Compare Apidra with other medications
- Diabetes, Type 1
- Diabetes, Type 2
Wednesday, 28 September 2016
Nasolina
Nasolina may be available in the countries listed below.
Ingredient matches for Nasolina
Oxymetazoline
Oxymetazoline hydrochloride (a derivative of Oxymetazoline) is reported as an ingredient of Nasolina in the following countries:
- Spain
International Drug Name Search
Amosept
Amosept may be available in the countries listed below.
Ingredient matches for Amosept
Didecyldimethylammonium Chloride
Didecyldimethylammonium Chloride is reported as an ingredient of Amosept in the following countries:
- Germany
International Drug Name Search
Optimectin
Optimectin may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Ingredient matches for Optimectin
Ivermectin
Ivermectin is reported as an ingredient of Optimectin in the following countries:
- Switzerland
International Drug Name Search
Ozole
Ozole may be available in the countries listed below.
Ingredient matches for Ozole
Fluconazole
Fluconazole is reported as an ingredient of Ozole in the following countries:
- Australia
International Drug Name Search
Lindynette
Lindynette may be available in the countries listed below.
Ingredient matches for Lindynette
Ethinylestradiol
Ethinylestradiol is reported as an ingredient of Lindynette in the following countries:
- Bulgaria
- Croatia (Hrvatska)
- Czech Republic
- Denmark
- Hungary
- Latvia
- Lithuania
- Peru
- Slovakia
- Slovenia
- Vietnam
Gestodene
Gestodene is reported as an ingredient of Lindynette in the following countries:
- Bulgaria
- Croatia (Hrvatska)
- Czech Republic
- Denmark
- Hungary
- Latvia
- Lithuania
- Peru
- Slovakia
- Slovenia
- Vietnam
International Drug Name Search
Ultralan Tablets
Ultralan Tablets may be available in the countries listed below.
Ingredient matches for Ultralan Tablets
Fluocortolone
Fluocortolone is reported as an ingredient of Ultralan Tablets in the following countries:
- Cyprus
- Germany
- Turkey
International Drug Name Search
Zopranol
Zopranol may be available in the countries listed below.
Ingredient matches for Zopranol
Zofenopril
Zofenopril calcium salt (a derivative of Zofenopril) is reported as an ingredient of Zopranol in the following countries:
- Italy
- Luxembourg
International Drug Name Search
Fragmin - Extended Treatment in Oncology (5000, 7500, 10000, 12500, 15000, 18000 I.U Syringes)
1. Name Of The Medicinal Product
Single Dose Syringes
1.
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3.
4.
5.
6.
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
Tuesday, 27 September 2016
Tremenza
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Monoethanolamine Oleate is reported as an ingredient of Oldamin in the following countries:
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Profilnine SD
factor IX complex
Dosage Form: injection
Factor IX Complex
Profilnine® SD
Solvent Detergent Treated
DESCRIPTION
Factor IX Complex, Profilnine® SD, Solvent Detergent Treated, is a sterile, lyophilized concentrate of Factor IX (antihemophilic factor B), Factor II (prothrombin), Factor X (Stuart-Prower Factor), and low levels of Factor VII (proconvertin) derived from human plasma. Factor II content has been assayed at no more than (NMT) 150 Units per 100 Factor IX Units, Factor X at NMT 100 Units per 100 Factor IX Units, and Factor VII at NMT 35 Units per 100 Factor IX Units. Profilnine SD is intended for intravenous administration only. Each vial is a single dose container.
Profilnine SD is a non-activated Factor IX Complex prepared from pooled human plasma and purified by DEAE cellulose adsorption. Profilnine SD is treated with a mixture of the organic solvent tri(n-butyl)phosphate (TNBP) and the nonionic detergent polysorbate 80 (Solvent Detergent Mixture) to reduce risks of transmission of viral infection. However, no procedure has been shown to be totally effective in removing viral infectivity from coagulation factor products. Each vial of Profilnine SD is labeled with the Factor IX potency expressed in International Units (IU). Profilnine SD does not contain heparin. Profilnine SD contains low levels of activated coagulation factors, as indicated by the non-activated Partial Thromboplastin Time Test.1,2 Profilnine SD contains no preservatives.
When reconstituted with the appropriate volume of Sterile Water for Injection, USP, Profilnine SD contains not more than 2.5 μg polysorbate 80 and 0.40 μg TNBP per IU of Factor IX.
CLINICAL PHARMACOLOGY
Profilnine SD is a mixture of vitamin K-dependent clotting factors. The administration of Factor IX Complex, Profilnine SD, temporarily increases the plasma levels of Factor IX, thus minimizing the hazards of hemorrhage. A clinical study, which evaluated twelve subjects with hemophilia B, indicated that, following administration of Profilnine SD, Factor IX in vivo half-life is 24.68 ± 8.29 hours and recovery is 1.15 ± 0.16 IU/dL per IU infused per kg body weight.3
Administration of Factor IX Complex can result in higher than normal levels of Factor II due to its significantly longer half-life.4
The retrovirus known as Human Immunodeficiency Virus (HIV-1) has been identified as the causative agent of Acquired Immunodeficiency Syndrome (AIDS) and has been shown to be transmissible via blood or blood products. The solvent detergent process used in the manufacture of Profilnine SD has been shown to provide a very high level of virus kill without compromising protein structure and function.5 The susceptibility of human pathogenic viruses such as HIV-1, hepatitis B virus, hepatitis C virus and marker viruses such as Sindbis and Vesicular Stomatitis Virus (VSV) to inactivation by organic solvent detergent treatment has been discussed in the literature.6-8
The solvent detergent process used in the manufacture of Profilnine SD was shown to inactivate greater than 12.2 logs of HIV-1 when the retrovirus was intentionally added to product samples under laboratory evaluation (as measured by virus antigen capture and reverse transcriptase assays). In addition, this process was shown to inactivate 6.0 logs of HIV-2 (as measured by reverse transcriptase assays) when the retrovirus was intentionally added to product samples. In order to assess the ability of the solvent detergent process to inactivate other viruses such as hepatitis B and C virus, the inactivation of the model viruses, Sindbis virus and vesicular stomatitis virus (VSV), by solvent detergent treatment was studied. Prior to solvent detergent treatment, samples were inoculated with a titer of either Sindbis or VSV. The results demonstrated that a minimum of 5.3 logs of Sindbis and a minimum of 4.9 logs of VSV were removed after 180 minutes of incubation with solvent detergent (when compared to an untreated control). It should be noted that the incubation time in the actual Profilnine SD process is twice (360 minutes total) that used in the model virus studies.
The ability of the Profilnine SD process to eliminate virus, by physically partitioning virus from product, was evaluated at the DEAE chromatography step. Addition of Sindbis virus prior to Factor IX Complex adsorption by DEAE chromatography showed this step to eliminate 1.4 logs of added virus.
However, no treatment method has yet been shown capable of totally eliminating all potential infective virus in preparations of coagulation factor concentrates.
INDICATIONS AND USAGE
Factor IX Complex, Profilnine SD is indicated for the prevention and control of bleeding in patients with Factor IX deficiency due to hemophilia B.
This product contains non-therapeutic levels of Factor VII, and is not indicated for use in the treatment of Factor VII deficiency.
CONTRAINDICATIONS
None known.
WARNINGS
Because Factor IX Complex, Profilnine SD is made from pooled human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. Stringent procedures designed to reduce the risk of adventitious agent transmission have been employed in the manufacture of this product, from the screening of plasma donors and the collection and testing of plasma to the application of viral elimination/reduction steps such as DEAE chromatography and solvent detergent treatment in the manufacturing process.9-10 Despite these measures, such product can potentially transmit disease, therefore the risk of infectious agents cannot be totally eliminated. The physician should weigh the risks and benefits of the use of this product and should discuss these with the patient.
Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections. Scientific opinion encourages hepatitis B and hepatitis A vaccinations for patients with hemophilia at birth or diagnosis.
In patients undergoing surgery and in patients with known liver disease, thrombosis or disseminated intravascular coagulation (DIC) are serious and potentially fatal adverse reactions associated with the administration of Factor IX Complex concentrates.11-13
Infrequent but consistent reports have been described which indicate that patients are at greater risk of developing thrombosis and DIC in the period following surgery. Cases have also been cited which indicate that patients with liver disease may be predisposed to thrombosis or DIC when treated with Factor IX Complex. Although the available data is limited, Profilnine SD should only be administered to patients when the beneficial effects of use outweigh the serious risk of potential hypercoagulation.
PRECAUTIONS
General
Factor IX Complex, Profilnine SD should not be administered at a rate exceeding 10 mL/minute. Rapid administration may result in vasomotor reactions.
Nursing personnel, and others who administer this material, should exercise appropriate caution in handling due to the risk of exposure to viral infection.
Discard any unused contents. Discard administration equipment after single use. Do not resterilize components. Do not reuse components.
Information for Patients
Patients should be informed of the early symptoms and signs of hypersensitivity reaction, including hives, generalized urticaria, chest tightness, dyspnea, wheezing, faintness, hypotension, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician and/or seek immediate emergency care, depending on the severity of the reaction, if these symptoms occur.
Some viruses, such as parvovirus B19 or hepatitis A, are particularly difficult to remove or inactivate at this time. Parvovirus B19 may most seriously affect sero-negative pregnant women, or immunocompromised individuals. The majority of parvovirus B19 and hepatitis A infections are acquired by environmental (natural) sources.
Pregnancy Category C
Animal reproduction studies have not been conducted with Profilnine SD. It is also not known whether Profilnine SD can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Profilnine SD should be given to a pregnant woman only if clearly indicated.
Pediatric Use
Clinical Trials for safety and effectiveness in pediatric patients 16 years of age and younger have not been conducted. Across a well controlled half-life and recovery clinical trial in patients previously treated with factor IX concentrates for Hemophilia B, the two pediatric patients receiving Profilnine SD (solvent detergent treated) responded similarly when compared with the adult patients. There were no adverse events in the pediatric patients and one mild adverse event in the adult population (headache). Anecdotal evaluation of the results indicate no safety and efficacy differences between pediatric and adult populations.3
Adverse Reactions
Adverse reactions characterized by either thrombosis or disseminated intravascular coagulation (DIC) are associated with administration of Factor IX Complex concentrates.11-14 In particular, patients who receive prolonged treatment with Factor IX Complex concentrates postoperatively or with known liver disease should be kept under close observation for signs or symptoms of intravascular coagulation. Continued administration should be left to the discretion of the physician.
Adverse reactions may include urticaria, fever, chills, nausea, vomiting, headache, somnolence, lethargy, flushing or tingling. For most reactive individuals, slowing the rate of infusion relieves the symptoms. For those highly reactive individuals, a different lot may be satisfactory.
To report SUSPECTED ADVERSE REACTIONS, contact Grifols at 1-888-GRIFOLS (1-888-474-3657) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DOSAGE AND ADMINISTRATION
For adult usage:
Factor IX Complex, Profilnine SD should be administered intravenously, promptly following reconstitution with the supplied diluent. Although Profilnine SD is stable for at least three (3) hours at room temperature after reconstitution, prompt administration is recommended to avoid the ill effect of any inadvertent bacterial contamination occurring during reconstitution. Profilnine SD may be administered by injection (plastic disposable syringe only) or infusion. Administer at room temperature, do not refrigerate after reconstitution and discard any unused contents.
Each vial of Profilnine SD is labeled with the total units expressed as International Units (IU) which is referenced to the WHO International Standard. One unit approximates the activity in one mL of normal plasma.
A 1.0% increase in Factor IX (0.01 IU)/IU administered/kg can be expected.15 The amount of Profilnine SD required to establish hemostasis will vary with each patient and depend on the circumstances. The following formula may be used as a guide in determining the number of units to be administered:
In normal clinical practice there is variability among patients and their clinical condition.
Therefore, the Factor IX level of each patient should be monitored frequently during replacement therapy.
Mild to moderate hemorrhages may usually be treated with a single administration sufficient to raise the plasma Factor IX level to 20 to 30 percent. In the event of more serious hemorrhage, the patient's plasma Factor IX level should be raised to 30 to 50 percent. Infusions are generally required daily.
Surgery in patients with Factor IX deficiency requires that the Factor IX level should be raised to 30 to 50 percent for at least one week following operation. For dental extractions, the Factor IX level should be raised to 50 percent immediately prior to the procedure; additional Factor IX Complex may be given if bleeding recurs.
For pediatric usage: See PRECAUTIONS
RECONSTITUTION
Use Aseptic Technique
- Warm diluent (Sterile Water for Injection, USP) and concentrate (Profilnine SD) to at least room temperature (but not above 37 °C).
- Remove the plastic flip off cap from the diluent vial.
- Gently swab the exposed stopper surface with a cleansing agent such as alcohol trying to avoid leaving any excess cleansing agent on the stopper.
- Open the Mix2Vial® package by peeling away the lid (Figure 1). Leave the Mix2Vial in the clear outer packaging.
- Place the diluent vial upright on an even surface and hold the vial tight and pick up the Mix2Vial in its clear outer packaging. Holding the diluent vial securely, push the blue end of the Mix2Vial vertically down through the diluent vial stopper (Figure 2).
- While holding onto the diluent vial, carefully remove the clear outer packaging from the Mix2Vial set, ensuring the Mix2Vial remains attached to the diluent vial (Figure 3).
- Place the product vial upright on an even surface, invert the diluent vial with the Mix2Vial attached.
- While holding the product vial securely on a flat surface, push the clear end of the Mix2Vial set vertically down through the product vial stopper (Figure 4). The diluent will automatically transfer out of its vial into the product vial. (NOTE: If the Mix2Vial is connected at an angle, the vacuum may be released from the product vial and the diluent will not transfer into the product vial.)
- With the diluent and product vials still attached to the Mix2Vial, gently swirl the product vial to ensure the product is fully dissolved (Figure 5). Reconstitution requires less than 10 minutes. Do not shake the vial.
- Disconnect the Mix2Vial into two separate pieces (Figure 6) by holding each vial adapter and twisting counterclockwise. After separating, discard the diluent vial with the blue end of the Mix2Vial.
- Draw air into an empty, sterile syringe. Keeping the product vial upright with the clear end of the Mix2Vial attached, screw the disposable syringe onto the luer lock portion of the Mix2Vial device by pressing and twisting clockwise. Inject air into the product vial.
- While keeping the syringe plunger depressed, invert the system upside down and draw the reconstituted product into the syringe by pulling the plunger back slowly (Figure 7).
- When the reconstituted product has been transferred into the syringe, firmly hold the barrel of the syringe and the clear vial adapter (keeping the syringe plunger facing down) and unscrew the syringe from the Mix2Vial (Figure 8). Hold the syringe upright and push the plunger until no air is left in the syringe. Attach the syringe to a venipuncture set.
- NOTE: If the same patient is to receive more than one vial of concentrate, the contents of two vials may be drawn into the same syringe through a separate unused Mix2Vial set before attaching to the venipuncture set.
- Use the prepared drug as soon as possible within three hours after reconstitution.
- After reconstitution, parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstitution procedure is strictly followed, a few small particles may occasionally remain. The Mix2Vial set will remove particles and the labeled potency will not be reduced.
- Discard all administration equipment after use into the appropriate safety container. Do not reuse.
HOW SUPPLIED
Profilnine SD is supplied in sterile lyophilized form in single dose vials accompanied by a suitable volume of diluent (Sterile Water for Injection, USP), according to Factor IX potency. Each vial is labeled with the Factor IX potency expressed in International Units which is referenced to the WHO International Standard. Profilnine SD is packaged with a Mix2Vial filter transfer set for use in administration.
It is available in the following potencies, and the product is also color coded based upon assay on the carton and vial label as follows:
| Potency | NDC | Assay Color Code |
| 500 IU FIX/5 mL single dose vial | 68516-3201-1 | 500 IU FIX Range - blue box |
| 1000 IU FIX/10 mL single dose vial | 68516-3202-2 | 1000 IU FIX Range - red box |
| 1500 IU FIX/10 mL single dose vial | 68516-3203-2 | 1500 IU FIX Range - black box |
STORAGE
Profilnine SD should be stored at temperatures between 2 and 8 °C. Do not freeze diluent. May be stored at room temperature not to exceed 30 °C for up to 3 months. When removed from refrigeration, record the date on the vial or carton.
Rx only
REFERENCES
- Kingdon, H.S., Lundblad, R.L., Veltkamp, J.J., Aronson, D.L. Potentially thrombogenic materials in Factor IX Concentrates. Thromb Diath Haemorrh 33:617- 631, 1975.
- Middleton, S.M., Forbes, C.D., Prentice, C.R.M. Thrombogenic Potential in Factor IX Concentrates Comparison of Tests. Thromb Haemost (Stuttg) 40:574-576, 1979.
- Data on file at Grifols Biologicals Inc.
- Aronson, D.L. Factor IX Complex. Semin Thromb Hemostas 6(1):28-43, 1979.
- Horowitz, B. Investigations into the Application of Tri(n-butyl) phosphate/Detergent Mixtures to Blood Derivatives. In Viral Inactivation of Plasma Products, Morgenthaler J.J. (ed), Karger.
- Horowitz, B., Wiebe, M.E. et al. Inactivation of viruses in labile blood derivatives. Transfusion 25:516-522, 1985.
- Edward, C.A., Piet, M.P.J. et al. Tri(n-butyl)phosphate/detergent treatment of licensed therapeutic and experimental blood derivatives. Vox Sang 52:53-59, 1987.
- Prince, A.M., Horowitz, B., Horowitz, M. et al. The development of virus-free labile blood derivatives-a review. Eur J Epidemiology, 3:103-118, 1987.
- Menache, D., Roberts, H.R. Summary Report and Recommendations of the Task Force Members and Consultants. Thromb Diath Haemorrh 33:645-647, 1975.
- Carnelli, V., Gomperts, E.D., Friedman, A., et al. Assessment for Evidence of Non A-Non B Hepatitis in Patients Given n-Heptane-Suspended Heat-Treated Clotting Factor Concentrate. Thromb Res, 46:827-834, 1987.
- Lusher, J.M. Management of Hemophiliacs with Inhibitors. Hemophilia in the Child and Adult. Raven Press, Ltd., New York, 1989, pp. 121-136.
- Aledort, L.M. Factor IX and Thrombosis. Scand J Haematol, Suppl 30:40-42, 1977.
- Kasper, C.K. Thromboembolic Complications. Thromb Diath Haemorrh (Stuttg) 33:640-644, 1975.
- Chistolini, A., Mazzucconi, M.G., Tirindelli, M.L., LaVerde, G., Ferrari, A., Mandelli, F. Disseminated intravascular coagulation and myocardial infarction in a haemophilia B patient during therapy with prothrombin complex concentrate. Acta Haematol 83:163-165, 1990.
- Zauber, N.P., Levin, J. Factor IX Levels in Patients with Hemophilia B (Christmas Disease) Following Transfusion with Concentrates of Factor IX or Fresh Frozen Plasma (FFP). Medicine 56(3):213-224, 1977.
Manufactured and Distributed by:
Grifols Biologicals Inc.
Los Angeles, CA 90032, U.S.A.
U.S. License No. 1694
DATE OF REVISION: August 2010
Part No.
PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 500 IU VIAL
GRIFOLS
NDC 68516-3201-1
Factor IX Complex
Profilnine® SD
MID
Solvent Detergent Treated 5 mL
Storage: Store between 2 and 8 °C. May be stored at room temperature not to exceed 30 °C for up to 3 months.
Rx only. Single dose container for intravenous administration only.
Grifols Biologicals Inc. Los Angeles, CA 90032, USA
U.S. License No. 1694
PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 500 IU CARTON
GRIFOLS
NDC 68516-3201-1
Factor IX Complex
Profilnine® SD
Solvent Detergent Treated
5 mL
MID
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| BLA | BLA102476 | 07/20/1981 | |
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| BLA | BLA102476 | 07/20/1981 | |
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