Active ingredients: Eptacog alfa (Factor VII from recombinant DNA)
NovoSeven 1 mg (50 KUI) powder and solvent for solution for injection
NovoSeven 2 mg (100 KUI) powder and solvent for solution for injection
NovoSeven 5 mg (250 KUI) powder and solvent for solution for injection
NovoSeven 8 mg (400 KUI) powder and solvent for solution for injection
Why is Novoseven used? What is it for?
NovoSeven is a blood clotting factor. When the clotting factors in the body are not working, this drug causes the blood to clot where a "bleed" occurs.
NovoSeven is used to treat bleeding and to prevent excessive bleeding following surgery or other major treatments. Early treatment with NovoSeven reduces the amount and duration of bleeding, including joint bleeding. This reduces the need for hospitalization and absence from work and school.
It is used in some groups of people:
- If you are haemophilic from birth and if you do not respond normally to treatment with coagulation factors VIII or IX
- If you have acquired haemophilia
- If you have a Factor VII deficiency
- If you have Glanzmann's thrombasthenia (a bleeding disorder) and your condition cannot be effectively treated with a platelet transfusion.
Contraindications When Novoseven should not be used
Do not use NovoSeven
- If you are allergic to eptacog alfa (active substance in NovoSeven) or to any of the other ingredients contained in the medicine.
- If you are allergic to bovine, mouse or hamster proteins (such as cow's milk).
If any of these happen, do not use NovoSeven. Talk to your doctor.
Precautions for use What you need to know before you take Novoseven
Before treatment with NovoSeven, pay attention to what your doctor tells you:
- If you have recently had surgery
- If you have recently suffered a crush injury
- If the size of the arteries is reduced due to a disease (atherosclerosis)
- If you have an increased risk of blood clots (thrombosis)
- If you have severe liver disease
- If you have a severe blood infection
- If you are predisposed to disseminated intravascular coagulation (DIC, a condition in which blood clots develop) you should be closely monitored.
If any of the above apply to you, contact your doctor before giving the injection.
Interactions Which drugs or foods can modify the effect of Novoseven
Tell your doctor or pharmacist if you are taking or have recently taken, or should take any other medicines.
Do not use NovoSeven at the same time as prothrombin complex concentrate or rFXIII. Talk to your doctor before using NovoSeven if you also use products with factor VIII and IX.
There is limited experience of using NovoSeven in combination with other medicines called antifibrinolytic drugs (such as aminocaproic acid and tranexamic acid) which are also used to control bleeding. Talk to your doctor before taking NovoSeven with these medicines.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breastfeeding, or planning to become pregnant ask your doctor for advice before using NovoSeven.
Driving and using machines
There are no studies on the effect of NovoSeven on the ability to drive and use machines. However, there is no clinical reason to think that it would affect this ability.
Dose, Method and Time of Administration How to use Novoseven: Posology
NovoSeven powder must be reconstituted with the solvent and injected into a vein. For detailed instructions see the back of the package insert.
When to treat yourself
Start bleeding treatment as soon as possible, ideally within the first 2 hours.
- If you have mild or moderate bleeding, it should be treated as soon as possible, ideally at home.
- In case of severe bleeding, you should contact your doctor. Serious bleeding is usually treated in the hospital and you can give yourself the first dose of NovoSeven on the way to the hospital.
Do not continue treatment for more than 24 hours without consulting your doctor
- Whenever you use NovoSeven, tell your doctor or hospital as soon as possible.
- If you cannot control the bleeding within 24 hours, contact your doctor immediately.He will need hospital treatment.
Dose
The first dose should be given as soon as possible after the bleeding starts. Consult your doctor for information on when and for how long to administer. The dose will be determined by your doctor based on your body weight, condition and type of bleeding.
For best results, follow the prescribed dose carefully. The doctor may change the dose.
If you have haemophilia:
The dose is usually 90 micrograms for each kilogram of weight: you can repeat the injection every 2 to 3 hours until the bleeding is under control. Your doctor may recommend a single dose of 270 micrograms for each kilogram of your body weight. There is no clinical experience with the administration of this single dose in patients over 65 years of age.
If you have a Factor VII deficiency:
The dose is usually between 15 and 30 micrograms for each kilogram of body weight, for each injection.
If you have Glanzmann's thrombasthenia:
The usual dose is 90 micrograms (between 80 and 120 micrograms) for each kilogram of body weight, for each injection.
If you forget an injection of NovoSeven
If you have missed an injection of NovoSeven, or if you want to stop treatment, consult your doctor immediately.
INSTRUCTIONS FOR THOSE USING NOVOSEVEN
Preparation of the solution Wash your hands. NovoSeven powder and solvent vials must be at room temperature when reconstituted. Remove the plastic caps from the two vials. If the caps are missing or lost, do not use the vials. Clean the rubber stoppers of the vials with alcohol swabs and allow them to dry before use. Use an appropriately sized disposable syringe and adapter, transfer needle (20 - 26G) or other suitable device.
Remove the protective paper from the adapter without removing the protective cap. Attach the adapter to the solvent vial. Once attached, remove the protective cap. Be careful not to touch the protruding end of the adapter. If you are using a transfer needle, remove the needle from the wrapping without removing the protective cap. Screw the transfer needle firmly onto the syringe.
Pull the plunger back and draw an amount of air into the syringe corresponding to the amount of solvent contained in the solvent vial (ml corresponds to cc on the syringe).
Screw the syringe firmly onto the vial adapter on the solvent vial. If using a transfer needle, remove the protective cap and insert the transfer needle into the rubber stopper of the solvent vial. Be careful not to touch the tip of the transfer needle. Inject the air into the vial by pushing the plunger until you feel a distinct resistance.
Hold the syringe with the solvent vial upside down. If you are using a transfer needle, make sure the tip of the transfer needle is in the solvent. Pull the plunger to draw the solvent into the syringe.
Remove the empty solvent vial. If you are using a vial adapter, tilt the syringe to remove it from the vial.
Attach the syringe with the adapter or transfer needle to the vial containing the powder. If you are using a transfer needle, be sure to pierce the center of the rubber stopper. Hold the syringe slightly tilted with the vial pointing downwards. Push the plunger slowly to inject the solvent into the vial with the powder. Make sure the solvent jet does not go directly to the NovoSeven powder to avoid foaming.
Gently swirl the vial until all the powder has dissolved. Do not shake the vial as this causes foaming. Check the solution for injection for any visible undissolved particles and discolouration. If you notice any of these conditions, do not use the product. Reconstituted NovoSeven is a clear and colorless solution. Keep the adapter or needle attached to the vial.
Although NovoSeven is stable for 24 hours after its preparation, you must use it immediately, to avoid the risk of infection. If not used immediately, it should be stored in a refrigerator, at 2 ° C to 8 ° C, for up to 24 hours. Keep the solution for injection only on the advice of your doctor.
Administration of the solution
Make sure the plunger is fully depressed before the syringe is turned upside down (it may be pushed out by the pressure in the syringe). If you are using a transfer needle, make sure the tip of the needle is in the solution. Hold the syringe with the vial upside down and pull the plunger to draw all of the solution into the syringe.
If you are using an adapter, unscrew the adapter along with the empty vial. If you are using a transfer needle, remove the needle from the vial, replace the needle cap, and unscrew the needle from the syringe.
NovoSeven is now ready to be injected. Follow the injection procedure as instructed by your healthcare professional.
Throw away the syringe, adapter, vials, any unused product and other waste materials in appropriate containers as directed by your healthcare professional.
Overdose What to do if you have taken too much Novoseven
If you inject too much NovoSeven, consult your doctor immediately.
Side Effects What are the side effects of Novoseven
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects Rare (may affect 1 in every 1000 treatment episodes)
- Allergy, hypersensitivity or anaphylactic reactions. The signs may include, rash, itching, redness, hives; difficulty in breathing; feeling faint and lightheaded; severe swelling of the tongue of the lips or the injection site.
- Blood clots in the arteries or heart (which could cause a heart attack or angina pectoris), in the brain (which could cause stroke), or in the intestines and kidneys. The signs may include severe chest pain, breathlessness, confusion , difficulty speaking or moving (paralysis) or abdominal pain.
Uncommon (may affect 1 in every 100 treatment episodes)
- Blood clots in the veins of the lungs, legs, liver, kidneys or the injection site. The signs may include difficulty in breathing, painful swelling and redness of the legs, or abdominal pain.
- Lack of or diminished effects in response to treatment.
If you experience any of these side effects, contact your doctor immediately. Please inform him that you are using NovoSeven.
Tell your doctor if you have had any allergic reactions in the past as you may need to be followed up more closely. In the vast majority of blood clotting cases, patients had a predisposition to thrombotic events.
Other unwanted effects
(may affect 1 in every 1000 treatment episodes)
- Nausea
- Headache
- Changes in some blood-hepatic values.
Other uncommon side effects
(may affect 1 case in every 100 treatment episodes
- Allergic reactions such as rash, itching and hives.
- Fever.
Reporting of side effects
If you notice any side effects, please tell your doctor. This also includes any side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
- Keep this medicine out of the sight and reach of children
- Do not use the medicine after the expiry date which is stated on the outer carton and labels. The expiry date refers to the last day of the month.
- Store powder and solvent below 25 ° C
- Store powder and solvent protected from light
- Do not freeze
- Use NovoSeven immediately after reconstituting the powder with the solvent to avoid infections. If not used immediately after reconstitution, you must store the vial with the syringe still attached in the refrigerator between 2 ° C and 8 ° C for no more than 24 hours. Do not store the solution without the advice of your doctor or nurse.
- Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What NovoSeven contains
The active substance is recombinant coagulation factor VIIa (activated eptacog alfa).
The other ingredients in the powder are sodium chloride, calcium chloride dihydrate, glycylglycine, polysorbate 80, mannitol, sucrose, methionine, hydrochloric acid, sodium hydroxide. The components of the solvent are histidine, hydrochloric acid, sodium hydroxide, water for injections.
The powder for solution for injection contains: 1 mg / vial (corresponding to 50 KUI / vial), 2 mg / vial (corresponding to 100 KUI / vial), 5 mg / vial (corresponding to 250 KUI / vial) or 8 mg / vial (corresponding to 400 KUI / vial). After reconstitution 1 ml of solution contains 1 mg of eptacog alfa (activated). 1KUI equals 1000 IU (International Units).
What NovoSeven looks like and contents of the pack
The powder vial contains white powder and the solvent vial contains a clear colorless solution. The reconstituted solution is colorless. Do not use the reconstituted solution if particle formation or discoloration is observed.
Each NovoSeven pack contains:
- 1 vial with white powder for solution for injection
- 1 vial with solvent for reconstitution
Pack sizes: 1 mg (50 KUI), 2 mg (100 KUI), 5 mg (250 KUI) and 8 mg (400 KUI). Please refer to the outer box for information on the contents of each package in use.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
NOVOSEVEN POWDER AND SOLVENT FOR SOLUTION FOR INJECTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
NovoSeven 1 mg (50 KUI)
NovoSeven is presented as a powder and solvent for solution for injection containing 1 mg of eptacog alfa (activated) per vial (corresponding to 50 KUI / vial).
NovoSeven 2 mg (100 KUI)
NovoSeven is presented as a powder and solvent for solution for injection containing 2 mg of eptacog alfa (activated) per vial (corresponding to 100 KIU / vial).
NovoSeven 5 mg (250 KUI)
NovoSeven is presented as a powder and solvent for solution for injection containing 5 mg of eptacog alfa (activated) per vial (corresponding to 250 KUI / vial).
NovoSeven 8 mg (400 KUI)
NovoSeven is presented as a powder and solvent for solution for injection containing 8 mg of eptacog alfa (activated) per vial (corresponding to 400 KII / vial).
1 KUI equals 1000 IU (International Units).
Eptacog alfa (activated) is recombinant coagulation factor VIIa (rFVIIa) with a molecular mass of approximately 50,000 daltons produced in newborn hamster kidney cells (BHK cells) by recombinant DNA technology.
After reconstitution, the product contains 1 mg / ml of eptacog alfa (activated) when reconstituted with the solvent.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder and solvent for solution for injection.
White freeze-dried powder. Solvent: clear colorless solution. The reconstituted solution has a pH of approximately 6.0.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
NovoSeven is indicated for the treatment of bleeding episodes and the prevention of bleeding during undergoing surgery or invasive procedures in the following patient groups
• in patients with congenital haemophilia with coagulation factor VIII or IX inhibitors> 5 Bethesda Units (BU)
• in patients with congenital haemophilia who are expected to have a severe anamnestic response to the administration of factor VIII or factor IX • in patients with acquired haemophilia
• in patients with congenital factor VII deficiency
• in patients with Glanzmann's thrombasthenia with antibodies to GP IIb - IIIa and / or HLA and with current or past refractory to platelet transfusion.
04.2 Posology and method of administration
Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia and / or bleeding disorders.
Dosage
Hemophilia A or B with inhibitors or when a severe anamnestic response is expected
Dose
NovoSeven should be administered as soon as possible after the onset of a bleeding episode. A starting dose of 90 micrograms per kg body weight given as an intravenous bolus is recommended.
After the initial dose of NovoSeven, further injections can be repeated. The duration of treatment and the interval between administrations vary according to the severity of the bleeding, invasive procedures or surgery performed.
Pediatric population
Current clinical experience does not generally justify a difference in dosage in children compared to adults, although clearance in children is faster than in adults. Therefore, higher doses of rFVIIa may be required in pediatric patients to achieve plasma concentrations similar to that of adults. those of adult patients (see section 5.2).
Interval of administration
Initially every 2 - 3 hours to achieve hemostasis.
If continued therapy is required, once effective haemostasis is achieved, the dosing interval can be increased to every 4, 6, 8, or 12 hours for as long as treatment is indicated.
Mild to moderate bleeding episodes (including home treatment)
Early intervention was found to be effective in treating mild to moderate joint, muscle and mucocutaneous bleeding episodes. Two dosage regimens can be recommended:
1) Two to three injections of 90 mcg per kg of body weight given at three hour intervals. If further treatment is required, another dose of 90 micrograms per kg of body weight may be given.
2) A single injection of 270 mcg per kg of body weight.
The duration of home treatment should not last beyond 24 hours. The continuation of home treatment can only be considered after consultation with the center for the treatment of haemophilia.
There is no clinical experience with the administration of a single dose of 270 micrograms per kg body weight in elderly patients.
Severe bleeding episodes
An initial dosage of 90 micrograms per kg of body weight is recommended which could be administered during transport to the hospital where the patient is usually treated. Subsequent administration varies according to the type and severity of the bleeding. The frequency of administration should be given. initially every 2 hours, until clinical improvement. If it is appropriate to prolong therapy, the interval between doses can be increased to 3 hours for 1 - 2 days. Thereafter, the intervals between doses can be increased at 4, 6, 8 or 12 hours for the time period deemed appropriate Extended bleeding can be treated for 2-3 weeks, but can also be further prolonged if there is clinical justification.
Invasive procedure / surgery
An initial dosage of 90 mcg per kg of body weight should be administered immediately before the operation. The dose should be repeated after 2 hours and thereafter at intervals of 2 - 3 hours for the first 24 - 48 hours, depending on the type of operation. performed and the clinical status of the patient. In major surgery, treatment should last for 6 - 7 days with intervals between one dose and another of 2 - 4 hours. Thereafter, the dose interval can be extended to 6 - 8 hours for a further 2 weeks of treatment.In major surgeries, therapy can be continued for a period of 2 - 3 weeks until healing is achieved.
Acquired haemophilia
Dose and interval between administrations
NovoSeven should be administered as soon as possible after the start of the bleeding episode. The recommended starting dose, given as an intravenous bolus injection, is 90 micrograms per kg of body weight. After the initial dose of NovoSeven, further injections may be given if required. The duration of treatment and the interval between injections depend on the severity of the bleeding, the invasive procedures or the surgery performed.
The initial interval between administrations should be 2 - 3 hours. Once haemostasis is achieved, the interval between administrations can be progressively increased to 4, 6, 8 or 12 hours for the period of time in which it is believed. that the treatment is indicated.
Factor VII deficiency
Dose, dosage range and administration interval
The recommended dosage range for the treatment of bleeding episodes in adults and children and for the prevention of bleeding in patients undergoing surgery or invasive procedures is 15 - 30 μg per kg of body weight every 4 - 6 hours up to achieve hemostasis. The dose and frequency of administration varies from patient to patient.
Pediatric population
Limited clinical experience in long-term prophylaxis has been gathered in the pediatric population below 12 years of age with a severe clinical phenotype (see section 5.1).
The dose and frequency of administration for prophylaxis is based on clinical responses and varies from patient to patient.
Glanzmann's thrombasthenia
Dose, dosage range and administration interval
The recommended dosage range for the treatment of bleeding episodes and for the prevention of bleeding in patients undergoing surgery or invasive procedures is 90 mcg (range 80 - 120 mcg) per kg of body weight, with intervals of 2 hours (1 , 5 - 2.5 hours). To ensure effective haemostasis, a minimum of 3 doses should be administered. The recommended route of administration is intravenous bolus administration as a lack of efficacy may occur in association with continuous infusion.
For those patients who are not refractory, platelets are the first line of treatment for Glanzmann's thrombasthenia.
Method of administration
For instructions on reconstitution of the medicinal product before administration, see section 6.6. Administer the solution as an intravenous bolus over 2 - 5 minutes.
Treatment monitoring - laboratory analysis
There is no need to monitor NovoSeven therapy. Dosage should be based on the severity of the bleeding conditions and the clinical response to administration of NovoSeven.
After administration of rFVIIa, prothrombin time (PT) and activated partial thromboplastin time (aPTT) are reduced, but no correlation between PT and aPTT and clinical efficacy of rFVIIa has been demonstrated.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to bovine, mouse or hamster proteins.
04.4 Special warnings and appropriate precautions for use
In pathological conditions in which tissue factor may be expressed more extensively than normal, there may be a potential risk of developing thrombotic events or inducing disseminated intravascular coagulation (DIC) in association with treatment with NovoSeven.
Such situations may involve patients with advanced atherosclerosis, crush injury, septicemia, or DIC. Due to the risk of thromboembolic complications, caution should be exercised when administering NovoSeven to patients with a history of coronary artery disease, liver disease, post surgery, neonates and patients at risk for thromboembolic events or disseminated intravascular coagulation. In each of these situations, the potential benefit of treatment with NovoSeven must be weighed against the risk of these complications.
Since NovoSeven, as recombinant coagulation factor VIIa, may contain traces of mouse IgG, bovine IgG and other residual culture proteins (hamster and bovine serum proteins), there is a remote possibility that patients treated with this product may develop hypersensitivity to these proteins. In such cases, treatment with IV antihistamines should be considered.
If allergic reactions or anaphylactic reactions occur, administration must be stopped immediately. In the event of shock, standard medical treatments should be implemented. Patients should be informed of the first signs of hypersensitivity reactions. If such symptoms occur, patients are advised to discontinue use of the product immediately and contact their physician.
In case of severe bleeding, the product should preferably be administered in centers specialized in the treatment of haemophiliac patients with coagulation factor VIII or IX inhibitors, or if this is not possible, in close collaboration with a physician specialized in the treatment of haemophilia.
Inpatient treatment is mandatory if bleeding is not controlled. Patients or caregivers should inform the referring physician / hospital of all uses of NovoSeven as soon as possible.
Factor VII deficient patients should be monitored for prothrombin time and factor VII clotting activity before and after administration of NovoSeven. In case factor VIIa activity does not reach expected levels or bleeding it is not controlled after recommended doses, antibody formation may be suspected and an antibody analysis should be performed. Thrombotic events have been reported in patients with factor VII deficiency treated with NovoSeven during surgery but the risk of thrombosis in patients with factor VII deficiency treated with NovoSeven is not known (see section 5.1).
04.5 Interactions with other medicinal products and other forms of interaction
The risk of a potential interaction between NovoSeven and coagulation factor concentrates is unknown. Simultaneous use of activated and non-activated prothrombin complex concentrates should be avoided.
Antifibrinolytics have been reported to reduce blood loss associated with surgery in haemophilic patients, especially in orthopedic surgery and in interventions involving regions rich in fibrinolytic activity, such as the oral cavity. However, experience with the administration of antifibrinolytics concomitantly with rFVIIa treatment is limited.
Based on a non-clinical study (see section 5.3) it is recommended not to combine rFVIIa and rFXIII. There are no clinical data available on the interaction between rFVIIa and rFXIII.
04.6 Pregnancy and breastfeeding
Pregnancy
As a precautionary measure, it is preferable to avoid the use of NovoSeven during pregnancy. Data on a limited number of pregnancies exposed according to approved indications indicate no adverse effects of rFVIIa on pregnancy or on the health of the fetus / newborn. To date, no other epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3).
Feeding time
It is unknown whether rFVIIa is excreted in human milk. The excretion of rFVIIa in milk has not been studied in animals. The decision whether to continue / discontinue breastfeeding or to continue / discontinue NovoSeven therapy must be made considering the benefit of breastfeeding for the infant and the benefit of therapy. with NovoSeven for women.
Fertility
Data from non-clinical and post-marketing studies do not indicate adverse effects of rFVIIa on male and female fertility.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
04.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse drug reactions are reduced therapeutic response, pyrexia, rash, arterial thromboembolic events, pruritus and urticaria. These reactions are reported as uncommon (≥ 1 / 1,000,
Table of adverse reactions
Table 1 lists adverse reactions reported during clinical trials and from spontaneous (post-marketing) reporting. In each frequency group, undesirable effects are listed in order of decreasing seriousness. Post-marketing adverse drug reactions (not those from clinical trials) are listed with an "not known" frequency.
Clinical studies in 484 patients (including 4297 treatment episodes) with haemophilia A and B, acquired haemophilia, factor VII defect, and Glanzmann's thrombasthenia show that adverse drug reactions are common (≥ 1/100 to 1 / 10,000 to
The most frequent adverse drug reactions are pyrexia and rash (uncommon:> 1 / 1,000 a
The frequencies of both serious and non-serious adverse drug reactions are listed by system organ class in the table below.
Table 1 Adverse reactions from clinical trials and spontaneous (post-marketing) reports
* Loss of efficacy (decreased therapeutic response) has been reported. It is important that the dosage of NovoSeven adheres to the recommended dosage as stated in section 4.2.
Description of selected adverse reactions
Formation of inhibitory antibodies
In post-marketing experience, no inhibitory antibodies to NovoSeven or factor VII have been reported in patients with haemophilia A or B. Development of inhibitory antibodies to NovoSeven has been reported in a post-marketing observational study registry of patients with congenital deficiency. of the FVII.
In clinical studies in patients with factor VII deficiency, antibody formation to NovoSeven and factor VII is the only reported adverse drug reaction (frequency: common (≥ 1/100 and in vitro. Risk factors were present that may have contributed the development of antibodies including previous treatments with human plasma and / or plasma-derived factor VII, severe mutation of the factor VII gene and overdose of NovoSeven. Factor VII deficient patients treated with NovoSeven should be monitored for antibodies to the factor VII (see section 4.4).
Thromboembolic events - arterial and venous
Arterial thromboembolic events are common (≥ 1/100 and placebo) was observed in a meta-analysis of data collected from placebo-controlled studies conducted outside the approved indications in various clinical settings, each involving distinct patient characteristics and therefore different intrinsic risk profiles.
Outside of the approved indications, the safety and efficacy of NovoSeven have not been established therefore NovoSeven should not be used in such situations.
Thromboembolic events can lead to cardiac arrest.
Other particular populations
Patients with acquired haemophilia
Clinical studies conducted on 61 patients with acquired haemophilia for a total of 100 treated episodes, showed that in these patients some adverse drug reactions are reported more frequently (1% based on treatment episodes): arterial thromboembolic events (occlusion of the " cerebral artery, cerebrovascular accident), venous thromboembolic events (pulmonary embolism and deep vein thrombosis), angina pectoris, nausea, pyrexia, erythematous rash and diagnostic tests for increased levels of fibrin breakdown products.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the reporting system.
04.9 Overdose
Limiting doses of NovoSeven have not been studied in clinical studies.
In 16 years, four cases of overdose have been reported in patients with haemophilia. The only reported complication related to an overdose was a transient slight increase in blood pressure in a 16-year-old patient treated with 24 mg of rFVIIa instead of 5.5 mg.
No cases of overdose have been reported in patients with acquired haemophilia or Glanzmann's thrombasthenia.
In patients with factor VII deficiency, for which the recommended dose is 15 - 30 mcg / kg rFVIIa, an overdose episode was associated with a thrombotic event (occipital stroke) in an elderly (> 80 years) male patient treated with a dose 10 - 20 times higher than recommended. Furthermore, the development of antibodies to NovoSeven and FVII has been associated with an overdose in a patient with factor VII deficiency.
The dosing schedule should not be intentionally increased above the recommended doses due to lack of information on the additional risks involved.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Coagulation factors. ATC code: B02BD08
Mechanism of action
NovoSeven contains activated recombinant DNA coagulation factor VII. The mechanism of action includes the binding of factor VIIa to the exposed tissue factor. This complex activates factor IX in factor IXa and factor X in factor Xa, triggering the transformation of small amounts of prothrombin into thrombin. activation of platelets and factors V and VIII at the site of the lesion and the formation of the hemostatic plug following the conversion of fibrinogen into fibrin. Drug doses of NovoSeven activate factor X directly on the surface of activated platelets, located at the site of the lesion, regardless of the tissue factor. This results in the transformation of prothrombin into large amounts of thrombin regardless of the tissue factor.
Pharmacodynamic effects
The pharmacodynamic effect of factor VIIa leads to an increase in the local formation of factor Xa, thrombin and fibrin.
A theoretical risk of developing systemic coagulation activation cannot be completely ruled out in patients with diseases predisposing to DIC.
In an observational study registry (F7HAEM-3578) conducted on subjects with congenital FVII deficiency, in 22 pediatric patients (under 12 years of age) with factor VII deficiency and severe clinical phenotype, the mean dose for prophylaxis long-term bleeding was 30 mcg / kg (17 mcg / kg to 200 mcg / kg; the most often used dose was 30 mcg / kg in 10 patients) with a mean dose frequency of 3 doses per week (1 to 7; the most often reported dose frequency was 3 times per week for 13 patients).
In the same registry 3 patients out of 91 operated patients had thromboembolic events.
05.2 Pharmacokinetic properties
Healthy subjects
Distribution, clearance and linearity
Using the factor VII coagulation assay, the pharmacokinetics of rFVIIa were studied in 35 healthy Caucasian and Japanese subjects in a dose escalation study. Subjects were divided by gender and ethnicity and treated with 40, 80, and 160 mcg of rFVIIa per kg of body weight (3 doses for each) and / or placebo. Pharmacokinetic profiles showed dose proportionality. Pharmacokinetics were very similar between genders and ethnic groups. The mean steady state volume of distribution ranged from 130 to 165 ml / kg, the mean clearance value ranged from 33.3 to 37.2 ml / h x kg.
The final mean half-life was between 3.9 and 6.0 hours.
Pharmacokinetic profiles showed dose proportionality.
Hemophilia A and B with inhibitors
Distribution, clearance and linearity
Using the factor VIIa coagulation assay, the pharmacokinetic properties of rFVIIa were studied in 12 pediatric patients (2-12 years) and 5 non-bleeding adult patients.
The mean steady state volume of distribution was 196 ml / kg in pediatric patients and 159 ml / kg in adults.
The mean clearance was found to be approximately 50% higher in pediatric patients than in adults (78 versus 53 ml / hx kg), while the mean final half-life was 2.3 hours in both groups. .
Clearance appears to be correlated with age, therefore in younger patients it may be greater than 50%.
Dose proportionality was determined in children with experimental doses of 90 and 180 mcg per kg body weight, in agreement with previous results at lower doses (17.5 - 70 mcg / kg rFVIIa).
Factor VII deficiency
Distribution and clearance
Single dose pharmacokinetics of rFVIIa, 15 and 30 micrograms per kg body weight, did not show significant differences between the two doses used with respect to dose-independent parameters:
Volume of distribution at steady state (280 - 290 ml / kg), half-life (2.82 - 3.11 h), total body clearance (70.8 - 79.1 ml / hx kg), mean residence time (3 , 75 - 3.80 h).
The mean in vivo plasma recovery was approximately 20%.
Glanzmann's thrombasthenia
The pharmacokinetics of NovoSeven in patients with Glanzmann's thrombasthenia have not yet been studied; however, behaviors similar to those seen in patients with haemophilia A and B are expected.
05.3 Preclinical safety data
All outcomes from the preclinical safety program were correlated with the pharmacological effects of rFVIIa.
In an advanced cardiovascular experimental model conducted in cynomolgus monkeys, a potential synergistic effect of the combined treatment of rFXIII and rFVIIa, at lower doses than the administration of the single components, resulted in an excessive pharmacological response (thrombosis and death).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Dust
Sodium chloride
Calcium chloride dihydrate
Glycylglycine
Polysorbate 80
Mannitol
Sucrose
Methionine
Hydrochloric acid (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Solvent
Histidine
Hydrochloric acid (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Water for injections
06.2 Incompatibility
NovoSeven must not be mixed with infusion solutions or given as a drip.
06.3 Period of validity
The shelf life in unopened packaging is 3 years when the product is stored below 25 ° C.
After reconstitution, physico-chemical stability has been demonstrated for 6 hours at 25 ° C and 24 hours at 5 ° C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not be longer than 24 hours at 2 ° C - 8 ° C, unless reconstitution has taken place in controlled and validated aseptic conditions. The reconstituted solution must be stored in the vial.
06.4 Special precautions for storage
- Store powder and solvent below 25 ° C.
- Store powder and solvent protected from light.
- Do not freeze.
- For the storage conditions of the reconstituted product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
NovoSeven solvent is supplied either in a vial or in a pre-filled syringe. Not all pack sizes may be marketed.
The NovoSeven 1 mg (50 KUI) / NovoSeven 2 mg (100 KUI) pack contains either
- 1 vial (2 ml) with white powder for solution for injection
- 1 vial (2 ml) with solvent for reconstitution
or
- 1 vial (2 ml) with white powder for solution for injection
- 1 pre-filled syringe (3 ml) with solvent for reconstitution
- 1 plunger
- 1 vial adapter, with an integrated particle filter with 25 micrometer pore size.
NovoSeven 5 mg (250 KUI) / NovoSeven 8 mg (400 KUI) pack contains either
- 1 vial (12 ml) with white powder for solution for injection
- 1 vial (12 ml) with solvent for reconstitution
or
- 1 vial (12 ml) with white powder for solution for injection
- 1 pre-filled syringe (10 ml) with solvent for reconstitution
- 1 plunger
- 1 vial adapter, with an integrated particle filter with 25 micrometer pore size
Vial: Type I glass vial closed with a chlorobutyl rubber stopper covered with an aluminum cap. The closed vial has a detachable polypropylene tamper evident cap.
Pre-filled syringe: Type I glass barrel with a movable polypropylene body and a bromobutyl rubber plunger. The syringe cap is made of bromobutyl rubber and a detachable polypropylene security seal.
Plunger: in polypropylene.
06.6 Instructions for use and handling
NovoSeven solvent is supplied either in a vial or in a pre-filled syringe. Not all pack sizes may be marketed. Follow the procedures for both packs as described below.
Powder in vial and solvent in vial:
Always use aseptic technique
Reconstitution
• NovoSeven powder and solvent vials must be at room temperature when reconstituted. Remove the protective plastic caps from the two vials. If caps are missing or lost, do not use the vials. Clean the rubber stoppers on vials with alcohol swabs and allow them to dry before use. Use an appropriately sized disposable syringe and vial adapter, transfer needle (20 - 26G) or other suitable device.
If other devices than those supplied by Novo Nordisk are used, ensure that an appropriate filter with a pore size of 25 micrometers is used.
• Attach the adapter to the solvent vial. If using a transfer needle, screw the needle tightly onto the syringe.
• Pull back the plunger to draw a quantity of air into the syringe corresponding to the volume of solvent contained in the solvent vial (in the syringe, ml corresponds to cc).
• Attach the syringe firmly to the adapter on the solvent vial. If using a transfer needle, insert the needle into the rubber stopper of the solvent vial. Inject the air into the vial by pushing the plunger until a distinct resistance is felt.
• Hold the syringe with the solvent vial upside down. If using a transfer needle, make sure the tip of the needle is in the solvent. Pull the plunger to draw the solvent into the syringe.
• Remove the empty solvent vial. If using an adapter, tilt the syringe to remove it from the vial.
• Attach the syringe with adapter or transfer needle to the vial containing the powder. If using a transfer needle, be sure to puncture the center of the rubber stopper. Hold the syringe slightly tilted with the vial pointing down. Press the plunger lightly to inject the solvent into the vial with the powder. Make sure not to direct the solvent jet directly on the NovoSeven powder to avoid foaming.
• Gently swirl the vial until the powder is dissolved. Do not shake the vial to avoid foaming.
The reconstituted solution of NovoSeven appears colorless and should be carefully observed before administration for any particles and discolouration.
Do not store NovoSeven reconstituted in plastic syringes.
It is recommended that NovoSeven be administered immediately after reconstitution.
Administration
• Make sure the plunger is fully depressed before turning the syringe upside down (it may be pushed out by the pressure of the syringe). If using a transfer needle, make sure the tip of the needle is in the solution. Hold the syringe with the vial upside down and pull the plunger to draw all of the solution for injection into the syringe.
• If using an adapter, unscrew the adapter with the empty vial. If using a transfer needle, remove the needle from the vial, put the cap back on the needle, and unscrew the needle from the syringe.
• NovoSeven is now ready to be injected. Locate a suitable site and slowly inject NovoSeven into a vein over 2 to 5 minutes without removing the needle from the injection site.
Discard the syringe, vials and any unused product taking the necessary precautions. Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
Powder in vial and solvent in pre-filled syringe:
Always use aseptic technique.
Reconstitution
• The vial of NovoSeven powder and the pre-filled syringe with the solvent must be at room temperature during reconstitution. Remove the plastic cap from the vial. If the cap is missing or lost, do not use the vial. Clean the rubber stopper on the vial with alcohol swabs and allow to dry before use. Do not touch the rubber stopper after cleaning it.
• Remove the protective seal from the vial adapter. Do not remove the adapter from the protective cap. If the protective seal is not tightly closed or is broken, do not use the adapter. Turn the protective cap, and clip the vial adapter onto the vial. Press the protective cap lightly with your thumb and forefinger. Remove the protective cap from the adapter.
• Screw the plunger clockwise into the plunger inside the pre-filled syringe until resistance is felt. Remove the syringe cap from the pre-filled syringe by bending down until it breaks. Do not touch the syringe tip under the cap of the If the syringe cap is loose or missing, do not use the pre-filled syringe.
• Screw the pre-filled syringe tightly onto the vial until resistance is felt. Hold the pre-filled syringe slightly tilted with the vial pointing downwards. Push the plunger to inject all of the solvent into the vial. Keep the plunger depressed and swirl the vial gently until all the powder is dissolved. Do not shake the vial as this causes foaming.
If a higher dose is required, repeat the procedure with additional vials, pre-filled syringes and vial adapters.
The reconstituted solution of NovoSeven is colorless and should be visually inspected prior to
administration due to the presence of particles and discolouration.
It is recommended that NovoSeven be used immediately after reconstitution
storage of the reconstituted medicinal product, see section 6.3.
Administration
• Keep the plunger pressed all the way down. Turn the syringe with the vial facing down. Stop depressing the plunger and let it come back on its own, while the reconstituted solution fills the syringe. Pull the plunger down slightly to draw the mixed solution into the syringe.
• With the vial pointing down, gently tap the syringe to make any air bubbles rise to the top. Push the plunger slowly until all air bubbles have risen.
If the full dose is not required, use the scale on the syringe to see how much mixed solution is administered.
• Unscrew the adapter with the vial.
• NovoSeven is ready for injection. Locate a suitable site and slowly administer NovoSeven into a vein for 2 to 5 minutes without removing the needle from the injection site.
Discard used materials. Unused medicine and waste must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Novo Nordisk A / S
Novo Allé
DK-2880 Bagsværd
Denmark
08.0 MARKETING AUTHORIZATION NUMBER
NovoSeven 1 mg (50 KUI)
EU / 1/96/006/004
EU / 1/96/006/008
NovoSeven 2 mg (100 KUI)
EU / 1/96/006/005
EU / 1/96/006/009
NovoSeven 5 mg (250 KUI)
EU / 1/96/006/006
EU / 1/96/006/010
NovoSeven 8 mg (400 KUI)
EU / 1/96/006/007
EU / 1/96/006/011
029447048
029447051
029447063
029447087
029447099
029447101
029447113
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 23 February 1996
Date of last renewal: 23 February 2006
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