NovoSeven RT

Name: NovoSeven RT

Introduction

Biosynthetic preparation (recombinant DNA origin) of blood coagulation factor VIIa.1

Precautions While Using NovoSeven RT

It is very important that your doctor check your progress closely while you are receiving this medicine to make sure it is working properly. Blood tests may be needed to check for unwanted effects.

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your doctor right away if you have a rash, itching, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are receiving this medicine.

This medicine may increase your chance of having blood clotting problems. The risk is higher if you have a medical condition such as disseminated intravascular coagulation (DIC) or severe artery disease, or if you are taking certain blood clotting medicines. Tell your doctor right away if you have sudden or severe headache, problems with vision or speech, chest pain, shortness of breath, or numbness or weakness while you are receiving this medicine.

NovoSeven RT Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common
  • Bleeding problems
  • fever
  • high blood pressure
  • joint or muscle pain or stiffness
Less common or rare
  • Bloating or swelling of the face, hands, lower legs, or feet
  • bluish color of the hands or feet
  • blurred vision
  • changes in facial color
  • chest pain
  • chills
  • cold sweats
  • confusion
  • continuing thirst
  • cough
  • dizziness
  • excessive sweating
  • faintness
  • fast heartbeat
  • hives, itching, or skin rash
  • large flat blue or purplish patches on the skin
  • lightheadedness when getting up suddenly from a lying or sitting position
  • persistent bleeding or oozing from puncture sites or mucous membranes (bowel, mouth, nose, or urinary bladder)
  • puffiness or swelling of the eyelids or around the eyes
  • shakiness
  • slow or irregular heartbeat (less than 50 beats per minute)
  • slurred speech
  • sneezing
  • sore throat
  • sudden decrease in the amount of urine
  • swelling of the face, fingers, feet, or lower legs
  • troubled breathing, tightness in the chest
  • unusual tiredness or weakness
  • unusual weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common or rare
  • Burning or stinging at the injection site
  • drowsiness
  • feeling of warmth
  • headache
  • nausea or vomiting
  • pinpoint red or purple spots on the skin
  • redness of the face, neck, arms and occasionally, upper chest

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

What do I need to tell my doctor BEFORE I take NovoSeven RT?

  • If you have an allergy to this medicine or any part of NovoSeven RT.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

How is this medicine (NovoSeven RT) best taken?

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • It is given as a shot into a vein.
  • Your doctor may teach you how to give the shot.
  • Follow how to use as you have been told by the doctor or read the package insert.
  • Wash your hands before and after use.
  • Before giving the shot, let it come to room temperature. Do not heat NovoSeven RT.
  • This medicine needs to be mixed before use. Follow how to mix as you were told by the doctor.
  • Do not shake.
  • Use within 3 hours of making.
  • Do not draw into a syringe and store for future use.
  • Do not mix with any other liquid drugs.
  • Do not use if the solution is cloudy, leaking, or has particles.
  • Do not use if solution changes color.
  • Throw away any part not used after use.
  • Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.

What do I do if I miss a dose?

  • Call your doctor to find out what to do.

Indications and Usage for NovoSeven RT

NovoSeven RT Coagulation Factor VIIa (Recombinant) Room Temperature Stable is indicated for:

Treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX and in patients with acquired hemophilia

Prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX and in patients with acquired hemophilia

Treatment of bleeding episodes in patients with congenital FVII deficiency

Prevention of bleeding in surgical interventions or invasive procedures in patients with congenital FVII deficiency

Contraindications

None

Warnings and Precautions

Thrombotic Events within the Licensed Indications

Clinical trials within the approved indications revealed that thrombotic events of possible or probable relationship to NovoSeven occurred in 0.28% of bleeding episodes treated, with the incidence within hemophilia patients with inhibitors to be 0.20%, and in acquired hemophilia an incidence of 4%. Thrombotic events have been identified through postmarketing surveillance following NovoSeven RT use for each of the approved indications2. The incidence of thrombotic events can not be determined from postmarketing data. Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with aPCCs/PCCs (activated or nonactivated prothrombin complex concentrates) have an increased risk of developing thrombotic events due to circulating tissue factor (TF) or predisposing coagulopathy [See Adverse Reactions (6.1) and Drug Interactions (7.1)]. Caution should be exercised when administering NovoSeven RT to patients with an increased risk of thromboembolic complications. These include, but are not limited to, patients with a history of coronary heart disease, liver disease, disseminated intravascular coagulation, post-operative immobilization, elderly patients and neonates. In each of these situations, the potential benefit of treatment with NovoSeven RT should be weighed against the risk of these complications.

Patients who receive NovoSeven RT should be monitored for development of signs or symptoms of activation of the coagulation system or thrombosis. When there is laboratory confirmation of intravascular coagulation or presence of clinical thrombosis, the NovoSeven RT dosage should be reduced or the treatment stopped, depending on the patient's symptoms.

Thrombotic Events outside the Licensed Indications

NovoSeven has been studied in placebo controlled trials outside the approved indications to control bleeding in intracerebral hemorrhage, advanced liver disease, trauma, cardiac surgery, spinal surgery, and other therapeutic areas. Safety and effectiveness has not been established in these settings and the use is not approved by FDA. Two meta analyses of these pooled data indicate an increased risk of thrombotic events (10.0% in patients treated with NovoSeven versus 7.5% in placebo-treated patients). Arterial thromboembolic adverse events including myocardial infarction, myocardial ischemia, cerebral infarction and cerebral ischemia were statistically significantly increased with the use of NovoSeven compared to placebo (5.3 to 5.6% in subjects treated with NovoSeven versus 2.8 to 3.0% in placebo-treated patients). Other arterial thromboembolic events (such as retinal artery embolism, renal artery thrombosis, arterial thrombosis of limb, bowel infarction and intestinal infarction) have also been reported.3,4,5,6,7 While venous thromboembolic events such as deep venous thrombosis, portal vein thrombosis and pulmonary embolism have been reported in clinical trials, the meta analysis of these pooled data from placebo-controlled trials performed outside the currently approved indications did not suggest an increased risk of venous thromboembolic events in patients treated with NovoSeven versus placebo (4.8% in patients treated with NovoSeven versus 4.7% in placebo-treated patients).

In spontaneous reports of women without a prior diagnosis of bleeding disorders receiving NovoSeven for uncontrolled post-partum hemorrhage, thrombotic events were observed. During this period, patients are at increased risk for thrombotic complications.

Post-Hemostatic Dosing

Precautions should be exercised when NovoSeven RT is used for prolonged dosing [See Dosage and Administration (2.2)].

Antibody Formation in Factor VII Deficient Patients

Factor VII deficient patients should be monitored for prothrombin time (PT) and factor VII coagulant activity before and after administration of NovoSeven RT. If the factor VIIa activity fails to reach the expected level, or prothrombin time is not corrected, or bleeding is not controlled after treatment with the recommended doses, antibody formation may be suspected and analysis for antibodies should be performed.

Hypersensitivity Reactions

NovoSeven RT should be administered with caution in patients with known hypersensitivity to NovoSeven RT or any of its components, or in patients with known hypersensitivity to mouse, hamster, or bovine proteins.

Laboratory Tests

Laboratory coagulation parameters (PT/INR, aPTT, FVII:C) have shown no direct correlation to achieving hemostasis. Assays of prothrombin time (PT/INR), activated partial thromboplastin time (aPTT), and plasma FVII clotting activity (FVII:C), may give different results with different reagents. Treatment with NovoSeven has been shown to produce the following characteristics:

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two mutagenicity studies have given no indication of carcinogenic potential for NovoSeven. The clastogenic activity of NovoSeven was evaluated in both in vitro studies (i.e., cultured human lymphocytes) and in vivo studies (i.e., mouse micronucleus test). Neither of these studies indicated clastogenic activity of NovoSeven. Other gene mutation studies have not been performed with NovoSeven RT (e.g., Ames test). No chronic carcinogenicity studies have been performed with NovoSeven RT.

A reproductive study in male and female rats at dose levels up to 3.0 mg/kg/day had no effect on mating performance, fertility, or litter characteristics.

Treatment of rats and rabbits with NovoSeven in reproduction studies has been associated with mortality at doses up to 6 mg/kg and 5 mg/kg. At 6 mg/kg in rats, the abortion rate was 0 out of 25 litters; in rabbits at 5 mg/kg, the abortion rate was 2 out of 25 litters. Twenty-three out of 25 female rats given 6 mg/kg of NovoSeven gave birth successfully, however, two of the 23 litters died during the early period of lactation. No evidence of teratogenicity was observed after dosing with NovoSeven.

References

1. Hedner, U.: Dosing and Monitoring NovoSeven® Treatment, Haemostasis 1996; 26 (suppl 1): 102-108.

2. Girolami, B., et al.: Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review, Haemophilia (2006); 12, 345-351.

3. Mayer, S.A., et al.: Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage, New England Journal of Medicine 2005; 352: 777-785.

4. Mayer, S.A., et al.: Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage, New England Journal of Medicine 2008; 358:2127-37.

5. Thomas, R, et al: Thromboembolic complications associated with Factor VIIa administration, J Trauma 2007; 62:564-569.

6. Hsia, Cyrus C., et al., “Use of Recombinant Activated Factor VII in Patients Without Hemophilia, A Meta-Analysis of Randomized Control Trials,” Annals of Surgery, Vol 248, No. 1, July 2008.

7. Hardy, Jean-Francois, et al, “Efficacy and Safety of Recombinant Activated Factor VII to Control Bleeding in Nonhemophiliac Patients: A Review of 17 Randomized Controlled Trials,” Ann Thorac Surg 2008; 86: 1038-48.

8. Parameswaran, R., et al.: Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry, Haemophilia 2005; 11: 100-106.

9. Roberts, H.R.: Thoughts on the mechanism of action of FVIIa, 2nd Symposium on New Aspects of Hemophilia Treatment, Copenhagen, Denmark, 1991, pgs. 153-156.

10. Butenas, S., et al.: Mechanism of factor VIIa-dependent coagulation in hemophilia blood, Blood 2002; 99: 923-930. Figure A Copyright American Society of Hematology, used with permission.

11. Allen, G.A., et al.: The effect of factor X level on thrombin generation and the procoagulant effect of activated factor VII in a cell-based model of coagulation, Blood Coagulation and Fibrinolysis 2000; 11 (suppl 1): 3-7.

12. Fridberg M.J., et al.: A study of the pharmacokinetics and safety of recombinant activated factor VII in healthy Caucasian and Japanese subjects, Blood Coagulation and Fibrinolysis 2005, 16 (4): 259-266.

13. Lindley, C.M., et al.: Pharmacokinetics and pharmacodynamics of recombinant Factor VIIa, Clinical Pharmacology & Therapeutics 1994; 55 (6): 638-648.

14. Bysted B.V., et al.: A randomized double-blind trial demonstrating bioequivalence of the current recombinant activated factor VII formulation and a new robust 25ºC stable formulation, Haemophilia 2007, 13, 527-532.

15. Villar, A., et al.: Pharmacokinetics of activated recombinant coagulation factor VIIa (NovoSeven®) in children vs. adults with haemophilia A, Haemophilia 2004; 10 (4):352-359.

16. Bauer, K.A.: Treatment of Factor VII deficiency with recombinant Factor VIIa, Haemostasis 1996; 26 (suppl 1): 155-158.

17. Lusher, J., et al.: Clinical experience with recombinant Factor VIIa, Blood Coagulation and Fibrinolysis 1998; 9: 119-128.

18. Bech, M.R.: Recombinant Factor VIIa in Joint and Muscle Bleeding Episodes, Haemostasis 1996; 26 (suppl 1): 135-138.

19. Lusher, J.M.: Recombinant Factor VIIa (NovoSeven®) in the Treatment of Internal Bleeding in Patients with Factor VIII and IX Inhibitors, Haemostasis 1996; 26 (suppl 1): 124-130.

20. Lusher, J.M., et al.: A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with hemophilia A and B, with and without inhibitor, Haemophilia 1998; 4: 790-798.

21. Shapiro A.D., et al: Prospective, Randomised Trial of Two Doses of rFVIIa (NovoSeven®) in Haemophilia Patients with Inhibitors Undergoing Surgery, Thrombosis and Haemostasis 1998; 80: 773-778.

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