Novoseven

The most serious adverse reactions observed in patients receiving NovoSeven (coagulation factor viia (recombinant)) are thrombotic events, however the extent of the risk of thrombotic adverse events after treatment with NovoSeven (coagulation factor viia (recombinant)) in individuals with hemophilia and inhibitors is considered to be low. (See WARNINGS)

The most common adverse reactions observed in clinical studies for all labeled indications of NovoSeven (coagulation factor viia (recombinant)) are pyrexia, hemorrhage, injection site reaction, arthralgia, headache, hypertension, hypotension, nausea, vomiting, pain, edema and rash.

The following sections describe the adverse event profile observed during clinical studies for each of the labeled indications. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in clinical trials of another drug, and may not reflect rates observed in practice.

Hemophilia A or B Patients with Inhibitors

The table below lists adverse events that were reported in ≥ 2% of the 298 patients with hemophilia A or B with inhibitors that were treated with NovoSeven (coagulation factor viia (recombinant)) for 1, 939 bleeding episodes. The events listed are considered to be at least possibly related or of unknown relationship to NovoSeven (coagulation factor viia (recombinant)) administration.

Events which were reported in 1% of patients and were considered to be at least possibly or of unknown relationship to NovoSeven (coagulation factor viia (recombinant)) administration were: allergic reaction, arthrosis, bradycardia, coagulation disorder, DIC, edema, fibrinolysis increased, headache, hypotension, injection site reaction, pain, pneumonia, prothrombin decreased, pruritus, purpura, rash, renal function abnormal, therapeutic response decreased, and vomiting.

Serious adverse events that were probably or possibly related, or where the relationship to NovoSeven (coagulation factor viia (recombinant)) was not specified, occurred in 14 of the 298 patients (4.7%). Six of the 14 patients died of the following conditions: worsening of chronic renal failure, anesthesia complications during proctoscopy, renal failure complicating a retroperitoneal bleed, ruptured abscess leading to sepsis and DIC, pneumonia, and splenic hematoma and GI bleeding. Thrombosis was reported in two of the 298 patients with hemophilia.

Surgery Studies

In Study C, six patients experienced serious adverse events: two of these patients had events which were considered probably or possibly related to study medication (acute post-operative hemarthrosis, internal jugular thrombosis). No deaths occurred during the study.

In Study D, seven of 24 patients had serious adverse events (4 for bolus injection, 3 for continuous infusion). There were 4 serious adverse events which were considered probably or possibly related to rFVIIa treatment (2 events of decreased therapeutic response in each treatment arm). No deaths occurred during the study period.

Congenital Factor VII Deficiency

Data collected from the compassionate/emergency use programs, the published literature, a pharmacokinetics study, and the HTRS registry showed that at least 75 patients with Factor VII deficiency had received NovoSeven (coagulation factor viia (recombinant)) - 70 patients for 124 bleeding episodes, surgeries, or prophylaxis regimens; 5 patients in the pharmacokinetics trial.

In the compassionate/emergency use programs, 28 adverse events in 13 patients and 10 serious adverse events in 9 patients were reported. Non-serious adverse events in the compassionate/emergency use programs were single events in one patient, except for fever (3 patients), intracranial hemorrhage (3 patients), and pain (2 subjects). The most common serious adverse event in the compassionate/emergency programs was serious bleeding in critically ill patients. All nine patients with serious adverse events died. One adverse event (localized phlebitis) was reported in the literature. No adverse events were reported in the pharmacokinetics reports or for the HTRS registry. No thromboembolic complications were reported for the 75 patients included here. Isolated cases of factor VII deficient patients developing antibodies against factor VII were reported after treatment with NovoSeven (coagulation factor viia (recombinant)) . These patients had previously been treated with human plasma and/or plasma-derived factor VII. In some cases the antibodies showed inhibitory effect in vitro.

Acquired Hemophilia

Data collected from four compassionate use programs, the HTRS registry, and the published literature showed that 139 patients with acquired hemophilia received NovoSeven (coagulation factor viia (recombinant)) for 204 bleeding episodes, surgeries and traumatic injuries.

Of these 139 patients, 10 experienced 12 serious adverse events that were of possible, probable, or unknown relationship to treatment with NovoSeven (coagulation factor viia (recombinant)) . Thrombotic serious adverse events included cerebral infarction, cerebral ischemia, angina pectoris, myocardial infarction, pulmonary embolism and deep vein thrombosis. Additional serious adverse events included shock and subdural hematoma.

Data collected for mortality in the compassionate use programs, the HTRS registry and the publications spanning a 10 year period, was overall 32/139 (23%). Deaths due to hemorrhage were 10, cardiovascular failure 4, neoplasia 4, unknown causes 4, respiratory failure 3, thrombotic events 2, sepsis 2, arrhythmia 2 and trauma 1.

Postmarketing Experience

The following post marketing adverse events are reported voluntarily from a population of uncertain size; hence, it is not possible to estimate their frequency or establish a causal relationship to exposure.

The following additional adverse events were reported following the use of NovoSeven (coagulation factor viia (recombinant)) in both labeled indications and unlabeled indications that included individuals with situational coagulopathy and without known coagulopathy: high D-dimer levels and consumptive coagulopathy, thromboembolic events including myocardial infarction, myocardial ischemia, cerebral infarction and/or ischemia, thrombophlebitis, arterial thrombosis, deep vein thrombosis and related pulmonary embolism, and isolated cases of hypersensitivity reactions including anaphylactic reactions. (See WARNINGS and PRECAUTIONS)

Evaluation and interpretation of these post marketing events is confounded by underlying diagnoses, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance. A causal relationship has not been established for the above events.

Additional data on the adverse event profile in general and regarding the frequency of thrombotic events in particular is being collected through a postmarket surveillance program. The Hemophilia and Thrombosis Research Society (HTRS) Registry surveillance program is designed to collect data on all uses of NovoSeven (coagulation factor viia (recombinant)) to expand the base of experience regarding the use of NovoSeven (coagulation factor viia (recombinant)) . 12 All prescribers can obtain information regarding contribution of patient data to this program by calling 1-877-362-7355.

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.

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:

• Bleeding problems
• fever
• high blood pressure
• joint or muscle pain or stiffness

• 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:

• 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.