Koāte-DVI is indicated:
• for the control and prevention of bleeding episodes, or
• in order to perform emergency and elective surgery in patients with hemophilia A (hereditary Factor VIII deficiency).

Koāte-DVI is not indicated for the treatment of von Willebrand disease.

For intravenous use after reconstitution only.
Posology
• Dose and duration of treatment depend on the severity of the Factor VIII deficiency, location and extent of bleeding, and the patient’s clinical condition.
• Each vial of Koāte-DVI is labeled with the actual Factor VIII potency in international units (IU). Calculation of the required dose of Factor VIII is based on the empirical finding that one IU of Factor VIII per kg body weight raises the plasma Factor VIII activity by approximately 2% of normal activity or 2 IU/dL.
• The required dose can be determined using the following formula:
Dose (IU) = Body Weight (kg) x Desired Factor VIII Rise (% normal or IU/dL) x 0.5
• Estimate the expected in vivo peak increase in Factor VIII level, expressed as IU/dL (or % normal), using the following formula:
Estimated Increment of Factor VIII
(% normal or IU/dL) = [Total Dose (IU)/Body Weight (kg)] x 2

• Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses. Base the dose and frequency on the individual clinical response.
Control and Prevention of Bleeding Episodes
A guide for dosing Koāte-DVI for the control and prevention of bleeding episodes is provided in Table 1. Consideration should be given to maintaining a Factor VIII activity at or above the target range.

It should be emphasized that the dosage of Koāte-DVI required for hemostasis must be individualized according to the needs of the patient, the severity of the deficiency, the severity of the hemorrhage, the presence of inhibitors, and the Factor VIII level desired. It is often critical to follow the course of therapy with Factor VIII level assays.
The clinical effect of Koāte-DVI is the most important element in evaluating the effectiveness of treatment. It may be necessary to administer more Koāte-DVI than would be estimated in order to attain satisfactory clinical results. If the calculated dose fails to attain the expected Factor VIII levels, or if bleeding is not controlled after administration of the calculated dosage, the presence of a circulating inhibitor in the patient should be suspected. Its presence should be substantiated and the inhibitor level quantitated by appropriate laboratory tests.
When an inhibitor is present, the dosage requirement for Antihemophilic Factor VIII (Human) is extremely variable and the dosage can be determined only by the clinical response. Some patients with low titer inhibitors (10 Bethesda Units) can be successfully treated with Factor VIII without a resultant anamnestic rise in inhibitor titer. Factor VIII levels and clinical response to treatment must be assessed to insure adequate response. Immune tolerance therapy using repeated doses of Factor VIII concentrate administered frequently on a predetermined schedule may result in eradication of the Factor VIII inhibitor. Most successful regimens have employed high doses of Factor VIII administered at least once daily, but no single dosage regimen has been universally accepted as the most effective. Consultation with a hemophilia expert experienced with the management of immune tolerance regimens is also advisable.

Method of administration
For intravenous use after reconstitution only.

• If the dose requires more than one vial of Koāte-DVI:
o Reconstitute each vial using a new transfer needle.
o Draw up all the solution into a single syringe.
• Visually inspect the final solution for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter or discoloration is observed.
• Attach the syringe to the connector end of an infusion set.
• Administer intravenously. The rate of administration should be determined by the patient’s comfort level, and no faster than 10 mL per minute.

Elderly population
Clinical studies of Koāte-DVI did not include any subjects aged 65 and over to determine whether they respond differently from younger subjects. Individualize dose selection for geriatric patients.

Paediatric population
Koāte-DVI has not been studied in paediatric patients. The unheated, solvent/detergent treated Koāte had been used extensively in paediatric patients. Because clearance of Factor VIII (based on per kilogram body weight) is higher in children, higher or more frequent dosing may be needed.

Spontaneous adverse event reports with the unheated product and Koāte-DVI for paediatric use were within the experience of those reports for adult use.

Hypersensitivity reactions
Hypersensitivity reactions, including anaphylaxis, are possible. Early signs of hypersensitivity reactions, which can progress to anaphylaxis, may include angioedema, chest tightness, hypotension, rash, nausea, vomiting, paresthesia, restlessness, wheezing and dyspnea. If hypersensitivity symptoms occur, discontinue use of the product immediately and administer appropriate emergency treatment.

Neutralizing antibodies
The formation of neutralizing antibodies (inhibitors) to Factor VIII may occur. Monitor all patients for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests. If expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures Factor VIII inhibitor concentration.

Intravascular hemolysis
Koāte-DVI contains blood group isoagglutinins which are not clinically significant when small doses are used to treat minor bleeding episodes. However, when large and/or frequent doses of Koāte-DVI are given to patients with blood groups A, B, or AB, acute hemolytic anemia may occur, resulting in increased bleeding tendency or hyperfibrinogenemia. Monitor these patients for signs of intravascular hemolysis and falling hematocrit. Should this condition occur, leading to progressive hemolytic anemia, discontinue Koāte-DVI and consider administering serologically compatible Type O red blood cells and providing alternative therapy.

Transmissible infectious agents
Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV. The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).

No interactions of Antihemophilic Factor VIII (Human) products with other medicinal products have been reported.
Monitoring Laboratory Tests
•Monitor plasma Factor VIII activity levels by performing a validated test (e.g., one-stageclotting assay) to confirm that adequate Factor VIII levels have been achieved andmaintained.
•Monitor for the development of Factor VIII inhibitors. Perform a Bethesda inhibitorassay if expected Factor VIII plasma levels are not attained, or if bleeding is notcontrolled with the expected dose of Koāte-DVI. Use Bethesda Units (BU) to reportinhibitor levels.
•Monitor for intravascular hemolysis and decreasing hematocrit values in patients with A,B or AB blood groups who are receiving large or frequent doses of Koāte-DVI.

Fertility
Effect of Koāte-DVI on reproduction and fertility is not known.

Pregnancy
Pregnancy Category C. Animal reproduction studies have not been conducted with Koāte-DVI. It is also not known whether Koāte-DVI can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Koāte-DVI should be given to a pregnant woman only if clearly needed.

Lactation
There is insufficient/limited information on the excretion of Antihemophilic Factor VIII (Human) in human or animal breast milk. A risk to the suckling child cannot be excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Koāte-DVI should be made taking into account the benefit of breast-feeding to the child and the benefit of Koāte-DVI therapy to the woman.

No studies on the effects on the ability to drive and use machines have been performed.

Summary of the safety profile
The most common adverse drug reactions (frequency ≥ 5% of subjects) observed in the clinical trial were nervousness, headache, abdominal pain, nausea, paresthesia and blurred vision.

Post Marketing
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
• Blood and Lymphatic System Disorders: Factor VIII inhibition, hemolytic anemia
• Immune System Disorders: Hypersensitivity including anaphylaxis, rash, pruritus
• Injury, Poisoning and Procedural Complications: Post-procedural hemorrhage
• Nervous System Disorders: Generalized clonic-tonic seizure

Overdose symptoms with Antihemophilic Factor VIII (Human) are not known.

Pharmacotherapeutic Group: coagulation factor viii. ATC code: B02BD02
Mechanism of action
Koāte-DVI temporarily replaces the missing clotting Factor VIII that is needed for effective hemostasis.
Pharmacodynamic effects
Hemophilia A is a bleeding disorder characterized by a deficiency of functional coagulation Factor VIII, resulting in a prolonged plasma clotting time as measured by the activated partial thromboplastin time (aPTT) assay. Treatment with Koāte-DVI normalizes the aPTT over the effective dosing period.
Clinical efficacy and safety
Efficacy
The efficacy of Koāte-DVI for the treatment of bleeding episodes was demonstrated in a 2-stage, safety, PK and efficacy clinical trial. Stage I was a randomized, single-blind, single-dose, crossover, and PK study comparing heat-treated Koāte-DVI with unheated Koāte-DVI. Nineteen subjects were randomized and received a single dose of 50 IU/kg of either heated Koāte-DVI or unheated Koāte-DVI for PK assessment. Stage II was a 6 month open-label safety study conducted at two hemophilia centers. Nineteen subjects received Koāte-DVI, including for on-demand treatment and control of bleeding episodes. The study populations included 15 Caucasians, 3 Hispanic, and 1 Black subjects. A total of 306 bleeding episodes were treated, of which 82% were treated with a single infusion of Factor VIII.
Safety
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.
The safety assessment of Koāte-DVI is based on data from a 2-stage, safety, pharmacokinetic (PK) and efficacy clinical trial in which twenty subjects with severe hemophilia A (<1% endogenous Factor VIII activity) were evaluable for safety. Nineteen subjects were enrolled in Stage I of the trial, including 15 Caucasian, 3 Hispanic, and 1 Black subjects. The mean age was 29 years (range: 13.9 – 46.4 years). Nineteen subjects, including the 18 subjects who completed Stage I, and one new subject were enrolled in Stage II. The mean age was 30 years (range: 13.9 – 46.4). The subjects received a total of 1053 infusions. Ten adverse reactions related to 7 infusions were reported in 4 subjects. These were: nervousness (2 subjects [10%]), headache (1 subject [5%]), abdominal pain (1 subject [5%]), nausea (1 subject [5%]), paresthesia (1 subject [5%]), and blurred vision (1 subject [5%]).

Subjects were monitored for neutralizing antibodies (inhibitors) to Factor VIII by the Bethesda assay at baseline and at 8, 17 and 26 weeks. No evidence of inhibitor formation was observed in the clinical trial.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, it may be misleading to compare the incidence of antibodies to Koāte-DVI in the study described above with the incidence of antibodies in other studies or to other products.

The pharmacokinetics (PK) of Koāte-DVI were evaluated in a prospective, two-stage clinical trial of 20 previously treated patients (PTPs) with severe hemophilia A. In Stage I, the PK parameters for 19 subjects were based on plasma Factor VIII activity after a single intravenous infusion of 50 IU/kg of Koāte-DVI. Bioequivalence of the dry heat-treated Koāte-DVI to the unheated Koāte-DVI was demonstrated by comparison of Cmax and the area under the curve, AUC0-48. The incremental in vivo recovery ten minutes after infusion of dry heat-treated Koāte-DVI was 1.90% unit/kg (unheated Koāte-DVI was 1.82% units/kg). Mean biologic half-life was 16.1 hours.
In Stage II of the study, participants received Koāte-DVI treatments for six months on home therapy with a median of 52 days (range 23 to 94 days). At the end of 6 months, the mean AUC0-48 was 1471 ± 237 unit*hour/100 mL, the Cmax was 99 ± 13 unit/100 mL, and the t1/2 was 16 ± 3.9 hours.

The Koāte-DVI manufacturing process includes two dedicated steps with virus inactivation capacity. The solvent/detergent treatment step has the capacity to inactivate enveloped viruses (such as HIV, HCV, HBV, and WNV). Heat treatment at 80ºC for 72 hours has the capacity to inactivate enveloped viruses (such as HIV and HCV) as well as non-enveloped viruses (such as HAV and B19V). The polyethylene glycol (PEG) precipitation/depth filtration step has the capacity to remove both enveloped and non-enveloped viruses. 

Additionally, the Koāte-DVI manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered a model for the variant Creutzfeldt-Jakob disease (vCJD) and Creutzfeldt-Jakob disease (CJD) agents. The manufacturing process has been shown to decrease TSE infectivity of that experimental model agent (a total of 5.1 log10 reduction), providing reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed.

Sodium Chloride
Calcium Chloride
L-Histidine
Human Albumin
Solvent: Water for Injection

Antihemophilic Factor VIII (Human) should not be mixed with other medicinal products.
Only the provided infusion set should be used because treatment failure can occur as a consequence of Antihemophilic Factor VIII (Human) adsorption to the internal surfaces of some infusion equipment.

• Store Koāte-DVI in its original package to protect it from light.
• Store the Koāte-DVI package at 2 to 8°C (36 to 46°F). Do not freeze.
• Koāte-DVI may also be stored at room temperature (up to 25°C or 77°F) for up to 6 months.
• Do not use after the expiration date.
• Use Koāte-DVI immediately or within 3 hours of reconstitution. Do not refrigerate the reconstituted solution

Koāte-DVI is supplied in a 20 mL clear type I glass vial closed with chlorobutyl stopper, protected with an aluminum flip-off cap. The vial contains 1000 IU Antihemophilic Factor VIII (Human).
Sterile Water for Injection, USP, is supplied in a type I glass vial closed with butyl rubber stopper, protected with an aluminum flip-off cap. The diluent vial contains 10 mL sterile water for injection.
Koāte-DVI is supplied in a kit containing one single use vial of Koāte-DVI lyophilized powder, one vial of Sterile Water for Injection, USP, one sterile double-ended transfer needle, one sterile filter needle, and one sterile administration set. The total activity of Factor VIII in International Units is stated on the label of the Koāte-DVI vial and carton.
Components of the packaging do not contain natural rubber latex.

1. Use aseptic technique (clean and sanitized) and a flat work surface during the
reconstitution procedure.
2. Bring the vials of Koāte-DVI and the diluent (Sterile Water for Injection) to room
temperature before use.
3. Remove the shrink band from Koāte-DVI vial. Do not use Koāte-DVI if the shrink band
is absent or shows signs of tampering, and notify Grifols Therapeutics Inc. immediately.
4. Remove the plastic cap from the Koāte-DVI vial and cleanthe top of the stopper
with an alcohol swab. Allow the stopper to dry.
5. Repeat this step with the vial of sterile water.
6. Carefully remove the plastic sheath from the short end of the transfer needle and insert
the exposed needle into the diluent vial to the hub.

7. Place the Koāte-DVI vial upright on a flat surface. Remove the sheath from the other end
of the transfer needle.
8. While holding the Koāte-DVI vial securely on a flat surface insert the needle into the vial
at a 45° angle to minimize foaming. The vacuum will draw the diluent into the
concentrate vial. If vacuum is lost, use a sterile syringe and needle to remove the sterile
water from the diluent vial and inject it into the Koāte-DVI, directing the stream of fluid
against the wall of the vial.
9. Remove the diluent vial and transfer needle.
10. Agitate vigorously for 10-15 seconds, then swirl continuously until completely
dissolved. Avoid excessive foaming. The reconstituted solution should be clear
to opalescent. Do not use if particulate matter and discoloration is observed.
11. Clean the top of the vial of reconstituted Koāte-DVI with alcohol swab and let surface
dry.
12. Attach the filter needle (from the package) to a sterile syringe. Withdraw the Koāte-DVI
solution into the syringe through the filter needle.
13. Remove the filter needle from the syringe and discard the filter needle into a puncture
proof container. Use Koāte-DVI within 3 hours after reconstitution. Do not refrigerate
after reconstitution.