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Humate-P

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Humate-P safely and effectively. See full prescribing information for Humate-P.

Humate-P
Antihemophilic Factor/von Willebrand Factor Complex (Human)
Lyophilized Powder for Reconstitution for Intravenous Use Only.
Initial U.S. Approval: 1986

INDICATIONS AND USAGE

Humate-P is an Antihemophilic Factor/von Willebrand Factor (VWF) Complex (Human) indicated for:

Hemophilia A – Treatment and prevention of bleeding in adults (1.1).
Von Willebrand disease (VWD) – in adults and pediatric patients in the

(1)

Treatment of spontaneous and trauma-induced bleeding episodes; it is not indicated for the prophylaxis of spontaneous bleeding episodes, and

Prevention of excessive bleeding during and after surgery.
This applies to patients with severe VWD as well as patients with mild to moderate VWD where the use of desmospressin is known or suspected to be inadequate (1.2). Humate-P is not indicated for the prophylaxis of spontaneous bleeding episodes in VWD.

(2)

DOSAGE AND ADMINISTRATION

For intravenous use only.

Hemophilia A

One IU of factor VIII (FVIII) activity per kg body weight increases the circulating FVIII level by approximately 2.0 IU/dL. Individualize dosage based on the patient's weight, type and severity of hemorrhage, FVIII level, and presence of inhibitors (see Table 1 for dosing recommendations) (2.1).

VWD

Treatment of bleeding episodes – Administer 40-80 IU VWF:Ristocetin Cofactor (RCo) per kg body weight every 8-12 hours (2.2).
Prevention of excessive bleeding during and after surgery for all types of VWD (2.3).

Type of Surgery (see Table 3 for complete surgical dosing)	Calculation of Loading Dose Initial maintenance dose should be half the loading dose (see Table 4 for monitoring recommendations).
IU = International Units.
BW = body weight.
* Δ = Target peak plasma VWF:RCo level – baseline plasma VWF:RCo level. † IVR = in vivo recovery as measured in the patient. If the IVR is unknown, use 2.0 IU/dL per IU/kg. Oral surgery is defined as extraction of fewer than three teeth, if the teeth are non-molars and have no bony involvement. ‡
Major Surgery (2.3)	Δ* VWF:RCo × BW (kg) IVR†	= IU VWF:RCo required
Minor / Oral Surgery‡ (2.3)	Δ* VWF:RCo × BW (kg) IVR	= IU VWF:RCo required
Emergency Surgery (2.3)	Administer a dose of 50-60 IU VWF:RCo/kg BW

DOSAGE FORMS AND STRENGTHS

Each vial of Humate-P lyophilized powder contains the labeled amount of VWF:RCo and FVIII activity expressed in IU1. The average ratio of VWF:RCo to FVIII is 2.4:1. Approximate potencies are shown below; check each carton/vial for the actual potency prior to reconstitution (3):

VWF:RCo/vial	FVIII/vial	Diluent
* International Units
600 IU	250 IU	5 mL
1200 IU	500 IU	10 mL
2400 IU	1000 IU	15 mL

CONTRAINDICATIONS

Anaphylactic or severe systemic reaction to antihemophilic factor or VWF preparations (4).

WARNINGS AND PRECAUTIONS

VWD patients receiving Humate-P may be at risk of developing thromboembolic events (5.1).
Monitor for intravascular hemolysis and decreasing hematocrit values in patients with A, B, and AB blood groups who are receiving large or frequent doses (5.2).
Monitor VWF:RCo and FVIII levels in VWD patients, especially those undergoing surgery (5.3).
Products made from human plasma may contain infectious agents (e.g., viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (5.4).

ADVERSE REACTIONS

Most common adverse reactions observed by >5% of subjects after receiving Humate-P are allergic-anaphylactic reactions (e.g., urticaria, chest tightness, rash, pruritus, edema and, in patients undergoing surgery, postoperative wound and injection-site bleeding, and epistaxis (6).

To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Pregnancy: No human or animal data. Use only if clearly needed (8.1).
The hemostatic efficacy of Humate-P has been studied in 34 pediatric subjects with VWD (8.4). Based on the data from a subset of these subjects, age had no effect on the pharmacokinetics of VWF:RCo (12.3).

See 17 for PATIENT COUNSELING INFORMATION

Revised: 01/2010

FULL PRESCRIBING INFORMATION: CONTENTS*

Sections or subsections omitted from the full prescribing information are not listed

1 INDICATIONS AND USAGE

1.1 Hemophilia A

1.2 Von Willebrand Disease (VWD)

2 DOSAGE AND ADMINISTRATION

2.1 Therapy for Hemophilia A

2.2 Treatment of Bleeding Episodes in VWD

2.3 Prevention of Excessive Bleeding During and After Surgery in VWD

2.4 Reconstitution and Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Thromboembolic Events (VWD Patients)

5.2 Monitoring for Intravascular Hemolysis

5.3 Monitoring VWF:RCo and FVIII Levels

5.4 Transmission of Infectious Agents

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

11.1 Virus Reduction Capacity

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

14 CLINICAL STUDIES

14.1 Treatment of Bleeding Episodes in VWD

14.2 Prevention of Excessive Bleeding During and After Surgery in VWD

14.3 Virus Transmission Studies

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Hemophilia A

Humate-P, Antihemophilic Factor/von Willebrand Factor Complex (Human), is indicated for treatment and prevention of bleeding in adults with hemophilia A (classical hemophilia).

1.2 Von Willebrand Disease (VWD)

Humate-P is also indicated in adult and pediatric patients with von Willebrand disease (VWD) for:

(1): treatment of spontaneous and trauma-induced bleeding episodes, and; prevention of excessive bleeding during and after surgery. This applies to patients with severe VWD as well as patients with mild to moderate VWD where use of desmopressin (DDAVP) is known or suspected to be inadequate.

Controlled clinical trials to eva luate the safety and efficacy of prophylactic dosing with Humate-P to prevent spontaneous bleeding have not been conducted in VWD subjects (see Clinical Studies [14]).
(2)

2 DOSAGE AND ADMINISTRATION

2.1 Therapy for Hemophilia A

One IU of Factor VIII (FVIII) activity per kg body weight will increase the circulating FVIII level by approximately 2.0 International Units (IU)/dL. Dosage must be individualized based on the patient's weight, type and severity of hemorrhage, FVIII level, and presence of inhibitors. Judge the adequacy of treatment by clinical effects and, in all cases, adjust doses as needed based on clinical judgment and on frequent monitoring of the patient's FVIII level. Table 1 provides dosing recommendations for the treatment of hemophilia A in adults.

Table 1: Dosing Recommendations for the Treatment of Hemophilia A in Adults1
Hemorrhagic Event	Dosage (IU FVIII:C/kg Body Weight)
IU = International Units.
Minor hemorrhage: Early joint or muscle bleed Severe epistaxis	Loading dose 15 IU FVIII:C/kg to achieve a FVIII:C plasma level of approximately 30% of normal; one infusion may be sufficient. If needed, half of the loading dose may be given once or twice daily for 1-2 days.
Moderate hemorrhage: Advanced joint or muscle bleed Neck, tongue, or pharyngeal hematoma (without airway compromise) Tooth extraction Severe abdominal pain	Loading dose 25 IU FVIII:C/kg to achieve a FVIII:C plasma level of approximately 50% of normal, followed by 15 IU FVIII:C/kg every 8-12 hours for the first 1-2 days to maintain the FVIII:C plasma level at 30% of normal. Continue the same dose once or twice daily for up to 7 days or until adequate wound healing is achieved.
Life-threatening hemorrhage: Major surgery Gastrointestinal bleeding Neck, tongue, or pharyngeal hematoma (with potential for airway compromise) Intracranial, intraabdominal, or intrathoracic bleeding Fractures	Initially 40-50 IU FVIII:C/kg, followed by 20-25 IU FVIII:C/kg every 8 hours to maintain the FVIII:C plasma level at 80-100% of normal for 7 days. Continue the same dose once or twice daily for another 7 days to maintain the FVIII:C level at 30-50% of normal.

2.2 Treatment of Bleeding Episodes in VWD

Administer 40 to 80 International Units (IU) VWF:RCo (corresponding to 17 to 33 International Units (IU) FVIII in Humate-P) per kg body weight every 8 to 12 hours. Adjust the dosage based on the extent and location of bleeding. Administer repeat doses as long as needed based on monitoring of appropriate clinical and laboratory measures (see Warnings and Precautions [5.2 and 5.3]). Expected levels of VWF:RCo are based on an expected in vivo recovery (IVR) of 2.0 International Units (IU)/dL rise per International Unit (IU)/kg VWF:RCo administered. The administration of 1 International Unit (IU) of FVIII per kg body weight can be expected to lead to a rise in circulating VWF:RCo of approximately 5 International Units (IU)/dL. Table 2 provides dosing recommendations for adult and pediatric patients (see also Pediatric Use [8.4]).2

Table 2: VWF:RCo Dosing Recommendations for the Treatment of Bleeding Episodes by VWD Type
VWD Type	Severity of Hemorrhage	Dosage (IU* VWF:RCo/kg Body Weight)
* IU = International Units. For major bleeds in all types of VWD where repeated dosing is required, monitor and maintain the patient's FVIII level according to the guidelines for hemophilia A therapy. †
Type 1 VWD – Mild (baseline VWF:RCo activity typically >30%)	Minor (e.g., epistaxis, oral bleeding, menorrhagia)	Typically treatable with desmopressin.
	Minor (when desmopressin is known or suspected to be inadequate) Major† (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, traumatic hemorrhage)	Loading dose 40-60 IU/kg. Then 40-50 IU/kg every 8-12 hours for 3 days to keep the trough level of VWF:RCo >50%. Then 40-50 IU/kg daily for up to 7 days.
Type 1 VWD – Moderate or severe (baseline VWF:RCo typically <30%)	Minor (e.g., epistaxis, oral bleeding, menorrhagia)	40-50 IU/kg (1 or 2 doses).
	Major (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic hemorrhage)	Loading dose 50-75 IU/kg. Then 40-60 IU/kg every 8-12 hours for 3 days to keep the trough level of VWF:RCo >50%. Then 40-60 IU/kg daily for up to 7 days.
Type 2 VWD (all variants) and Type 3 VWD	Minor (clinical indications above)	40-50 IU/kg (1 or 2 doses).
	Major (clinical indications above)	Loading dose 60-80 IU/kg. Then 40-60 IU/kg every 8-12 hours for 3 days to keep the trough level of VWF:RCo >50%. Then 40-60 IU/kg daily for up to 7 days.

2.3 Prevention of Excessive Bleeding During and After Surgery in VWD

The following information provides guidelines for calculating loading and maintenance doses of Humate-P for patients undergoing surgery. However in the case of emergency surgery, administer a loading dose of 50 to 60 International Units (IU) VWF:RCo/kg body weight and, subsequently, closely monitor the patient's trough coagulation factor levels.

Measure incremental IVR and assess plasma VWF:RCo and FVIII:C levels in all patients prior to surgery when possible.

To determine IVR:

Measure the baseline plasma VWF:RCo level.
Infuse a calculated dose [International Units (IU)/kg] of VWF:RCo product intravenously at "time 0".
At "time+30 minutes", measure the plasma VWF:RCo level.

Use the following formula to calculate IVR:

IVR =	(Plasma VWF:RCotime+30 min – Plasma VWF:RCobaseline International Units (IU)/dL)
	Calculated dose (International Units (IU)/kg)

For example, assuming a baseline VWF:RCo of 30 International Units (IU)/dL at "time 0", a calculated dose of 60 International Units (IU)/kg, and a VWF:RCo of 120 International Units (IU)/dL at "time+30 minutes", the IVR would be 1.5 International Units (IU)/dL per International Units (IU)/kg of VWF:RCo administered.

Loading Dose

Table 3 provides guidelines for calculating the loading dose for adult and pediatric patients based on the target peak plasma VWF:RCo level, the baseline VWF:RCo level, body weight in kilograms, and IVR. When individual recovery values are not available, a standardized loading dose can be used based on an assumed VWF:RCo IVR of 2.0 International Units (IU)/dL per International Unit (IU)/kg of VWF:RCo administered.

Table 3: VWF:RCo and FVIII:C Loading Dose Calculations for the Prevention of Excessive Bleeding During and After Surgery for All Types of VWD
Type of Surgery	VWF:RCo Target Peak Plasma Level	FVIII:C Target Peak Plasma Level	Calculation of Loading Dose (to be administered 1 to 2 hours before surgery)
IU = International Units. BW = body weight.
* Δ = Target peak plasma VWF:RCo level – baseline plasma VWF:RCo level. † IVR = in vivo recovery as measured in the patient. Oral surgery is defined as extraction of fewer than three teeth, if the teeth are non-molars and have no bony involvement. Extraction of more than one impacted wisdom tooth is considered major surgery due to the expected difficulty of the surgery and the expected blood loss, particularly in subjects with type 2A or type 3 VWD. Extraction of more than two teeth is considered major surgery in all patients. ‡
Major	100 IU/dL	80-100 IU/dL	Δ* VWF:RCo × BW (kg) IVR†	= IU VWF:RCo required
			If the IVR is not available, assume an IVR of 2.0 IU/dL per IU/kg and calculate the loading dose as follows: (100 – baseline plasma VWF:RCo) × BW (kg) / 2.0
Minor / oral‡	50-60 IU/dL	40-50 IU/dL	Δ* VWF:RCo × BW (kg) IVR	= IU VWF:RCo required
Emergency	100 IU/dL	80-100 IU/dL	Administer a dose of 50-60 IU VWF:RCo/kg body weight.

For example, the loading dose of Humate-P required assuming a target VWF:RCo level of 100 International Units (IU)/dL, a baseline VWF:RCo level of 20 International Units (IU)/dL, an IVR of 2.0 International Units (IU)/dL per International Units (IU)/kg, and a body weight of 70 kg would be 2,800 International Units (IU) VWF:RCo, calculated as follows:

IU = International Units.
(100 IU/dL – 20 IU/dL) × 70 kg	= 2,800 IU VWF:RCo required
2.0 (IU/dL)/(IU/kg)

Attaining a target peak FVIII:C plasma level of 80 to 100 International Units (IU) FVIII:C/dL for major surgery and 40 to 50 International Units (IU) FVIII:C/dL for minor surgery or oral surgery might require additional dosing with Humate-P. Because the ratio of VWF:RCo to FVIII:C activity in Humate-P is 2.4:1, any additional dosing will increase VWF:RCo proportionally more than FVIII:C. Assuming an incremental IVR of 2.0 International Units (IU) VWF:RCo/dL per International Units (IU)/kg infused, additional dosing to increase FVIII:C in plasma will also increase plasma VWF:RCo by approximately 5 International Units (IU)/dL for each International Units (IU)/kg of FVIII administered.

Maintenance Doses

The initial maintenance dose of Humate-P for the prevention of excessive bleeding during and after surgery should be half of the loading dose, irrespective of additional dosing required to meet FVIII:C targets. Subsequent maintenance doses should be based on the patient's VWF:RCo and FVIII levels. Table 4 provides recommendations for target trough plasma levels (based on type of surgery and number of days following surgery) and minimum duration of treatment for subsequent maintenance doses. These recommendations apply to both adult and pediatric patients.

Table 4: VWF:RCo and FVIII:C Target Trough Plasma Level and Minimum Duration of Treatment Recommendations for Subsequent Maintenance Doses for the Prevention of Excessive Bleeding During and After Surgery
Type of Surgery	VWF:RCo Target Trough Plasma Level*		FVIII:C Target Trough Plasma Level*		Minimum Duration of Treatment
Type of Surgery	Up to 3 days following surgery	After Day 3	Up to 3 days following surgery	After Day 3	Minimum Duration of Treatment
IU = International Units.
* Trough levels for either coagulation factor should not exceed 100 IU/dL. † Oral surgery is defined as extraction of fewer than three teeth, if the teeth are non-molars and have no bony involvement. Extraction of more than one impacted wisdom tooth is considered major surgery due to the expected difficulty of the surgery and the expected blood loss, particularly in subjects with type 2A or type 3 VWD. Extraction of more than two teeth is considered major surgery in all patients. Administer at least one maintenance dose following oral surgery based on individual pharmacokinetic values. Subsequent therapy with an antifibrinolytic agent is usually administered until adequate healing is achieved. ‡
Major	>50 IU/dL	>30 IU/dL	>50 IU/dL	>30 IU/dL	72 hours
Minor	≥30 IU/dL	–	–	>30 IU/dL	48 hours
Oral†	≥30 IU/dL	–	–	>30 IU/dL	8-12 hours‡

Based on individual pharmacokinetic-derived half-lives, the frequency of maintenance doses is generally every 8 or 12 hours; patients with shorter half-lives may require dosing every 6 hours. In the absence of pharmacokinetic data, it is recommended that Humate-P be administered initially every 8 hours with further adjustments determined by monitoring trough coagulation factor levels. When hemostatic levels are judged insufficient or trough levels are outside the recommended range, consider modifying the administration interval and/or the dose.

It is advisable to monitor trough VWF:RCo and FVIII:C levels at least once a day in order to adjust Humate-P dosing as needed to avoid excessive accumulation of coagulation factors. The duration of treatment generally depends on the type of surgery performed, but must be assessed for individual patients based on their hemostatic response (see Clinical Studies [14.2]).

2.4 Reconstitution and Administration

Humate-P is for intravenous (IV) use only.

Inspect visually for particulate matter and discoloration prior to administration.

Use either the Mix2Vial™ filter transfer set provided with Humate-P (see How Supplied/Storage and Handling [16]) or a commercially available double-ended needle and vented filter spike.

Plastic disposable syringes are recommended for use with Humate-P. Protein solutions of this type tend to adhere to the ground glass surface of all-glass syringes.

Ensure that the Humate-P and diluent are at room temperature. Using aseptic technique, follow these steps to reconstitute Humate-P. 1.
Place the product vial, diluent vial and Mix2Vial on a flat surface. 2.
Remove product and diluent vial flip caps and treat the stoppers with the alcohol swab provided, and allow to dry prior to opening the Mix2Vial package. 3.
Open the Mix2Vial package by peeling away the lid (Fig. 1). Leave the Mix2Vial in the clear package. Place the diluent vial on a flat surface and hold the vial tight. Grip the Mix2Vial together with the package and snap the blue end onto the diluent stopper (Fig. 2). 4.	Fig. 1 Fig. 2
Carefully remove the clear package from the Mix2Vial set. Make sure that you only pull up the package and not the Mix2Vial set (Fig. 3). 5.	Fig. 3
With the product vial placed firmly on a flat surface, invert the diluent vial with the set attached and snap the transparent adapter onto the product vial stopper (Fig. 4). The diluent will automatically transfer into the product vial. 6.	Fig. 4
With the diluent and product vial still attached, gently swirl the product vial to ensure the product is fully dissolved (Fig. 5). Do not shake vial. 7.	Fig. 5

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