Antihemophilic Factor (Human) (Monograph)

Brand names: Alphanate, Hemofil-M, Humate-P, Koate-DVI, Monoclate-P
Drug class: Hemostatics
VA class: BL500
CAS number: 9001-27-8

Medically reviewed by Drugs.com on Feb 14, 2024. Written by ASHP.

Introduction

Antihemophilic factor (human): Antihemophilic factor (blood coagulation factor VIII) prepared from pooled human plasma.^{153 158 167}

Antihemophilic factor/von Willebrand factor complex (human): Antihemophilic factor and von Willebrand factor prepared from pooled human plasma.^{122 133}

Uses for Antihemophilic Factor (Human)

Hemophilia A

Prevention and control of bleeding episodes in patients with hemophilia A (congenital factor VIII deficiency; classic hemophilia).^{122 133 153 158 167}

Maintenance of hemostasis in patients with hemophilia A undergoing surgery (i.e., perioperative management).^{122 133 153 158 167}

Antihemophilic factor replacement therapy generally is required in patients with mild to moderate hemophilia A who do not respond adequately to desmopressin or those with moderate to severe hemophilia A and factor VIII levels <5% of normal.^{154 160 175 177 183 215 246}

Also used for routine prophylaxis (i.e., administration at regular intervals) to prevent or reduce frequency of bleeding events.^{158 215 224 225 226 231} Such prophylaxis considered the current standard of care for patients with hemophilia A.^{215 218} Decreases frequency of spontaneous musculoskeletal bleeding, preserves joint function, and improves quality of life.^{215 224 231}

Several antihemophilic factor concentrates are currently available in the US, including a variety of recombinant and plasma-derived preparations; the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation recommends preferential use of recombinant antihemophilic factor preparations because of their potentially superior safety profile with respect to pathogen transmission.^{218 246 247} Other experts (e.g., World Federation of Hemophilia) state that choice of preparation should be determined by local criteria.²¹⁵ When selecting an appropriate antihemophilic factor preparation, consider characteristics of each clotting factor concentrate, individual patient variables, patient/provider preference, and emerging data.^{215 243 246 247}

Has been used for treatment of bleeding in patients with hemophilia A who have developed relatively low levels of neutralizing antibodies (alloantibodies; inhibitors) to factor VIII.^{153 154 160 176 179 180 181 182 184 186 215 255} (See Neutralizing Antibodies to Factor VIII under Cautions.)

Acquired Hemophilia A

Although antihemophilic factor (human) therapy may be effective in some patients with low levels of acquired factor VIII inhibitors when given in high dosages,^{160 184 185 251} bypassing agents are substantially more effective and are considered treatment of choice.^{179 184 213 214 251 253}

von Willebrand Disease

Antihemophilic factor/von Willebrand factor complex (human) is used to prevent or control bleeding (e.g., spontaneous or trauma-induced bleeding or for prevention of bleeding during surgery) in patients with von Willebrand disease.^{122 133 161 201 244 246 250} Generally used in patients with severe (e.g., type 3) von Willebrand disease or when use of desmopressin is inadequate or contraindicated.^{122 133 161 201 244 246}

Designated an orphan drug by FDA for treatment of von Willebrand disease.¹⁶⁹

Certain preparations (i.e., Alphanate) should not be used in patients with type 3 von Willebrand disease undergoing major surgery because of a lack of demonstrated efficacy.^{122 232}

Certain antihemophilic factor (human) preparations that contain naturally occurring von Willebrand factor as part of the manufacturing process (i.e., Koate-DVI) may be effective in the management of von Willebrand disease^{† [off-label]}.^{161 201 244 246} However, preparations containing antihemophilic factor but little or no von Willebrand factor generally not useful in the treatment of von Willebrand disease.²⁵⁰

Antihemophilic Factor (Human) Dosage and Administration

General

• Individualize dosage and duration of therapy based on severity of factor VIII or von Willebrand factor deficiency, location and extent of bleeding, and patient's clinical and pharmacokinetic (e.g., in vivo recovery, half-life) response.^{122 133 158 167 215}

• Monitor factor VIII or von Willebrand factor: Ristocetin cofactor (vWF:RCo) levels periodically during treatment to individualize dosage and assess response to therapy.^{122 133 153 158 167} Careful control is especially important in cases of life-threatening bleeding or major surgery.^{122 153} (See Laboratory Monitoring under Cautions.)

Administration

IV Administration

Administer by slow IV injection or by IV infusion over several minutes.^{122 133 153 158 167}

Has been given as a continuous IV infusion^{† [off-label]}.^{228 229 230}

Reconstitute and administer using plastic syringes only.^{122 133 153 167}

Instructions on reconstitution, dilution, and administration vary according to preparation; consult manufacturer’s labeling for specific information on each antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) product.^{122 133 153 158 167}

Reconstitution

Prior to reconstitution, allow lyophilized drug and diluent to warm to room temperature; do not exceed 37°C.^{122 133 153 158 167}

Reconstitute using diluent provided by manufacturer.^{122 133 153 158 167}

Following addition of diluent, gently swirl solution to dissolve powder completely; do not shake.^{122 133 153 167}

Rate of Administration

Individualize infusion rates according to patient response.^{122 158 167} Monitor pulse before and during infusion.¹⁵³ Slow infusion rate or temporarily discontinue therapy if there is a substantial increase in pulse rate.¹⁵³

Alphanate, Hemofil-M: Administer at a rate ≤10 mL/minute.^{122 153}

Humate-P: Administer at a rate ≤4 mL/minute.¹³³

Koate-DVI: Generally well-tolerated when given over 5–10 minutes.¹⁵⁸

Monoclate-P: Administer at a rate of approximately 2 mL/minute.¹⁶⁷

Dosage

Dosage (potency) expressed in terms of international units (IU, units).^{122 133 153 158 167} One unit is approximately equivalent to amount of factor VIII or vWF:RCo in 1 mL of fresh pooled human plasma.^{122 133 158 167}

Administration of 1 unit/kg antihemophilic factor (human) generally increases factor VIII level by approximately 2% and vWF:Co by approximately 5%.^{133 154 160 167 176 194 215}

Use following formulas to calculate dose or expected increase in factor VIII levels from a given dose in patients with hemophilia A:

Dose required to achieve desired factor VIII levels:^{122 153 158 167}

Dose (units) = body weight (in kg) × 0.5 × desired factor VIII increase (in % of normal)

Approximate % increase in factor VIII levels expected from a given dose:^{122 153 158 167}

Expected factor VIII increase (in % of normal) = [dose (units)/body weight (in kg)] × 2

Determine desired factor VIII level by the clinical situation and severity of bleeding.^{122 133 153 158 167} (For recommendations on target factor VIII levels, see the individual preparation-specific dosage sections below.) These calculations and suggested dosage regimens are only approximations and should not preclude appropriate clinical monitoring and laboratory determinations of factor VIII levels.^{122 133 153 158 167} Perform serial assays of factor VIII at suitable intervals to ensure that adequate levels have been attained and maintained.^{122 133 153 158 167}

If calculated dosage is ineffective in achieving adequate factor VIII levels or if bleeding is not controlled, consider possibility of inhibitor development.^{122 153 215} (See Neutralizing Antibodies to Factor VIII under Cautions.) Some patients with inhibitors may require higher or more frequent doses.^{122 153 158}

Consult manufacturers’ prescribing information for specific dosage recommendations for each antihemophilic factor (human) preparation.^{122 133 153 158 167}

Pediatric Patients

Prevention and Control of Bleeding Episodes in Hemophilia A

Alphanate

IV

Pediatric patients >16 years of age with minor bleeding (e.g., large bruises, substantial cuts or scrapes, uncomplicated joint bleeding): 15 units/kg twice daily to achieve a plasma factor VIII level of 30% of normal; usually for 1–2 days (until bleeding stops and healing achieved).¹²²

Pediatric patients >16 years of age with moderate bleeding (e.g., epistaxis, mouth and gum bleeding, tooth extraction, hematuria): 25 units/kg twice daily to achieve a plasma factor VIII level of 50% of normal; usually for 2–7 days (until healing achieved).¹²²

Pediatric patients >16 years of age with major bleeding (e.g., joint or muscle bleeding, major trauma, hematuria, intracranial or intraperitoneal hemorrhage): Initially, 40–50 units/kg twice daily to achieve a plasma factor VIII level of 80–100% of normal for at least 3–5 days; give additional doses of 25 units/kg twice daily for up to 10 days (until healing is achieved) to maintain a plasma factor VIII level of 50% of normal.¹²² Intracranial hemorrhage may require treatment for up to 6 months.¹²²

Pediatric patients >16 years of age undergoing surgery: Initially, 40–50 units/kg to achieve a plasma factor VIII level of 80–100% of normal prior to surgery.¹²² Give additional doses of 30–50 units/kg twice daily for 7–10 days (or until healing achieved) to maintain a plasma factor VIII level of 60–100% of normal.¹²²

Hemofil-M

IV

Early hemarthrosis, muscle bleeding or oral bleeding: Administer appropriate dose to achieve a peak plasma factor VIII postinfusion level of 20–40% of normal.¹⁵³ To maintain adequate levels, administer doses every 12–24 hours for 1–3 days until bleeding resolves (indicated by relief of pain) or healing achieved.¹⁵³

More extensive hemarthrosis, muscle bleeding, or hematoma: Administer appropriate dose to achieve peak plasma factor VIII postinfusion level of 30–60% of normal.¹⁵³ Give doses every 12–24 hours for 3 days or longer until pain and disability resolve.¹⁵³

Life-threatening bleeding (e.g., head injury, throat bleeding, severe abdominal pain): Administer appropriate dose to achieve a peak plasma factor VIII postinfusion level of 60–100% of normal.¹⁵³ Give doses every 8–24 hours until bleeding resolves.¹⁵³

Minor surgery (e.g., tooth extraction): Administer appropriate dose to achieve a peak plasma factor VIII postinfusion level of 60–80% of normal.¹⁵³ A single infusion given in conjunction with an oral antifibrinolytic agent usually is sufficient in about 70% of patients.¹⁵³

Major surgery: Administer appropriate dose to achieve peak plasma factor VIII pre- and postoperative levels of 80–100% of normal.¹⁵³ Repeat doses every 8–24 hours depending on state of healing.¹⁵³

Monoclate-P

IV

Mild bleeding: A single infusion may be sufficient to achieve a plasma factor VIII level of ≥30% of normal.¹⁶⁷

Moderate bleeding: Initially, 15–25 units/kg to achieve a plasma factor VIII level of 30–50% of normal.¹⁶⁷ If needed, give additional doses of 10–15 units/kg every 8–12 hours.¹⁶⁷

Severe bleeding (e.g., neck, throat, subperitoneal bleeding): Initially, 40–50 units/kg and a maintenance dosage of 20–25 units/kg given every 8–12 hours to achieve a plasma factor VIII level of 80–100% of normal.¹⁶⁷

Minor surgery: Initially, 15–25 units/kg to achieve a plasma factor VIII level of 30–50% of normal.¹⁶⁷ If needed, give additional doses of 10–15 units/kg every 8–12 hours.¹⁶⁷

Major surgery: Administer an appropriate dose to achieve a plasma factor VIII level of 80–100% of normal 1 hour before surgery; administer a second dose equal to 50% of the initial dose 5 hours later.¹⁶⁷ Maintain a plasma factor VIII level of ≥30% of normal for 10–14 days after surgery.¹⁶⁷

Routine Prophylaxis of Bleeding Episodes in Hemophilia A

IV

Various dosing regimens have been recommended.^{215 218 225 231} MASAC states that an antihemophilic factor dosage of 25–50 units/kg 3 times a week or every other day usually is sufficient to maintain trough factor VIII concentrations >1% between infusions.²¹⁸

MASAC states that prophylaxis should be instituted at an early age (e.g., 1–2 years) prior to the onset of frequent bleeding; however, optimum duration of prophylaxis not known.²¹⁸

Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.²¹⁸

von Willebrand Disease (Alphanate)

Amount of vWF:RCo and factor VIII contained in each vial of Alphanate is indicated on the label.¹²² Ratio of vWF:RCo to factor VIII varies depending on the manufacturing lot; therefore, reevaluate dosage of Alphanate for management of von Willebrand disease whenever a different manufacturing lot is indicated on the vial.¹²²

IV

Patients undergoing a minor surgical or invasive procedure: Initially, 75 units/kg of vWF:RCo prior to procedure to achieve factor VIII levels of 40–50%; follow with additional doses of 50–75 units/kg of vWF:RCo every 8–12 hours as clinically needed for 1–3 days to maintain factor VIII levels at 40–50%.¹²²

Type 1 or type 2 patients undergoing a major surgical or invasive procedure: Initially, 75 units/kg of vWF:RCo prior to procedure to achieve factor VIII levels of 100%; follow with additional doses of 50–75 units/kg of vWF:RCo every 8–12 hours as clinically needed for at least 3–7 days to maintain factor VIII levels at 100%.¹²²

Therapeutic goal is to achieve trough factor VIII and vWF:RCo levels >50%; do not exceed 150%.¹²²

von Willebrand Disease (Humate-P)

IV

Adjust dosage according to extent and location of bleeding.¹³³ Usually administer doses of 40–80 units/kg of vWF:RCo (corresponding to 17–33 units/kg of antihemophilic factor) every 8–12 hours; repeat doses for as long as needed based on repeated monitoring of appropriate clinical and laboratory measures.¹³³

Expected levels of vWF:RCo based on expected in vivo recovery of 2% increase per unit/kg of vWF:RCo administered.¹³³ Administration of 1 unit/kg of antihemophilic factor can be expected to result in an increase in circulating vWF:RCo of approximately 5%.¹³³

In all patients with major bleeding, monitor and maintain factor VIII levels according to the usual guidelines for patients with hemophilia A.¹³³

Type 1 (Mild) von Willebrand Disease (Baseline vWF:RCo Activity Typically >30%)

IV

Pediatric patients (excluding neonates) with major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, traumatic bleeding) or minor bleeding when use of desmopressin is inadequate or contraindicated: Initially, 40–60 units/kg of vWF:RCo, followed by 40–50 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a trough vWF:RCo level of >50%.¹³³ Continue with 40–50 units/kg vWF:RCo daily for up to 7 days.¹³³

Type 1 (Moderate or Severe) von Willebrand Disease (Baseline vWF:RCo Activity Typically <30%)

IV

Pediatric patients (excluding neonates) with minor bleeding (e.g., epistaxis, oral bleeding, menorrhagia): 40–50 units/kg of vWF:RCo given as 1 or 2 doses.¹³³

Pediatric patients (excluding neonates) with major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic bleeding): Initially, 50–75 units/kg of vWF:RCo, followed by 40–60 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a vWF:RCo trough level of >50%.¹³³ Continue with 40–60 units/kg of vWF:RCo daily for up to 7 days.¹³³

Type 2 (All Variants) and Type 3 von Willebrand Disease

IV

Pediatric patients (excluding neonates) with minor bleeding (e.g., epistaxis, oral bleeding, menorrhagia): 40–50 units/kg of vWF:RCo given as 1 or 2 doses.¹³³

Pediatric patients (excluding neonates) with major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic bleeding): Initially, 60–80 units/kg of vWF:RCo, followed by 40–60 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a vWF:RCo trough level >50%.¹³³ Continue with 40–60 units/kg of vWF:RCo daily for up to 7 days.¹³³

Prevention of Excessive Perioperative Bleeding in von Willebrand Disease

Whenever possible, calculate dosages for surgical prophylaxis based on incremental in vivo recovery (IVR) values.¹³³ If individual IVR values not available, assume IVR of 2% per unit/kg of vWF:RCo.¹³³ In case of emergency surgery, administer a loading dose of 50–60 units/kg of vWF:RCo and closely monitor trough coagulation factor levels.¹³³

To calculate IVR, use the following formula.¹³³ Measure plasma vWF:RCo level at baseline and 30 minutes following a calculated dose.¹³³

IVR = (plasma vWF:RCo_{time + 30 minutes} - plasma vWF:RCo_baseline) / calculated dose (in units/kg)

Calculate loading dose (administered 1–2 hours prior to surgery) using the following formula:¹³³

Dose required (units of vWF:RCo) = [(target peak plasma vWF:RCo - baseline plasma vWF:RCo) x body weight (in kg)]/IVR

Administer loading doses to achieve specific target peak vWF:RCo and factor VIII levels.¹³³ Additional doses may be necessary to achieve recommended factor VIII levels; because of a higher ratio of vWF:RCo to factor VIII (2.4 to 1), vWF:RCo will increase proportionally more than factor VIII with increasing doses.¹³³

Administer initial maintenance dose equal to one-half the loading dose (irrespective of any additional loading doses given to meet target factor VIII goals); follow with additional maintenance doses based on trough plasma vWF:RCo and factor VIII levels.¹³³ Frequency of administration depends on individual pharmacokinetic parameters; in the absence of such data, administer every 8 hours initially.¹³³

Monitor trough vWF:RCo and factor VIII levels at least once daily, and during and after surgery.¹³³ Modify dose and/or frequency of antihemophilic factor administration if hemostasis is insufficient or measured trough coagulation factor levels are not within recommended range.¹³³ Because factor VIII is the main predictor of surgical hemostasis, some clinicians recommend monitoring factor VIII levels every 12 hours on the day a dose is administered, then every 24 hours thereafter.²⁴⁴ Determine duration of therapy based on hemostatic response.¹³³

IV

Pediatric patients (excluding neonates) undergoing major surgery: Administer appropriate loading dose to achieve a target peak plasma vWF:RCo level of 100% and a peak plasma factor VIII level of 80–100%.¹³³ Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough vWF:RCo levels of >50% (>50% of factor VIII activity) for up to 3 days following surgery and target trough vWF:RCo levels of >30% (>30% of factor VIII activity) after day 3.¹³³ Minimum duration of treatment is 72 hours.¹³³

Pediatric patients (excluding neonates) undergoing minor surgery: Administer appropriate loading dose to achieve a target peak plasma vWF:RCo level of 50–60% and a peak plasma factor VIII level of 40–50%.¹³³ Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough plasma vWF:RCo levels of ≥30% for up to 3 days following surgery and target trough factor VIII levels >30% after day 3.¹³³ Minimum duration of treatment is 48 hours.¹³³

Pediatric patients (excluding neonates) undergoing oral surgery: Administer appropriate loading dose to achieve a target peak vWF:RCo level of 50–60% and a peak plasma factor VIII level of 40–50%.¹³³ Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough vWF:RCo levels of ≥30% for up to 3 days following surgery and target trough factor VIII levels >30% after day 3.¹³³ Minimum duration of treatment is 8–12 hours.¹³³

Adults

Prevention and Control of Bleeding Episodes in Hemophilia A

Alphanate

IV

Minor bleeding (e.g., large bruises, cuts or scrapes, uncomplicated joint bleeding): 15 units/kg twice daily to achieve a plasma factor VIII level of 30% of normal; usually for 1–2 days (until bleeding stops and healing achieved).¹²²

Moderate bleeding (e.g., epistaxis, mouth and gum bleeding, tooth extraction, hematuria): 25 units/kg twice daily to achieve a plasma factor VIII level of 50% of normal; usually for 2–7 days, until healing achieved.¹²²

Major bleeding (e.g., joint or muscle bleeding, major trauma, hematuria, intracranial and intraperitoneal bleeding): Initially, 40–50 units/kg twice daily to achieve a plasma factor VIII level of 80–100% of normal for at least 3–5 days.¹²² Give additional doses of 25 units/kg twice daily for up to 10 days (until healing is achieved) to maintain a plasma factor VIII level of 50% of normal.¹²² Intracranial hemorrhage may require treatment for up to 6 months.¹²²

Surgery: Initially, 40–50 units/kg to achieve a plasma factor VIII level of 80–100% of normal prior to surgery.¹²² Give additional doses of 25–50 units/kg twice daily for 7–10 days (or until healing achieved) to maintain a plasma factor VIII level of 60–100% of normal.¹²²

Humate-P

IV

Minor bleeding (e.g., early joint or muscle bleeding, severe epistaxis): Initially, 15 units/kg to achieve a plasma factor VIII level of approximately 30% of normal.¹³³ A single dose may be sufficient; if necessary, administer additional doses equal to 50% of the loading dose once or twice daily for 1–2 days.¹³³

Moderate bleeding (e.g., advanced joint or muscle bleeding; neck, tongue, or pharyngeal hematoma without airway compromise; severe abdominal pain; tooth extraction): Initially, 25 units/kg to achieve a plasma factor VIII level of approximately 50% of normal,¹³³ followed by 15 units/kg every 8–12 hours for the first 1–2 days to maintain a plasma factor VIII level of 30% of normal.¹³³ Thereafter, the same dose may be given once or twice daily for up to 7 days or until adequate wound healing.¹³³

Life-threatening bleeding (e.g., major surgery, GI bleeding; neck, tongue, or pharyngeal hematoma with potential for airway compromise; intracranial, intra-abdominal, or intrathoracic bleeding; fractures): Initially, 40–50 units/kg followed by 20–25 units/kg every 8 hours to maintain a plasma factor VIII level of 80–100% of normal for 7 days.¹³³ Thereafter, the same dose may be given once or twice daily for another 7 days to maintain a plasma factor VIII level of 30–50% of normal.¹³³

Hemofil-M

IV

Early hemarthrosis, muscle bleeding or oral bleeding: Administer appropriate dosage to achieve a peak plasma factor VIII postinfusion level of 20–40% of normal.¹⁵³ To maintain adequate levels, administer doses every 12–24 hours for 1–3 days until bleeding resolves (indicated by relief of pain) or healing achieved.¹⁵³

More extensive hemarthrosis, muscle bleeding, or hematoma: Administer appropriate dose to achieve peak plasma factor VIII postinfusion level of 30–60% of normal.¹⁵³ Give doses every 12–24 hours for 3 days or longer until pain and disability resolve.¹⁵³

Life-threatening bleeding (e.g., head injury, throat bleeding, severe abdominal pain): Administer appropriate dose to achieve a peak plasma factor VIII postinfusion level of 60–100% of normal.¹⁵³ Give doses every 8–24 hours until bleeding resolves.¹⁵³

Minor surgery (e.g., tooth extraction): Administer appropriate dose to achieve a peak plasma factor VIII postinfusion level of 60–80% of normal.¹⁵³ A single infusion given in conjunction with an oral antifibrinolytic agent usually is sufficient in about 70% of patients.¹⁵³

Major surgery: Administer appropriate dose to achieve peak plasma factor VIII pre- and postoperative levels of 80–100% of normal.¹⁵³ Repeat doses every 8–24 hours depending on state of healing.¹⁵³

Koate-DVI

IV

Mild bleeding (superficial or early bleeding): A single 10-unit/kg dose may be sufficient to achieve an in vivo factor VIII level of approximately 20% of normal.¹⁵⁸ Repeat only if evidence of further bleeding.¹⁵⁸

Moderate bleeding (more serious bleeding episodes including definite hemarthroses, known trauma): Initially, 15–25 units/kg to achieve a plasma factor VIII level of 30–50% of normal.¹⁵⁸ If additional therapy is required, give additional doses of 10–15 units/kg every 8–12 hours.¹⁵⁸

Severe bleeding (life-threatening bleeding or possible hemorrhage involving vital structures [e.g., CNS, retropharyngeal and retroperitoneal spaces, iliopsoas sheath]): Increase plasma factor VIII level to 80–100% of normal with an initial dose of 40–50 units/kg and a maintenance dosage of 20–25 units/kg every 8–12 hours.¹⁵⁸

Major surgery: Increase plasma factor VIII level to approximately 100% with a preoperative 50-unit/kg dose.¹⁵⁸ Check plasma factor VIII levels to verify that the expected level is achieved prior to surgery.¹⁵⁸ Give additional doses if necessary, every 6–12 hours initially, and for a total of 10–14 days until healing complete.¹⁵⁸

Intensity of antihemophilic factor therapy required depends on the type of surgery and postoperative regimen employed; less intensive treatment schedules may provide adequate hemostasis for minor surgical procedures.¹⁵⁸

Monoclate-P

IV

Mild bleeding: A single infusion may be sufficient to achieve a plasma factor VIII level of ≥30% of normal.¹⁶⁷

Moderate bleeding: Initially, 15–25 units/kg to achieve a plasma factor VIII level of 30–50% of normal.¹⁶⁷ If needed, give additional doses of 10–15 units/kg every 8–12 hours.¹⁶⁷

Severe bleeding (e.g., neck, throat, subperitoneal bleeding): Initially, 40–50 units/kg and a maintenance dosage of 20–25 units/kg given every 8–12 hours may be sufficient to achieve a plasma factor VIII level of 80–100% of normal.¹⁶⁷

Minor surgery: Initially, 15–25 units/kg to achieve a plasma factor VIII level of 30–50% of normal; maintenance doses of 10–15 units/kg may be given every 8–12 hours if needed.¹⁶⁷

Major surgery: Administer appropriate dosage to achieve plasma factor VIII level of 80–100% of normal 1 hour before surgery; administer a second dose equal to 50% of the initial dose 5 hours later.¹⁶⁷ Maintain a plasma factor VIII level of ≥30% of normal for 10–14 days after surgery.¹⁶⁷

Routine Prophylaxis of Bleeding Episodes in Hemophilia A

IV

Various dosing regimens have been recommended.^{215 218 231} MASAC states that an antihemophilic factor dosage of 25–50 units/kg 3 times a week or every other day usually is sufficient to maintain trough factor VIII concentrations >1% between infusions.²¹⁸

Individualize prophylactic regimens; evaluate patients periodically to determine continued need for prophylaxis.²¹⁸

von Willebrand Disease (Alphanate)

Amount of vWF:RCo and factor VIII contained in each vial of Alphanate is indicated on the label.¹²² Ratio of vWF:RCo to factor VIII varies depending on the manufacturing lot; therefore, reevaluate dosage of Alphanate for management of von Willebrand disease whenever a different manufacturing lot is indicated on the vial.¹²²

IV

Patients undergoing a minor surgical or invasive procedure: Initially, 60 units/kg of vWF:RCo prior to procedure to achieve a target factor VIII level of 40–50% of normal; follow with additional doses of 40–60 units/kg of vWF:RCo every 8–12 hours as clinically needed for 1–3 days to maintain factor VIII levels at 40–50% of normal.¹²²

Type 1 or type 2 patients undergoing a major surgical or invasive procedure: Initially, 60 units/kg of vWF:RCo prior to procedure to achieve a factor VIII level of 100% of normal; follow with additional dosages of 40–60 units/kg of vWF:RCo every 8–12 hours as clinically needed for 3–7 days to maintain factor VIII levels at 100%.¹²²

Therapeutic goal is to achieve trough factor VIII and vWF:RCo levels >50%; do not exceed 150%.¹²²

von Willebrand Disease (Humate-P)

IV

Adjust dosage according to extent and location of bleeding.¹³³ Usually administer dosage of 40–80 units/kg of vWF:RCo (corresponding to 17–33 units/kg of antihemophilic factor) every 8–12 hours; repeat doses for as long as needed based on monitoring of appropriate clinical and laboratory measures.¹³³

Expected levels of vWF:RCo based on expected in vivo recovery of 2% increase per unit/kg of vWF:RCo administered.¹³³ Administration of 1 unit/kg of antihemophilic factor can be expected to result in an increase in circulating vWF:RCo of approximately 5%.¹³³

In all patients with major bleeding, monitor and maintain factor VIII levels according to the usual guidelines for patients with hemophilia A.¹³³

Type 1 (Mild) von Willebrand Disease (Baseline vWF:RCo Activity Typically >30%)

IV

Major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, traumatic bleeding) or minor bleeding when use of desmopressin is inadequate or contraindicated: Initially, 40–60 units/kg of vWF:RCo, followed by 40–50 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a trough vWF:RCo level of >50%.¹³³ Continue with 40–50 units/kg of vWF:RCo daily for up to 7 days.¹³³

Type 1 (Moderate or Severe) von Willebrand Disease (Baseline vWF:RCo Activity Typically <30%)

IV

Minor bleeding (e.g., epistaxis, oral bleeding, menorrhagia): 40–50 units/kg of vWF:RCo given as 1 or 2 doses.¹³³

Major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic bleeding): Initially, 50–75 units/kg of vWF:RCo, followed by 40–60 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a vWF:RCo trough level of >50%.¹³³ Continue with 40–60 units/kg of vWF:RCo daily for up to 7 days.¹³³

Type 2 (All Variants) and Type 3 von Willebrand Disease

IV

Minor bleeding (e.g., epistaxis, oral bleeding, menorrhagia): 40–50 units/kg of vWF:RCo given as 1 or 2 doses.¹³³

Major bleeding (e.g., severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, traumatic bleeding): Initially, 60–80 units/kg of vWF:RCo, followed by 40–60 units/kg of vWF:RCo every 8–12 hours for 3 days to maintain a vWF:RCo trough level of >50%.¹³³ Continue with 40–60 units/kg of vWF:RCo daily for up to 7 days.¹³³

Prevention of Excessive Perioperative Bleeding in von Willebrand Disease

Whenever possible, calculate dosages for surgical prophylaxis based on IVR values.¹³³ If individual IVR values not available, assume IVR of 2% per unit/kg.¹³³ In case of emergency surgery, administer loading dose of 50–60 units/kg of vWF:RCo and closely monitor trough coagulation factor levels.¹³³

To calculate IVR, use the following formula.¹³³ Measure plasma vWF:RCo level at baseline and 30 minutes following a calculated dose.¹³³

IVR = (plasma vWF:RCo_{time + 30 minutes} - plasma vWF:RCo_baseline) / calculated dose (in units/kg)

Calculate loading dose (administered 1–2 hours prior to surgery) using the following formula:¹³³

Dose required (units vWF:RCo) = [(target peak plasma vWF:RCo - baseline plasma vWF:RCo) x body weight (in kg)]/IVR

Administer loading doses to achieve specific target peak vWF:RCo and factor VIII levels.¹³³ Additional doses may be necessary to achieve recommended factor VIII levels; because of a higher ratio of vWF:RCo to factor VIII (2.4 to 1), vWF:RCo will increase proportionally more than factor VIII with increasing doses.¹³³

Administer initial maintenance dose equal to one-half the loading dose (irrespective of any additional loading doses given to meet target factor VIII goals); follow with additional maintenance doses based on trough plasma vWF:RCo and factor VIII levels.¹³³ Frequency of administration depends on individual pharmacokinetic parameters; in the absence of such data, administer every 8 hours initially.¹³³

Monitor trough vWF:RCo and factor VIII levels at least once daily, and during and after surgery.¹³³ Modify dose and/or frequency of antihemophilic factor administration if hemostasis is insufficient or measured trough coagulation factor levels are not within recommended range.¹³³ Because factor VIII is the main predictor of surgical hemostasis, some clinicians recommend monitoring factor VIII levels every 12 hours on the day a dose is administered, then every 24 hours thereafter.²⁴⁴ Determine duration of therapy based on hemostatic response.¹³³

IV

Major surgery: Administer appropriate loading dose to achieve a target peak plasma vWF:RCo level of 100% and a peak plasma factor VIII level of 80–100%.¹³³ Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough vWF:RCo levels of >50% (>50% of factor VIII activity) for up to 3 days following surgery and target trough vWF:RCo levels of >30% (>30% of factor VIII activity) after day 3.¹³³ Minimum duration of treatment is 72 hours.¹³³

Minor surgery: Administer appropriate loading dose to achieve a target peak plasma vWF:RCo level of 50–60% and a peak plasma factor VIII level of 40–50%.¹³³ Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough plasma vWF:RCo levels of ≥30% for up to 3 days following surgery and target trough factor VIII levels >30% after day 3.¹³³ Minimum duration of treatment is 48 hours.¹³³

Oral surgery: Administer appropriate loading dose to achieve a target peak vWF:RCo level of 50–60% and a peak plasma factor VIII level of 40–50%.¹³³ Give initial maintenance dose equal to one-half the loading dose and subsequent doses to achieve target trough vWF:RCo levels of ≥30% for up to 3 days following surgery and target trough factor VIII levels >30% after day 3.¹³³ Minimum duration of treatment is 8–12 hours.¹³³

Prescribing Limits

Pediatric Patients

Hemophilia A

IV

Hemofil-M: Maximum infusion rate 10 mL/minute.¹⁵³

von Willebrand Disease

IV

Alphanate: Maximum infusion rate 10 mL/minute.¹²²

Humate-P: Maximum infusion rate 4 mL/minute.¹³³

Adults

Hemophilia A

IV

Alphanate, Hemofil-M: Maximum infusion rate 10 mL/minute.^{122 153} Higher rates may result in vasomotor reactions.¹²²

Humate-P: Maximum infusion rate 4 mL/minute.¹³³

von Willebrand Disease

IV

Alphanate: Maximum infusion rate 10 mL/minute.¹²²

Humate-P: Maximum infusion rate 4 mL/minute.¹³³

Cautions for Antihemophilic Factor (Human)

Contraindications

• Hypersensitivity or severe systemic reaction to antihemophilic factor or von Willebrand factor preparations or any ingredient in the formulations.^{122 133 153}

• Known hypersensitivity to murine protein (Hemofil-M, Monoclate-P).^{153 167}

• The manufacturer states that there are no known contraindications to the use of Koate-DVI.¹⁵⁸

Warnings/Precautions

Warnings

Risk of Transmissible Agents in Plasma-derived Preparations

Improved donor screening, viral-inactivating procedures (e.g., solvent/detergent, heat treatment), and/or immunoaffinity chromatography procedures have reduced but not completely eliminated risk of pathogen transmission with plasma-derived antihemophilic factor preparations.^{122 133 153 154 158 167 183 215 246 247}

Possibility still exists for transmission of human viruses (e.g., HIV, hepatitis A virus [HAV], HBV, HCV) and other infectious agents (e.g., other unknown viruses, causative agents for Creutzfeldt-Jakob disease [CJD] or variant CJD [vCJD]).^{122 133 153 154 158 167 174 183 196 199 200 202 246 247}

Although transmission of nonenveloped viruses, including HAV and parvovirus B19, has been documented following administration of plasma-derived coagulation factors, risk has been reduced with additional viral attenuation methods such as nanofiltration.^{133 167 195 153 246 247}

Carefully weigh risk of pathogen transmission versus benefits of therapy.^{122 153 158 247} Report any suspected infections associated with the drug to the manufacturer, FDA, and CDC.^{122 133 153 158 167 246}

Risk of Hepatitis

Risk of hepatitis A or hepatitis B infection.^{133 233 235 246}

Monitor closely for signs and symptoms of hepatitis A during therapy.¹³³ (See Advice to Patients.)

Experts recommend administration of hepatitis B vaccine to all individuals with bleeding disorders who are seronegative and have not already been vaccinated; vaccination is recommended at birth or at time of diagnosis.^{122 133 158 197 246}

Immunization with hepatitis A vaccine is recommended for all individuals ≥12 months of age with hemophilia A or other congenital bleeding disorders who are HAV seronegative.^{233 235 246}

Risk of HIV Infection

Potential vehicle for transmission of HIV.²⁴⁶ HIV seroconversion reported in the past in patients who received blood or blood products from donors not screened for HIV and/or prepared using suboptimal viral-inactivating procedures.^{100 101 102 107 127 136 142 147 148 149} (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions.)

No reports to date of HIV seroconversion with currently available antihemophilic factor (human) preparations.^{153 246}

Risk of Creutzfeldt-Jakob Disease

Theoretical possibility of transmitting causative agent of CJD or vCJD.^{122 174 202 247} Several probable cases of vCJD transmission reported from transfusion of human RBCs.^{174 219} However, no cases of CJD or vCJD from antihemophilic factor preparations reported to date.²⁴⁷ For further information on CJD and vCJD precautions related to blood and blood products, consult the FDA’s guidance for industry ().²⁰²

Risk of West Nile Virus

Evidence of West Nile virus (WNV) transmission through transplanted organs (e.g., heart, liver, kidney) and blood products.^{205 208 209 237} However, WNV transmission through commercially available factor VIII preparations unlikely due to current viral-inactivating procedures.^{207 237}

For further information on WNV precautions related to blood and blood products, consult the FDA’s guidance for industry ().²³⁷

Thromboembolism

Thromboembolic events reported in patients with von Willebrand disease receiving antihemophilic factor/von Willebrand factor complex (human), usually occurring in setting of known thrombotic risk factors.^{122 133}

Although a causal relationship not established, high levels of endogenous factor VIII have been associated with thrombosis.^{122 133}

Exercise caution when using coagulation factor replacement therapy in all von Willebrand disease patients with high thrombotic risk.^{122 133} Consider use of antithrombotic measures.¹²²

Neutralizing Antibodies to Factor VIII

Risk of development of neutralizing antibodies (inhibitors) to factor VIII following treatment with any antihemophilic factor preparation.^{110 122 134 160 167 179 180 181 182 194 222 255} Reported to occur in approximately 20–30% of patients with severe hemophilia A and 5–10% of those with mild to moderate disease.²¹⁵

Inhibitors may diminish or neutralize response to therapy.^{122 164 165 166 169 222} Anamnestic responses and increased levels of inhibitor possible with continued administration of drug.^{160 176 179 180 182 194 215}

Monitor for development of inhibitors during treatment with clinical observation and appropriate laboratory tests.¹⁵³ Consider possibility of inhibitors in patients who fail to respond to adequate dosages of antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human), particularly in those who previously achieved a response.^{122 153 158 215 222}

Some reports suggest possible development of alloantibodies to von Willebrand factor following replacement therapy in patients with type 3 von Willebrand disease.¹²²

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., hives, generalized urticaria, tightness of the chest, wheezing, hypotension, anaphylaxis) reported.^{122 133 153} (See Contraindications under Cautions.)

The principal protein in Hemofil M is albumin human.¹⁵³ Adverse reactions associated with IV administration of albumin are rare; however, nausea, fever, chills, and urticaria have been reported in patients receiving the protein.¹⁵³

If hypersensitivity reaction occurs, discontinue drug immediately and initiate appropriate therapy.^{122 153 167}

Antibody Formation to Nonhuman Mammalian Proteins

Some preparations of antihemophilic factor (human) contain trace amounts of animal proteins (Hemofil-M, Monoclate-P) which may stimulate antibody production and cause hypersensitivity reactions.^{153 167}

Latex Sensitivity

Packaging components for some preparations (e.g., Hemofil-M, Koate-DVI) may contain natural latex proteins; take appropriate precautions if injection is handled by or administered to individuals with a history of natural latex sensitivity.^{153 158 238 241}

General Precautions

Hematologic Effects

Some preparations of antihemophilic factor (human) contain trace amounts of blood groups A and B isohemagglutins; intravascular hemolysis and anemia possible, especially when large or frequently repeated doses are given to individuals with blood groups A, B, or AB.^{122 133 158}

Monitor for signs of intravascular hemolysis and progressive anemia (performing hematocrit and direct antiglobulin [Coombs test]) in such individuals.^{122 133 158 167} If hemolysis or hemolytic anemia occurs, discontinue therapy and initiate appropriate treatment; consider administration of serologically compatible RBCs from blood group O.¹²²

Laboratory Monitoring

To ensure adequate therapeutic response, monitor factor VIII and vWF:RCo (if used in patients with von Willebrand disease) levels at regular intervals during therapy, especially in patients with major bleeding or who require surgery.^{122 133 153 158 167}

Monitor for development of inhibitors during treatment.²¹⁵ (See Neutralizing Antibodies to Factor VIII under Cautions.)

Specific Populations

Pregnancy

Category C.^{122 133 153 158 167}

Lactation

Not known whether antihemophilic factor (human) or antihemophilic factor/von Willebrand factor (human) is distributed into human milk.^{234 236} Use with caution and only if clearly indicated.^{122 133}

Pediatric Use

Alphanate: Safety and efficacy not established in children ≤16 years of age with hemophilia A.¹²² Evaluated in a limited number of pediatric patients ≤18 years of age with von Willebrand disease; no clinically important differences observed between pediatric patients and adults.¹²²

Humate-P: No adequate and well-controlled studies in pediatric patients with hemophilia A.¹³³ Long-term evaluation of joint damage not available for pediatric patients; joint damage may result from suboptimal treatment of hemarthroses.¹³³ Safety and efficacy established in infants, children, and adolescents with von Willebrand disease, but not in neonates.¹³³

Koate-DVI: Not studied in pediatric patients; manufacturer states that the predecessor product (Koate-HP, solvent/detergent-treated antihemophilic factor [human]) has been used extensively in pediatric patients.¹⁵⁸ Adverse effects reported in pediatric patients generally have been similar to those reported in adults.¹⁵⁸

Monoclate-P: Safety and efficacy established in children with hemophilia A; manufacturer recommends following adult dosage guidelines.¹⁶⁷

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.^{133 167} Use with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.¹⁶⁷ Individualize dosage.^{133 167}

Common Adverse Effects

Hemophilia A: Urticaria,^{122 133 153} fever,^{122 133 153} chills,^{122 133 153 167} nausea,^{122 133 153 158 167} chest tightness,^{133 153} stinging at infusion site,^{122 167} paresthesia,^{133 158} headache,^{122 158} rash,¹³³ pruritus,¹³³ edema,¹³³ vasodilation,¹³³ postoperative bleeding,¹³³ vomiting,¹²² pain,^{122 133} somnolence,¹²² lethargy,¹²² jitteriness,¹⁵⁸ abdominal pain,¹⁵⁸ blurred vision.¹⁵⁸

Von Willebrand disease: Urticaria,¹³³ chest tightness,¹³³ rash,^{122 133} pruritus,^{122 133} chills,^{122 133} paresthesia,^{122 133} edema,^{122 133} phlebitis,¹³³ pharyngitis,¹²² headache,^{122 133} fever,¹³³ pseudothrombocytopenia,¹³³ extremity pain,¹³³ vasodilation,¹³³ hypervolemia,¹³³ constipation,¹³³ urinary retention,¹³³ dizziness,¹³³ postoperative complications (e.g., bleeding,¹³³ nausea,¹³³ pain¹³³ ).

Drug Interactions

No formal drug interaction studies to date.¹²²

Antihemophilic Factor (Human) Pharmacokinetics

Absorption

Bioavailability

Following IV administration, peak plasma concentrations of factor VIII generally occur 10–15 minutes after end of infusion; may occur up to 1–2 hours later.²²³

Plasma Concentrations

Following IV infusion over 5–15 minutes, plasma concentrations of factor VIII increase by approximately 0.02–0.025 unit/mL per units/kg administered.²²³

Duration

Von Willebrand disease: Decreased bleeding time generally persists for <6 hours.¹²²

Distribution

Extent

Circulates in plasma; minimally distributed (about 14%) outside vascular system.²²³

Does not readily cross placenta.^a

Not known whether antihemophilic factor (human) is distributed into human milk.^{234 236}

Plasma Binding

Binds noncovalently to von Willebrand factor.^{110 154 160 175 194 223}

Elimination

Elimination Route

Rapidly cleared from plasma following IV administration.^a Possibly eliminated partly via reticuloendothelial system.²²³

Half-life

Factor VIII: About 12 hours (range: 8–18 hours).^{122 133 153 158 167 a}

Von Willebrand factor: Approximately 7–11 hours.^{122 133}

Special Populations

Possible increased clearance of factor VIII in patients with severe von Willebrand disease.²²³

Stability

Storage

Parenteral

Powder for Infusion

Alphanate: ≤25°C (avoid freezing).¹²² Store reconstituted solution at room temperature (≤30°C); use within 3 hours of reconstitution.¹²²

Hemofil-M: 2–8°C (avoid freezing to prevent damage to the diluent vial) or at room temperature ≤30°C up to expiration date.¹⁵³ Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.¹⁵³

Humate-P: ≤25°C up to expiration date; avoid freezing.¹³³ Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.¹³³

Koate DVI: 2–8°C (avoid freezing to prevent damage to the diluent vial); may store at room temperature ≤25°C up to 6 months.¹⁵⁸ Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.¹⁵⁸

Monoclate-P: 2–8°C (avoid freezing to prevent damage to the diluent vial) up to expiration date or store at room temperature ≤25°C for up to 6 months.¹⁶⁷ Use solution within 3 hours of reconstitution.¹⁶⁷

Actions

• Antihemophilic factor (human) preparations are concentrates of factor VIII derived from pooled human plasma.^{153 158 167} Antihemophilic factor/von Willebrand factor complex (human) preparations are concentrates of factor VIII and von Willebrand factor prepared from pooled human plasma.^{122 133}

• Factor VIII is essential for blood clotting and maintenance of hemostasis.^{110 122 123 134 153 154 155 160 175 194}

• Patients with hemophilia A (classic hemophilia) have decreased levels of endogenous factor VIII or dysfunctional factor VIII, resulting in a bleeding tendency and clinical manifestations such as bleeding into soft tissues, muscles, and weight-bearing joints.^{110 123 134 160 175 194}

• Decreased levels of endogenous factor VIII also may occur in patients with von Willebrand disease who have levels of vWF that are insufficient for in vivo stabilization of factor VIII.^{123 134 176 177}

• Clinical severity and frequency of bleeding in patients with hemophilia A correlate with the degree of deficiency in factor VIII activity.^{110 123 134 154 194} Patients with mild hemophilia A generally have >5% of normal activity, those with moderate disease generally have 1–5% of normal activity, and those with severe disease have <1% of normal activity.^{110 123 160 194}

• Administration of antihemophilic factor (human) or antihemophilic factor/von Willebrand factor complex (human) increases plasma levels of factor VIII and temporarily corrects the coagulation defect in patients with hemophilia A.^{122 153 158 160 194}

• Provides exogenous source of von Willebrand factor (Alphanate, Humate-P); decreases bleeding time and temporarily corrects coagulation defect in patients with von Willebrand disease.^{122 133} Von Willebrand factor promotes platelet adhesion and aggregation on damaged vascular endothelium; binds noncovalently to factor VIII, and stabilizes and protects factor VIII from degradation.^{110 133 154 160 175 194 223}

• Prepared using different methods (e.g., precipitation, gel filtration, chromatography, nanofiltration) to isolate and purify factor VIII and von Willebrand factor (for Alphanate and Humate-P).^{122 133 153 158 167}

• Undergoes viral inactivation processes (solvent/detergent, heat treatment [pasteurization, dry heat]) to reduce risk of viral transmission.^{122 133 153 158 159 167 246}

Advice to Patients

• Risk of developing neutralizing antibodies (inhibitors) to factor VIII; importance of informing clinician if usual dosages of factor VIII not able to control bleeding.^{110 122 134 160 167 179 180 181 182 194 222}

• Risk of transmission of parvovirus B19 and/or hepatitis A from plasma-derived factor concentrates.^{122 133 153 158 167} Importance of informing clinician if symptoms of potential parvovirus B19 infection (e.g., low grade fever, drowsiness, chills, runny nose, rash, arthralgias, arthritis, joint pain) or hepatitis A infection (e.g., low grade fever, anorexia, nausea, vomiting, fatigue, jaundice, dark urine, abdominal pain) occur.^{122 133 153 158 167}

• Importance of discontinuing therapy and immediately informing clinician if hives, urticaria, chest tightness, dyspnea, faintness, hypotension, wheezing, or other manifestations of hypersensitivity reaction or anaphylaxis occur.^{122 133 153 167}

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{122 133 153 158 167}

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{122 133 153 158 167}

• Importance of informing patients of other important precautionary information.^{122 133 153 158 167} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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