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INFUMORPH

 * Generic Name: morphine sulfate preservative-free sterile solution
 * Brand Name: Infumorph
 * Drug Class: Opioid Analgesics

Medical Editor: John P. Cunha, DO, FACOEP Last updated on RxList: 3/1/2022

home drugs a-z list side effects drug center infumorph (morphine sulfate
preservative-free sterile solution) drug

 * Side Effects Center
   
   
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 * Drug Description
 * Indications & Dosage
 * Side Effects & Drug Interactions
 * Warnings & Precautions
 * Overdose & Contraindications
 * Clinical Pharmacology
 * Medication Guide

Drug Description

WHAT IS INFUMORPH AND HOW IS IT USED?

Infumorph is a prescription medicine used to treat the symptoms of Acute Pain
and Chronic Severe Pain. Infumorph may be used alone or with other medications.

Infumorph belongs to a class of drugs called Opioid Analgesics.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF INFUMORPH?

Infumorph may cause serious side effects including:

 * hives,
 * difficulty breathing,
 * swelling of your face, lips, tongue, or throat,
 * slowed or breathing that stops,
 * slow breathing with long pauses,
 * blue colored lips,
 * difficulty wake up,
 * slow heart rate,
 * sighing,
 * shallow breathing,
 * breathing that stops during sleep,
 * extreme drowsiness,
 * lightheadedness,
 * flushing (sudden warmth, redness, or tingly feeling),
 * seizure,
 * nausea,
 * vomiting,
 * loss of appetite,
 * dizziness,
 * worsening tiredness,
 * weakness,
 * agitation,
 * hallucinations,
 * fever,
 * sweating,
 * shivering,
 * fast heart rate,
 * muscle stiffness,
 * twitching,
 * loss of coordination, and
 * diarrhea

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Infumorph include:

 * breathing problems,
 * drowsiness,
 * dizziness,
 * constipation,
 * nausea,
 * vomiting,
 * sweating, and
 * numbness, tingling, or cold feeling in your hands and feet

Tell the doctor if you have any side effect that bothers you or that does not go
away.

These are not all the possible side effects of Infumorph. For more information,
ask your doctor or pharmacist.

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


DESCRIPTION

Morphine is the most important alkaloid of opium and is a phenanthrene
derivative. It is available as the sulfate salt, having the following structural
formula:







7,8-Didehydro-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3,6-diol sulfate (2:1)
(salt), pentahydrate (C17H19NO3) • H2SO4• 5H2O MW is 758.83

INFUMORPH is a sterile, nonpyrogenic, isobaric, high potency solution of
morphine sulfate, free of antioxidants, preservatives or other potentially
neurotoxic additives. INFUMORPH is intended for use in continuous microinfuson
devices for intraspinal administration in the management of pain.

Each 20 mL ampul of INFUMORPH 200 contains morphine sulfate, USP 200 mg or 10
mg/mL and sodium chloride 8 mg/mL in Water for Injection, USP. Each 20 mL ampul
of INFUMORPH 500 contains morphine sulfate, USP 500 mg or 25 mg/mL and sodium
chloride 6.25 mg/mL in Water for Injection, USP. If needed, sodium hydroxide
and/or sulfuric acid are added for pH adjustment to 4.5. Each 20 mL ampul of
INFUMORPH is intended for single use only. Discard any unused portion. DO NOT
HEAT-STERILIZE.


Indications & Dosage


INDICATIONS

ALPHANATE, (antihemophilic factor/von Willebrand factor complex [human]), is
indicated for:

 * Control and prevention of bleeding episodes and perioperative management in
   adult and pediatric patients with Factor VIII (FVIII) deficiency due to
   hemophilia A.
 * Surgical and/or invasive procedures in adult and pediatric patients with von
   Willebrand Disease (VWD) in whom desmopressin (DDAVP) is either ineffective
   or contraindicated. It is not indicated for patients with severe VWD (Type 3)
   undergoing major surgery.


DOSAGE AND ADMINISTRATION

For intravenous injection after reconstitution only

 * Treatment with ALPHANATE should be initiated under the supervision of a
   physician experienced in the treatment of hemophilia.
 * Each vial of ALPHANATE has the antihemophilic factor (AHF) potency (FVIII:C
   activity) expressed in International Units (IU) FVIII/vial on the label.
   Additionally, ALPHANATE contains von Willebrand Factor:Ristocetin Cofactor
   (VWF:RCo), which is expressed in IU VWF:RCo/vial for the treatment of VWD.

DOSE

TREATMENT AND PREVENTION OF BLEEDING EPISODES AND EXCESS BLEEDING DURING AND
AFTER SURGERY IN PATIENTS WITH HEMOPHILIA A

 * Dosage and duration of treatment depend on the severity of the FVIII
   deficiency, the location and extent of bleeding, presence of inhibitors, and
   the patient’s clinical condition. Careful control of replacement therapy is
   especially important in cases of major surgery or life-threatening bleeding
   episodes.
 * Dosing requirements and frequency of dosing is calculated on the basis of an
   expected initial response of 2% of normal FVIII:C increase per IU FVIII:C/kg
   body weight administered.1 The expected in vivo peak increase in FVIII level
   expressed as IU/dL (or % of normal) can be estimated using the following
   formulas:

Dosage (international units) = body weight (kg) x desired FVIII rise (IU/dL or %
normal) x 0.5 (IU/kg per IU/dL)

or

IU/dL (or % of normal) = [Total Dose (IU)/body weight (kg)] x 2

 * Titrate dose and frequency to the patient’s clinical response, including
   individualized needs, severity of the deficiency, severity of the hemorrhage,
   presence of inhibitors, and FVIII level desired. Patients may vary in their
   pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to
   ALPHANATE.
 * Table 1 provides dosage guidelines for the control and prevention of bleeding
   episodes in hemophilia A patients. Dosing should aim at maintaining a plasma
   factor VIII activity level at or above the plasma levels (in IU/dL or in % of
   normal) outlined in the table.

Table 1: Dosage Guidelines for Patients with Hemophilia A

Type of BleedingFVIII:C Level Required (% of normal)Doses (IU/kg)Frequency of
Doses (hours)Duration of Therapy (days)Minor
 * Large bruises
 * Significant cuts or scrapes
 * Uncomplicated joint hemorrhage

301512 (twice daily)Until hemorrhage stops and healing has been achieved (1-2
days).Moderate
 * Nose, mouth and gum bleeds
 * Dental extractions Hematuria

502512 (twice daily)Until healing has been achieved (2-7 days, on average).Major
 * Joint hemorrhage
 * Muscle hemorrhage
 * Major trauma
 * Hematuria
 * Intracranial and intraperitoneal bleeding

80-100Initial: 40-50 Maintenance: 2512 (twice daily)For at least 3-5 days Until
healing has been achieved for up to 10 days. Intracranial hemorrhage may require
prophylaxis therapy for up to 6 months.SurgeryPrior to surgery:
80-10040-50OncePrior to surgeryAfter surgery: 60-10030-5012 (twice daily)For the
next 7-10 days, or until healing has been achieved.



 * Monitoring parameters:
   * Monitor plasma FVIII levels periodically to evaluate individual patient
     response to the dosage regimen.
   * If dosing studies have determined that a particular patient exhibits a
     lower/higher than expected response and shorter/longer half-life, adjust
     the dose and the frequency of dosing accordingly.
   * Failure to achieve the expected plasma FVIII:C level or to control bleeding
     after an appropriately calculated dosage may be indicative of the
     development of an inhibitor (an antibody to FVIII:C). Quantitate the
     inhibitor level by appropriate laboratory procedures and document its
     presence. Treatment with AHF in such cases must be individualized.2

TREATMENT AND PREVENTION OF EXCESS BLEEDING DURING AND AFTER SURGERY OR OTHER
INVASIVE PROCEDURES IN PATIENTS WITH VON WILLEBRAND DISEASE

 * The ratio of VWF:RCo to FVIII in ALPHANATE varies by lot, so with each new
   lot, check IU VWF:RCo/vial to ensure accurate dosing.
 * Dosage and duration of treatment depend on the severity of the VWF
   deficiency, the location and extent of bleeding, and the patient’s clinical
   condition. Careful control of replacement therapy is especially important in
   cases of major surgery or life-threatening bleeding episodes.
 * The median incremental in vivo recoveries of VWF:RCo and FVIII:C were 3.12
   (IU/dL)/(IU/kg) [mean, 3.29 ± 1.46 (IU/dL)/(IU/kg); range: 1.28 to 5.73
   (IU/dL)/(IU/kg)] for VWF:RCo and 1.95 (IU/dL)/(IU/kg) [mean, 2.13 ± 0.58
   (IU/dL)/(IU/kg); range: 1.33 to 3.32 (IU/dL)/(IU/kg)] for FVIII:C.
 * Table 2 provides dosing guidelines for pediatric and adult patients with von
   Willebrand Disease. 3-6

Table 2: Dosage Guidelines for Patients with von Willebrand Disease (Except Type
3 Subjects Undergoing Major Surgery)

Minor Surgery/BleedingParameterVWF:RCoTarget FVIII :C Activity
LevelsPre-operative/pre-procedure dose:Adults: 60 IU VWF:RCo/kg body weight.
Pediatrics: 75 IU VWF:RCo/kg body weight.40-50 IU/dLMaintenance dose:Adults: 40
to 60 IU VWF:RCo/kg body weight at 8 to 12 hour intervals as clinically needed
for 1-3 days. Pediatrics: 50 to 75 IU VWF:RCo/kg body weight at 8 to 12 hour
intervals as clinically needed for 1-3 days.40-50 IU/dLTherapeutic Goal
(Trough)a:>50 IU/dL>50 IU/dLSafety Monitoring:Peak and trough at least once
dailyPeak and trough at least once dailySafety Parameterb:Should not exceed 150
IU/dLShould not exceed 150 IU/dLMajor Surgery/BleedingParameterVWF:RCoTarget
FVIII :C Activity LevelsPre-operative/pre-procedure dose:Adults: 60 IU
VWF:RCo/kg body weight. Pediatrics: 75 IU VWF:RCo/kg body weight.100
IU/dLMaintenance dose:Adults: 40 to 60 IU VWF:RCo/kg body weight at 8 to 12 hour
intervals as clinically needed for at least 3-7 days. Pediatrics: 50 to 75 IU
VWF:RCo/kg body weight at 8 to 12 hour intervals as clinically needed for at
least 3-7 days.100 IU/dLTherapeutic Goal (Trough)a:>50 IU/dL>50 IU/dLSafety
Monitoring:Peak and trough at least dailyPeak and trough at least dailySafety
Parameterb:Should not exceed 150 IU/dLShould not exceed 150 IU/dLaThe
therapeutic goal is referenced in the NHLBI Guidelines.7
bThe safety parameter is extracted from Mannucci 2009.8



RECONSTITUTION

NOTE: If the Mix2Vial is connected at an angle, the vacuum may be released from
the product vial and the diluent will not transfer into the product vial.

NOTE: If the same patient is to receive more than one vial of concentrate, the
contents of two vials may be drawn into the same syringe through a separate
unused Mix2Vial set before attaching to the venipuncture set.

 1.  Always use aseptic technique.
 2.  Ensure that concentrate (ALPHANATE) and diluent (Sterile Water for
     Injection, USP) are at room temperature (but not above 37 °C) before
     reconstitution.
 3.  Remove the plastic flip off cap from the diluent vial.
 4.  Gently swab the exposed stopper surface with a cleansing agent such as
     alcohol trying to avoid leaving any excess cleansing agent on the stopper.
 5.  Open the Mix2Vial package by peeling away the lid (Figure 1). Leave the
     Mix2Vial in the clear outer packaging.
 6.  Place the diluent vial upright on an even surface and hold the vial tight
     and pick up the Mix2Vial in its clear outer packaging. Holding the diluent
     vial securely, push the blue end of the Mix2Vial vertically down through
     the diluent vial stopper (Figure 2).
 7.  While holding onto the diluent vial, carefully remove the clear outer
     packaging from the Mix2Vial set, ensuring the Mix2Vial remains attached to
     the diluent vial (Figure 3).
 8.  Place the product vial upright on an even surface, invert the diluent vial
     with the Mix2Vial attached.
 9.  While holding the product vial securely on a flat surface, push the clear
     end of the Mix2Vial set vertically down through the product vial stopper
     (Figure 4). The diluent will automatically transfer out of its vial into
     the product vial.
 10. With the diluent and product vials still attached to the Mix2Vial, gently
     swirl the product vial to ensure the product is fully dissolved (Figure 5).
     Reconstitution requires less than 5 minutes. Do not shake the vial.
 11. Disconnect the Mix2Vial into two separate pieces (Figure 6) by holding each
     vial adapter and twisting counterclockwise. After separating, discard the
     diluent vial with the blue end of the Mix2Vial.
 12. Draw air into an empty, sterile syringe. Keeping the product vial upright
     with the clear end of the Mix2Vial attached, screw the disposable syringe
     onto the luer lock portion of the Mix2Vial device by pressing and twisting
     clockwise. Inject air into the product vial.
 13. While keeping the syringe plunger depressed, invert the system upside down
     and draw the reconstituted product into the syringe by pulling the plunger
     back slowly (Figure 7).
 14. When the reconstituted product has been transferred into the syringe,
     firmly hold the barrel of the syringe and the clear vial adapter (keeping
     the syringe plunger facing down) and unscrew the syringe from the Mix2Vial
     (Figure 8). Hold the syringe upright and push the plunger until no air is
     left in the syringe. Attach the syringe to a venipuncture set.
 15. When reconstitution procedure is strictly followed, a few small particles
     may occasionally remain. The Mix2Vial set will remove particles and the
     labeled potency will not be reduced.
 16. Discard all reconstitution equipment after use into the appropriate safety
     container. Do not reuse.
 17. Use the prepared drug as soon as possible within 3 hours after
     reconstitution.







ADMINISTRATION

For intravenous use after reconstitution only

 * Inspect parenteral drug products visually for particulate matter and
   discoloration prior to administration, whenever solution and container
   permit.
 * Do not refrigerate after reconstitution. Store reconstituted ALPHANATE at
   room temperature (not to exceed 30 °C) prior to administration, but
   administer intravenously within three hours.
 * Use plastic disposable syringes.
 * Do not administer ALPHANATE at a rate exceeding 10 mL/minute.
 * Discard any unused contents into the appropriate safety container.


HOW SUPPLIED

DOSAGE FORMS AND STRENGTHS

ALPHANATE is available as a lyophilized powder for intravenous injection after
reconstitution. It is available in the following potencies:

250 IU FVIII/5 mL single dose vial
500 IU FVIII/5 mL single dose vial
1000 IU FVIII/10 mL single dose vial
1500 IU FVIII/10 mL single dose vial
2000 IU FVIII/10 mL single dose vial

ALPHANATE is supplied in sterile, lyophilized form in a single dose vial with a
vial of diluent (Sterile Water for Injection, USP) and a Mix2Vial filter
transfer set. IU activity of FVIII and VWF:RCo are stated on the carton and
label of each vial.

ALPHANATE is available in the following potencies and color coded based upon
assay on the carton and label as follows:



PotencyNDCAssay Color Code250 IU FVIII/5 mL single dose vial68516-4601-1
or
68516-4611-1250 IU FVIII Range - grey box500 IU FVIII/5 mL single dose
vial68516-4602-1
or
68516-4612-1500 IU FVIII Range - blue box1000 IU FVIII/10 mL single dose
vial68516-4603-2
or
68516-4613-21000 IU FVIII Range - red box1500 IU FVIII/10 mL single dose
vial68516-4604-2
or
68516-4614-21500 IU FVIII Range - black box2000 IU FVIII/10 mL single dose
vial68516-4609-2
or
68516-4615-22000 IU FVIII Range - green box



STORAGE AND HANDLING

ALPHANATE is stable for three years, up to the expiration date printed on its
label, provided that the storage temperature does not exceed 25 °C (77 °F). Do
not freeze.

REFERENCES

1. Srivastava, A., Brewer, A.K., et al. WFH Guidelines: Guidelines for the
management of hemophilia. Haemophilia 2013; 19, e1-e47.

2. Kempton, C.L., White, G.C. How we treat a hemophilia A patient with a factor
VIII inhibitor. Blood 2009; 113:11-17.

3. Federici, A.B., Baudo, F., Caracciolo, C., Mancuso, G., Mazzucconi, M.G.,
Musso, R., Schinco, P.C., Targhetta. R., Mannucci, P.M. Clinical efficacy of
highly purified, doubly virus-inactivated factor VIII/von Willebrand factor
concentrate (Fanhdi) in the treatment of von Willebrand disease: a retrospective
clinical study. Haemophilia 2002; 8:761-767.

4. Federici, A.B. Management of von Willebrand disease with factor VIII/von
Willebrand factor concentrates: results from current studies and surveys. Blood
Coagul Fibrinolysis 2005; 16(Suppl 1):S17-S21.

5. Mannucci, P.M. How I treat patients with von Willebrand disease. Blood 2001;
97:1915-1919.

6. Mannucci, P.M. Treatment of von Willebrand’s Disease. N Engl J Med 2004;
351:47-58.

7. Nichols, W.L. et al.; NHLBI VWD Expert Panel. The Diagnosis, Evaluation, and
Management of von Willebrand Disease. US Department of Health and Human
Services, National Institutes of Health, National Heart, Lung, and Blood
Institute 2007; NIH No. 08-5832.

8. Mannucci, P.M., Franchini, M., Castaman, G., Federici, A.B.; Italian
Association of Haemophilia Centres. Evidence-based recommendations on the
treatment of von Willebrand disease in Italy. Blood Transfus 2009; 7:117-126.

Manufactured by: Grifols Biologicals LLC, 5555 Valley Boulevard, Los Angeles, CA
90032, U.S.A., U. S. License No. 1694. Revised: Jun 2018

SLIDESHOW

Back Pain: 16 Back Pain Truths and Myths See Slideshow
Side Effects & Drug Interactions


SIDE EFFECTS

Serious adverse drug reactions (ADRs) observed in patients receiving ALPHANATE
include anaphylaxis/hypersensitivity reactions. Thromboembolic events also have
been observed in patients receiving ALPHANATE for VWD [see WARNINGS AND
PRECAUTIONS].

CLINICAL TRIAL EXPERIENCE

Because clinical trials are conducted under widely varying conditions, adverse
drug reaction (ADR) rates observed in the clinical trials of a drug cannot be
directly compared to rates in clinical trials of another drug and may not
reflect the rates observed in clinical practice.

HEMOPHILIA A

In a prospective clinical study with ALPHANATE, 23 subjects were exposed to 1217
infusions (median=42, range 2-160). The total number of exposure days was 1133,
and the total number of months on study across all subjects was 234 (19.5
subject years). No ADRs or inhibitors to FVIII were reported during the study.

VON WILLEBRAND DISEASE

In the prospective clinical study of ALPHANATE[using both ALPHANATE Solvent
Detergent (A-SD, a previous generation product) and ALPHANATE Solvent
Detergent/Heat Treated (A-SD/HT, the current generation product)] in subjects
with von Willebrand Disease, ADRs occurred in 5 of 36 subjects (13.9%) treated
with ALPHANATE.

Sixty-one total ADRs were reported in 204 infusions. The majority of ADRs were
rated as mild (55 of 61 [90.2%]). Six ADRs (9.8%) were rated as moderate. No
reactions rated as serious were reported. The adverse drug reaction grading
scale is defined as follows:

 * Mild: the event was noted but the administration of the compound was not
   interrupted; the event resolved spontaneously or no treatment was required
   beyond administration of nonprescription analgesics.
 * Moderate: the administration of the compound was not necessarily interrupted;
   the event required momentary treatment with prescription drugs and produced
   no sequelae.

Overall, the proportion of infusions associated with ADRs was 14 of 204
infusions (6.9%).

The most common ADRs reported (> 1% of infusions) were pruritus, headache,
backpain, paresthesia, respiratory distress, facial edema, pain, rash, and
chills.

One incident of pulmonary embolism was reported that was considered to have a
possible relationship to the product. This subject received a dose of 60 IU
VWF:RCo/kg body weight and the FVIII:C level achieved was 290%.

In the retrospective study conducted to determine the efficacy and safety of
ALPHANATE (A-SD/HT) in a surgical or invasive procedure setting as perioperative
prophylaxis against excessive bleeding, [see Clinical Studies], 3 out of 39
subjects (7.7%) experienced 6 adverse drug reactions. Four were considered mild
and 2 were considered moderate. No subject discontinued their treatment due to
an adverse drug reaction. The adverse drug reactions were pruritus, paresthesia
(2 events) and hemorrhage (all considered mild), and one event each of moderate
hematocrit decrease and orthostatic hypotension.

One adverse drug reaction (pain) related to the treatment with heat-treated
ALPHANATE (A-SD/HT) was reported in the four pediatric subjects with von
Willebrand Disease during the course of the prospective study and in none of the
five pediatric subjects in the retrospective clinical study.

POST-MARKETING EXPERIENCE

Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.

The most common post-marketing ADRs reported include allergic/hypersensitivity
reactions, nausea, fever, joint pain, fatigue, and infusion site pain.


DRUG INTERACTIONS

No Information provided

Warnings & Precautions


WARNINGS

Included as part of the PRECAUTIONS section.


PRECAUTIONS

HYPERSENSITIVITY REACTIONS

Anaphylaxis and severe hypersensitivity reactions are possible with ALPHANATE.
Early signs of allergic reactions, which can progress to anaphylaxis, may
include angioedema, chest tightness, hypotension, rash, nausea, vomiting,
paresthesia, restlessness, wheezing and dyspnea. Discontinue use of ALPHANATE if
hypersensitivity symptoms occur, and initiate appropriate treatment.

NEUTRALIZING ANTIBODIES

Development of procoagulant activity-neutralizing antibodies (inhibitors) has
been detected in patients receiving FVIII-containing products. Carefully monitor
patients treated with AHF products for the development of FVIII inhibitors by
appropriate clinical observations and laboratory tests. No specific studies have
been conducted with ALPHANATE to evaluate inhibitor formation. If expected
plasma FVIII activity levels are not attained, or if bleeding is not controlled
with an appropriate dose, perform an appropriate assay that measures FVIII
inhibitor concentration.

THROMBOEMBOLIC EVENTS

Thromboembolic events have been reported in von Willebrand Disease patients
receiving replacement therapy with Antihemophilic Factor/von Willebrand Factor
Complexes, especially in those with known risk factors for thrombosis including
but not limited to elderly age, previous thrombosis, metabolic syndrome, cancer,
surgery, oral contraceptive and hormone therapy, diabetes, hypertension,
hyperlipidemia, smoking, and pregnancy.9 Monitor plasma levels of VWF:RCo and
FVIII activities to avoid sustained excessive VWF and FVIII activity levels
(greater than 150 IU/dL), which may increase the risk of thrombotic events,
during continued treatment of replacement therapy with Antihemophilic Factor/von
Willebrand Factor Complexes. Consider antithrombotic measures in VWD patients at
risk for thrombosis [see ADVERSE REACTIONS].

INTRAVASCULAR HEMOLYSIS

ALPHANATE contains blood group specific isoagglutinins. Monitor the patient for
signs of intravascular hemolysis and decreasing hematocrit when large and/or
frequent doses of Antihemophilic Factor/von Willebrand Factor Complexes are
required in patients of blood groups A, B, or AB, as cases of acute hemolytic
anemia, increased bleeding tendency or hyperfibrinogenemia have been reported.
These events typically subside after cessation of the factor concentrate
infusion.10 Consider alternative therapy should this condition worsen despite
discontinuation of ALPHANATE.

VASOMOTOR REACTIONS

Rapid administration of a FVIII concentrate may result in vasomotor reactions.
Do not administer ALPHANATE at a rate exceeding 10 mL/minute.

TRANSMISSIBLE INFECTIOUS AGENTS

Because ALPHANATE is made from human plasma, it may carry a risk of transmitting
infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob Disease (vCJD)
agent and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk
that such products will transmit an infectious agent has been reduced by
screening plasma donors for prior exposure to certain viruses, by testing for
the presence of certain virus infections, and by inactivating and/or removing
certain viruses during manufacturing. [see DESCRIPTION].

MONITORING LABORATORY TESTS

Monitor for development of FVIII and VWF inhibitors. Perform appropriate assays
to determine if FVIII and/or VWF inhibitor(s) are present if bleeding is not
controlled with expected dose of ALPHANATE.

Monitor plasma levels of VWF:RCo and FVIII activities to avoid sustained
excessive VWF and FVIII activity levels (greater than 150 IU/dL), which may
increase the risk of thrombotic events, particularly in patients with known risk
factors.

USE IN SPECIFIC POPULATIONS

PREGNANCY

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

LABOR AND DELIVERY

No human or animal data. Use only if clearly needed.

NURSING MOTHERS

No human or animal data. Use only if clearly needed.

PEDIATRIC USE

HEMOPHILIA A

A total of 21 children (ages 7-16) were included in clinical trials with
ALPHANATE. Subjects received ALPHANATE weekly for prophylaxis or suspected
bleeds. They were successfully treated for 1499 bleeding episodes or as
prophylaxis to prevent them (e.g. pain in the joint). The median number of units
needed to treat the bleeds was 420 IU, with a range of 210 to 1620 IU. Adult and
pediatric subjects did not differ in their response to treatment.

VON WILLEBRAND DISEASE

The hemostatic efficacy of ALPHANATE has been studied in 20 pediatric subjects
(ages 7-18) with VWD. Based on the data from a subset of these subjects, age had
no effect on the pharmacokinetics of VWF:RCo. Adult and pediatric subjects did
not differ in their response to treatment.

GERIATRIC USE

No human or animal data. Use only if clearly needed.

REFERENCES

9. Coppola, A., Franchini, M., Makris M. Santagostino, E. Minno, G.DI, Mannucci,
P.M. Thrombotic adverse events to coagulation factor concentrates for treatment
of patients with haemophilia and von Willebrand disease: a systematic review of
prospective studies. Haemophilia 2012; 18, e173-e187.

10. Soni, N.S., Patel A.R., Vohra, R.M., Shah P.C. Hemophiliac with Hemolytic
Anemia resulting from Factor VIII Concentrate. Acta Haemato 1977; 58:294-297.

Overdosage & Contraindications


OVERDOSE

No Information provided


CONTRAINDICATIONS

ALPHANATE is contraindicated in patients who have manifested life-threatening
immediate hypersensitivity reactions, including anaphylaxis, to the product or
its components [see ADVERSE REACTIONS].

Clinical Pharmacology


CLINICAL PHARMACOLOGY

MECHANISM OF ACTION

ALPHANATE contains antihemophilic factor (FVIII) and von Willebrand factor
(VWF), constituents of normal plasma. FVIII is an essential cofactor in
activation of factor X leading to formation of thrombin and fibrin. VWF promotes
platelet aggregation and platelet adhesion on damaged vascular endothelium; it
also serves as a stabilizing carrier protein for the procoagulant protein
FVIII.12,13

After administration, ALPHANATE temporarily replaces the missing coagulation
factor VIII and von Willebrand factor needed for effective hemostasis.

PHARMACOKINETICS

PHARMACOKINETICS IN HEMOPHILIA A

Following the administration of ALPHANATE during clinical trials, the mean in
vivo half-life of FVIII observed in 12 adult subjects with severe hemophilia A
was 17.9 ± 9.6 hours. In this same study, the in vivo recovery was 96.7 ± 14.5%
at 10 minutes postinfusion. Recovery at 10 minutes post-infusion was also
determined as 2.4 ± 0.4 IU FVIII rise/dL plasma per IU FVIII infused/kg body
weight.

PHARMACOKINETICS IN VON WILLEBRAND DISEASE (VWD)

A pharmacokinetic crossover study was conducted in 14 non-bleeding subjects with
VWD (1 type 1, 2 type 2A, and 11 type 3) comparing the pharmacokinetics of
ALPHANATE (A-SD/HT) and an earlier formulation, ALPHANATE (A-SD). Subjects
received, in random order at least seven days apart, a single intravenous dose
of each product, 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg in subjects younger than 18
years of age). Pharmacokinetic parameters were similar for the two products and
indicated that they were biochemically equivalent. Pharmacokinetic analysis of
ALPHANATE (A-SD/HT) in the 14 subjects revealed the following results: the
median plasma levels (% normal) of VWF:RCo rose from 10 IU/dL (range: 10 to 27
IU/dL) at baseline to 206 IU/dL (range: 87 to 440 IU/dL) 15 minutes
post-infusion; median plasma levels of FVIII:C rose from 5 IU/dL (range: 2 to
114 IU/dL) to 206 IU/dL (range: 110 to 421 IU/dL). The median bleeding time (BT)
prior to infusion was 30 minutes (mean, 28.8 ± 4.41 minutes; range: 13.5 to 30
minutes), which shortened to 10.38 minutes (mean, 10.4 ± 3.2 minutes; range: 6
to 16 minutes) 1 hour post-infusion.

Following infusion of ALPHANATE (A-SD/HT), the median half-lives for VWF:RCo,
FVIII:C and VWF:Ag were 6.91 hours (range: 3.8 to 16.22 hours), 20.92 hours
(range: 7.19 to 32.2 hours), and 12.8 hours (range: 10.34 to 17.45 hours),
respectively. The median incremental in vivo recoveries of VWF:RCo and FVIII:C
were 3.12 (IU/dL)/(IU/kg) [range: 1.28 to 5.73 (IU/dL)/(IU/kg)] for VWF:RCo and
1.95 (IU/dL)/(IU/kg) [range: 1.33 to 3.32 (IU/dL)/(IU/kg)] for FVIII:C.

The pharmacokinetic data in VWD are summarized in Table 4.

Table 4: Pharmacokinetic data in VWD

ParameterPlasma VWF:RCo (Mean ± SD)Plasma FVIII:C (Mean ± SD)Plasma VWF:Ag (Mean
± SD)Number of subjects141414Mean plasma levels (IU/dL)Baseline11.86 ±4.9721.00
±33.83-15 minutes post infusion215.50 ± 101.70215.29 ±94.26-T½ (Half-life in
hours)7.67 ±3.3221.58 ±7.7913.06 ±2.20Incremental iti vivo recovery in
(IU/dL)/(IU/kg)3.29 ± 1.462.13 ±0.58-



Following infusion of both ALPHANATE (A-SD) and ALPHANATE (A-SD/HT), an increase
in the size of VWF multimers was seen and persisted for at least 24 hours. The
shortening of the BT was transient, lasting less than 6 hours following
treatment and did not correlate with the presence of large and intermediate size
VWF multimers.14

CLINICAL STUDIES

In a prospective, multi-center clinical study, 37 subjects with VWD (6 Type 1,
19 Type 2, 12 Type 3) underwent 59 surgical procedures for which ALPHANATE (ASD)
or ALPHANATE (A-SD/HT) was administered [21 subjects received ALPHANATE (A-SD),
18 received ALPHANATE (A-SD/HT), and 2 received both products] for bleeding
prophylaxis (see Table 5). An initial pre-operative infusion of 60 IU VWF:RCo/kg
(75 IU VWF:RCo/kg for subjects less than 18 years of age), was administered one
hour before surgery. A blood sample was obtained 15 minutes after the initial
infusion for the determination of the plasma FVIII:C level. The level had to
equal or exceed 100% of normal for an operation to proceed. No cryoprecipitate
or alternative FVIII product was administered during these surgical procedures.
Platelets were required in two subjects. The protocol permitted intra-operative
infusions of ALPHANATE (A-SD) and ALPHANATE (A-SD/HT) at 60 IU VWF:RCo/kg (75 IU
VWF:RCo/kg for subjects less than 18 years of age) to be administered as
required according to the judgment of the investigator.

Table 5: Number of and Types of Surgical Procedures

ParameterTreatment with AlphanateTotalType of Surgical
ProcedureA-SDA-SD/HTNumber of
Subjects211837^Dental14620Demiatologic112Gastrointestinal448Gastrointestinal
(diagnostic)606Genitourinary022Gynecologic213Head and
neck112Orthopedic437Vascular369Total number of procedures352459^ Two subjects
received both preparations; the total number of subjects is therefore less than
the sum of the columns.



Post-operative infusions at doses of 40 to 60 IU VWF:RCo/kg (50 to 75 IU
VWF:RCo/kg for pediatric subjects) were administered at 8 to 12-hour intervals
until healing had occurred. For maintenance of secondary hemostasis (after
primary hemostasis was achieved), the dose was reduced after the third
post-operative day [see DOSAGE AND ADMINISTRATION].

Overall, in the surgical procedures using either product, the BT at 30 minutes
post-infusion was fully corrected in 18 (32.7%) cases, partially corrected in 24
(43.6%) cases, not corrected in 12 (21.8%) cases, and was not done in one case
(1.8%). Overall, the mean blood loss was lower than predicted prospectively.

Surgical infusion summary data are included in Table 6.

Table 6: Prophylaxis with ALPHANATE (A-SD) and/or ALPHANATE (A-SD/HT) in Surgery

ParameterA-SDA-SD/HTTotalNumber of subjects211837*Number of surgical
procedures352459Median number of infusions per surgical procedure
(range)3(1-13)4(1 - 18)4(1-18)Median dosage IU VWF:RCo/kgInfusion #1 (range)59.8
(19.8-75.1)59.9
(40.6-75.0)59.9
(19.8-75.1)Infusion ≥ #2 combined (range)40.0
(4.5-75.1)40.0
(10.0-63.1)40.0
(4.5-75.1)* Two subjects received both products



Additionally, surgical procedures using ALPHANATE SD/HT only were categorized as
major, minor or invasive procedures according to definitions used in the study.
The outcome of each surgery was evaluated according to a clinical rating scale
(excellent, good, poor or none) and was considered successful if the outcome was
excellent or good.

Study results also were evaluated independently by two referees with clinical
experience in this field in the same way (surgery categorization and outcome of
each surgery according to a clinical rating scale). There was a high level of
agreement between the referee evaluations and the analyzed outcome data, with a
decrease of only a single success in achieving hemostasis (21/24 [referees
evaluation] vs. 22/24 [investigators evaluation]).

A retrospective, multi-center study was performed to assess the efficacy of
ALPHANATE (A-SD/HT) as replacement therapy in preventing excessive bleeding in
subjects with congenital VWD undergoing surgical or invasive procedures, for
whom DDAVP was ineffective or inadequate. A total of 61 surgeries/procedures in
39 subjects were evaluated.15

Of the 39 subjects, 18 had Type 1 VWD (46.2%); 12 subjects (30.8%) had Type 2
VWD, and 9 subjects (23.1%) had Type 3 VWD. Median age was 40 years;
approximately one-half of the subjects were male.

The primary efficacy variable was the overall treatment outcome for each
surgical or invasive procedure, as rated by the investigator using a 4-point
verbal rating scale (VRS): “excellent,” “good,” “poor,” or “none (no indication
of efficacy).” The categorization of the replacement treatment outcome was based
upon the investigator’s clinical experience and defined in Table 7.

Table 7: Rating Scale and Clinical Efficacy of ALPHANATE Therapy

RatingClinical Efficacy*HemostasisDosingExcellentHemostasis not different from
that expected for subjects without known bleeding disorders.No upward dosage
adjustment for ALPHANATE replacement therapy.GoodHemostasis slightly inferior
from that expected for subjects without known bleeding disorders but judged as
not clinically relevant.Minor upward dosage adjustment for ALPHANATE replacement
therapy.PoorLess hemostasis than expected for subjects without known bleeding
disorders attributed to vWD despite ALPHANATE replacement therapy.Relevant
upward dosage adjustment for ALPHANATE replacement therapy. No need for
alternative therapy. No need for alternative therapy.NoneSevere bleeding
attributed to vWD despite ALPHANATE replacement therapy.Relevant upward dosage
adjustment for ALPHANATE replacement therapy and/or need for alternative
unexpected therapy.*The efficacy assessment period included the entire
perioperative period.



In addition, an independent referee committee was convened to evaluate the
efficacy outcomes. More than 90% of the surgical outcomes received an
investigator and referee’s overall and daily rating of “effective”
(“excellent” or “good”) in achieving hemostasis/preventing bleeding.

The majority of ratings were considered “excellent” (≥ 81.3% in each VWD type).
Nine Type 3 subjects underwent 1 major and 15 minor procedures. Two procedures
(1 major and 1 minor) in 1 subject with Type 3 VWD received an overall efficacy
rating of “none,” and one minor procedure in a subject with Type 2 VWD received
an overall efficacy rating of “poor.”

REFERENCES

14. Mannucci, P.M., Chediak, J., Hanna, W. Byrnes, J.J., Kessler, C.M, Ledford,
M., Retzios, A.D., Kapelan, B.A., Gallagher, P., Schwartz, R.S., and the
Alphanate Study Group. Treatment of von Willebrand’s Disease (VWD) with a high
purity factor VIII concentrate: Dissociation between correction of the bleeding
time (BT), VWF multimer pattern, and treatment efficacy. Blood 1999; 94 (Suppl
1, Part 2 of 2):98b.

15. Rivard, G.E., Aledort, L., et al. Efficacy of factor VIII/von Willebrand
factor concentrate Alphanate in preventing excessive bleeding during surgery in
subjects with von Willebrand disease. Haemophilia 2008; 14, 271-275.

Medication Guide


PATIENT INFORMATION

Advise the patient:

 * To contact their healthcare provider or go to the emergency department right
   away if a hypersensitivity reaction occurs. Early signs of hypersensitivity
   reactions may include rash, hives, itching, facial swelling, tightness of the
   chest, and wheezing [see WARNINGS AND PRECAUTIONS].
 * To contact their physician or treatment center for further treatment and/or
   assessment if they experience a lack of clinical response to factor VIII
   replacement therapy, as this may be a manifestation of an inhibitor [see
   WARNINGS AND PRECAUTIONS].
 * To contact their healthcare provider or go to the emergency department right
   away if a thromboembolic event should occur [see WARNINGS AND PRECAUTIONS].
 * That despite stringent procedures designed to reduce risk, the risk of
   transmitting infectious agents cannot be totally eliminated. Advise patients,
   especially pregnant women and immunocompromised individuals, to report any
   signs and symptoms of fever, rash, joint pain, or sore throat, to their
   physician immediately [see WARNINGS AND PRECAUTIONS].




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