Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/625
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Dilatrate-SR (Capsule, Extended Release)
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| dailymed-instance:dosage |
Each vial of RECOMBINATE is labeled with the Factor VIII activity
expressed in IU per vial. This potency assignment is referenced to the World
Health Organization International Standard for Factor VIII:C Concentrate and is
evaluated by appropriate methodology to ensure accuracy of the results. The expected in vivo peak
increase in Factor VIII level expressed as IU/dL of plasma or % (percent) of
normal can be estimated by multiplying the dose administered per kg body weight
(IU/kg) by two. This calculation is based on the clinical findings of
Abildgaard et aland is
supported by the data generated by 419 clinical pharmacokinetic studies with
RECOMBINATE in 67 patients over time. This pharmacokinetic data demonstrated a
peak recovery point above the pre-infusion baseline of approximately 2.0 IU/dL
per IU/kg body weight. Examples (Assuming patient���s baseline Factor VIII level is at<1%): (1)�� ������ A dose of 1750 IU RECOMBINATE administered to a 70 kg
patient, i.e. 25 IU/kg (1750 IU/70 kg),
should be expected to cause a peak post-infusion Factor VIII increase of 25
IU/kg x 2 (IU/dL)/(IU/kg) = 50 IU/dL (50% of normal). (2)���������� A peak level of 70% is required in a 40 kg child. In this
situation, the dose would be 70 IU/dL/[2(IU/dL)/(IU/kg)]��x��40 kg��= 1400
IU.<br/>Recommended Dosage Schedule: Physician supervision of the dosage is required.�� The following
dosage schedule may be used as a guide. The careful control of the substitution therapy is especially
important in cases of major surgery or life threatening hemorrhages. Although dosage can be estimated by the calculations above, it is
strongly recommended that whenever possible, appropriate laboratory tests
including serial Factor VIII assays be performed on the patient���s plasma
at suitable intervals to assure that adequate Factor VIII levels have
been reached and are maintained. Other dosage regimens have been proposed such as that of Schimpf,
et al, which describes
continuous maintenance therapy.<br/>Reconstitution using the BAXJEXT II Device: Use Aseptic Technique: NOTE: Do not refrigerate after reconstitution. (See Administration)<br/>Administration: Use Aseptic Technique: Administer at room temperature.RECOMBINATE should be
administered not more than 3 hours after reconstitution. Intravenous Syringe Injection Parenteral drug products should be inspected for particulate
matter and discoloration prior to administration, whenever solution and
container permit. The solution should be colorless to faint yellow in
appearance. If not, do not use the solution and notify Baxter
immediately. Plastic syringes are recommended for use with this product since
proteins such as RECOMBINATE tend to stick to the surface of glass
syringes.<br/>Rate of Administration: Preparations of RECOMBINATE can be administered at a rate of up
to 10 mL per minute with no significant reactions. The pulse rate should be determined before and during
administration of RECOMBINATE. Should a significant increase in pulse
rate occur, reducing the rate of administration or temporarily halting
the injection usually allows the symptoms to disappear
promptly.
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| dailymed-instance:descripti... |
RECOMBINATE [Antihemophilic Factor (Recombinant)] is a glycoprotein
synthesized by a genetically engineered Chinese Hamster Ovary (CHO) cell
line.�� In culture, the CHO cell line secretes recombinant
Factor VIII (rFVIII) into the cell culture medium. The rFVIII is purified from
the culture medium utilizing a series of chromatography columns. A key step in
the purification process is an immunoaffinity chromatography methodology in
which a purification matrix, prepared by immobilization of a monoclonal
antibody directed to Factor VIII, is utilized to selectively isolate the rFVIII
in the medium. The synthesized rFVIII produced by the CHO cells has the same
biological effects as human Factor VIII. Structurally the protein has a similar
combination of heterogenous heavy and light chains as found in human Factor
VIII. RECOMBINATE is formulated as a sterile, nonpyrogenic, off-white to
faint yellow, lyophilized powder preparation of concentrated recombinant Factor
VIII for intravenous injection. RECOMBINATE is available in single-dose vials,
which contain nominally 250, 500 and 1000 International Units per
vial.�� When reconstituted with the appropriate volume of
diluent, the product contains the following stabilizers in maximum amounts:
12.5 mg/mL Albumin (Human), 0.20 mg/mL calcium, 1.5 mg/mL polyethylene glycol
(3350), 180 mEq/L sodium, 55 mM histidine, 1.5��g/Factor VIII International
Unit (IU) polysorbate-80.�� Recombinant Von Willebrand Factor
(rVWF) is coexpressed with the rFVIII and helps to stabilize it. The final
product contains not more than 2 ng rVWF/IU rFVIII, which will not have any
clinically relevant effect in patients with von Willebrand���s disease. The
product contains no preservative. Manufacturing of RECOMBINATE is shared by Baxter Healthcare Corporation
and Wyeth BioPharma. The recombinant Antihemophilic Factor Concentrate (For
Further Manufacturing Use), is produced by Baxter Healthcare Corporation and
Wyeth BioPharma (For Further Manufacturing Use) and subsequently formulated and
packaged at Baxter Healthcare Corporation. Each vial of RECOMBINATE is labeled with the Factor VIII activity
expressed in IU per vial. Biological potency is determined by an in vitro assay which is referenced to the
World Health Organization (WHO) International Standard for Factor VIII:C
Concentrate.
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Factor VIII is the specific clotting factor deficient in patients with
hemophilia A (classical hemophilia).�� Hemophilia A is a
genetic bleeding disorder characterized by hemorrhages, which may occur
spontaneously or after minor trauma. The administration of RECOMBINATE provides
an increase in plasma levels of Factor VIII and can temporarily correct the
coagulation defect in these patients. Pharmacokinetic studies on sixty-nine
(69) patients revealed the circulating mean half-life for RECOMBINATE to be
14.6 �� 4.9 hours (n=67), which was not statistically significantly different
from plasma-derived HEMOFIL M,
[Antihemophilic Factor (Human), Method M, Monoclonal
Purified]. The mean half-life of HEMOFIL M was 14.7�� 5.1 hours (n=61). The actual baseline recovery
observed with RECOMBINATE was 123.9 �� 47.7 IU/dL (n=23), which is significantly
higher than the actual HEMOFIL M baseline
recovery of 101.7 �� 31.6 IU/dL (n=61). However, the calculated ratio of actual
to expected recovery with���� RECOMBINATE (121.2 �� 48.9%) is
not different on average from HEMOFIL M
(123.4 �� 16.4%). The clinical study of�� RECOMBINATE in previously
treated patients (individuals with hemophilia A who had been treated with
plasma derived Factor VIII) was based on observations made on a study group of
69 patients. These individuals received cumulative amounts of Factor VIII
ranging from 20,914 to 1,383,063 IU over the48 month study. Patients were
given a total of 17,700 infusions totaling 28,090,769 IU RECOMBINATE. These patients were successfully treated for bleeding episodes on a
demand basis and also for the prevention of bleeds (prophylaxis). Spontaneous
bleeding episodes successfully managed include hemarthroses, soft tissue and
muscle bleeds. Management of hemostasis was also evaluated in surgeries. A
total of 24 procedures on 13 patients were performed during this study. These
included minor (e.g. tooth extraction) and major (e.g. bilateral osteotomies,
thoracotomy and liver transplant) procedures. Hemostasis was maintained
perioperatively and postoperatively with individualized Factor VIII
replacement. A study of RECOMBINATE in previously untreated patients was also
performed as part of an ongoing study. The study group was comprised of
seventy-nine (79) patients, of whom seventy-six (76) had received at least one
infusion of RECOMBINATE. To date, this cohort has been given 12,209 infusions
totaling over 11,277,043 IU of RECOMBINATE.�� Hemostasis was
appropriately managed in spontaneous bleeding episodes, intracranial hemorrhage
and surgical procedures.
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Known hypersensitivity to mouse, hamster or bovine protein may be a
contraindication to the use of RECOMBINATE (see Precautions).
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RECOMBINATE is available in three different strengths in single-dose
vials.�� The strength is designated on the outer box and
on the vial label using the following color codes: Light blue bar:���� ������ For low
potencies between 220-400 IU per vial (NDC 0944-2831-10)Light pink bar:���� ������ For medium potencies
between 401-800 IU per vial (NDC 0944-2832-10)Light green bar:������ �� For high potencies between 801-1240 IU per
vial (NDC 0944-2833-10) RECOMBINATE is packaged with 10 mL of Sterile Water for Injection, USP,
a BAXJECT II Needleless Transfer Device, one physician
insert and one patient insert.
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| dailymed-instance:precautio... |
General: Certain components used in the
packaging of this product contain natural rubber latex. Identification of the clotting defect
as a Factor VIII deficiency is essential before the administration of
RECOMBINATE [Antihemophilic Factor (Recombinant)] is initiated.
No benefit may be expected from this product in treating other
deficiencies. The formation of neutralizing antibodies, inhibitors to Factor
VIII, is a known complication in the management of individuals with
hemophilia A. The reported prevalence of these antibodies in patients
receiving plasma-derived Factor VIII is 10-20%..�� These inhibitors are invariably IgG
immunoglobulins, the Factor VIII procoagulant inhibitory activity of
which is expressed as Bethesda Units (B.U.) per mL of plasma or
serum.Over the investigational period, none of the 69
previously treated individuals, without an inhibitor at entry into the
study, developed an inhibitor. In the previously untreated patient group
there were 73 eligible patients with Factor VIII levels less than or
equal to 2% who received at least one RECOMBINATE treatment (median days
100, range 3-821) and who were tested for an inhibitor after treatment
with RECOMBINATE. Of this group, 23 individuals developed a detectable
inhibitor (median days 10, range 3-69) and of these, 8 patients showed a
titer greater than 10 B.U. Patients treated with Factor VIII should be
carefully monitored for the development of antibodies toFactor VIII by
appropriate clinical observations and laboratory tests.<br/>Formation of Antibodies to Mouse, Hamster or Bovine Protein: As RECOMBINATE contains trace amounts of mouse protein (maximum
of 0.1 ng/IU RECOMBINATE), hamster protein (maximum of 1.5 ng CHO
protein/IU RECOMBINATE), and bovine protein (maximum of 1 ng BSA/IU
RECOMBINATE), the remote possibility exists that patients treated with
this product may develop hypersensitivity to these non-human mammalian
proteins.<br/>INFORMATION FOR PATIENTS: The patients and physician should discuss the risks and benefits
of this product. Allergic type hypersensitivity reactions have been observed with
RECOMBINATE.�� Patients should be informed of the
early signs of hypersensitivity reactions including hives, generalized
urticaria, tightness of the chest, wheezing, hypotension, and
anaphylaxis. Patients should be advised to discontinue use of the product
and contact their physician if these symptoms occur.<br/>LABORATORY TESTS: Although dosage can be estimated by the calculations that
follow, it is strongly recommended that whenever possible, appropriate
laboratory tests be performed on the patient���s plasma at suitable
intervals to assure that adequate Factor VIII levels have been reached
and are maintained. If the patient���s plasma Factor
VIII fails to reach expected levels or if bleeding is not controlled
after adequate dosage, the presence of inhibitor should be suspected. By
performing appropriate laboratory procedures, the presence of an
inhibitor can be demonstrated and quantified in terms of Factor VIII
International Units neutralized by each mL of plasma or by the total
estimated plasma volume. If the inhibitor is present at levels less than
10 Bethesda Units per mL, administration of additional Factor VIII may
neutralize the inhibitor. Thereafter, the administration of additional
Factor VIII International Units should elicit the predicted response. The
control of Factor VIII levels by laboratory assay is necessary in this
situation.<br/>CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT of FERTILITY: RECOMBINATE was tested for mutagenicity at doses considerably
exceeding plasma concentrations of Factor VIII in vitro and at doses up to ten times
the expected maximum clinical dose in
vivo, and did not cause reverse mutations, chromosomal
aberrations, or an increase in micronuclei in bone marrow polychromatic
erythrocytes. Long-term studies in animals have not been performed to
evaluate carcinogenic potential.<br/>PEDIATRIC USE: RECOMBINATE is appropriate for use in children of all ages,
including the newborn. Safety and efficacy studies have been performed in
both previously treated (n=23) and previously untreated (n=75) children.��
(See Clinical Pharmacology and
Precautions).<br/>PREGNANCY:
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Antihemophilic Factor, Human Recombinant
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Dilatrate-SR (Capsule, Extended Release)
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| dailymed-instance:adverseRe... |
During the clinical studies conducted in the previously treated patient
group, there were 13 infusion related minor adverse reactions reported out of
10,446 infusions (0.12%).�� One patient experienced flushing and nausea during
his first infusion, which abated on decreasing the infusion rate.�� A second
patient experienced mild fatigue during and following one infusion and a third
patient had a series of eleven bleeds with a periodicity associated with the
infusions. The protein in greatest concentration in RECOMBINATE is Albumin
(Human).�� Reactions associated with intravenous administration of albumin are
extremely rare, although nausea, fever, chills or urticaria have been
reported.�� Other allergic reactions could be encountered in the use of this
Factor VIII preparation.�� (See Information for
Patients).
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None
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| dailymed-instance:indicatio... |
The use of RECOMBINATE [Antihemophilic Factor (Recombinant)] is
indicated in hemophilia A (classical hemophilia) for the prevention and control
of hemorrhagic episodes.RECOMBINATE is also indicated in the
perioperative management of patients with hemophilia A (classical hemophilia). RECOMBINATE can be of therapeutic value in patients with acquired
Factor VIII inhibitors not exceeding 10 Bethesda Units per
mL.�� In clinical studies with RECOMBINATE,
patients with inhibitors who were entered into the previously treated patient
trial and those previously untreated children who have developed inhibitor
activity on study, showed clinical hemostatic response when the titer of
inhibitor was less than 10 Bethesda Units per mL. However, in such uses, the
dosage of RECOMBINATE should be controlled by frequent laboratory
determinations of circulating Factor VIII levels. RECOMBINATE is not indicated in von Willebrand���s disease.
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Dilatrate-SR
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