Written in Blood
developed early grade ≥2 transaminitis (after 28 days of idelalisib
therapy), a second group of patients
(n=4) developed a delayed grade
≥1 hepatotoxicity (around day 130
of treatment). A third group of
patients did not experience hepatotoxicity but discontinued idelalisib
due to other adverse events (AEs),
including colitis and rash.
Immunosuppression with
steroids was an effective treatment
AMICAR® (aminocaproic acid) Oral Solution and Tablets
Rx only
DESCRIPTION
AMICAR (aminocaproic acid) is 6-aminohexanoic acid, which acts
as an inhibitor of fibrinolysis.
Its chemical structure is:
H 2 C(CH 2 ) 3 CH 2 COOH
|
NH 2
C 6 H 13 NO 2 M.W. 131.17
AMICAR is soluble in water, acid, and alkaline solutions; it
is sparingly soluble in methanol and practically insoluble in
chloroform.
AMICAR (aminocaproic acid) Oral Solution for oral
administration, contains 0.25 g/mL of aminocaproic acid with
methylparaben 0.20%, propylparaben 0.05%, edetate disodium
0.30% as preservatives and the following inactive ingredients:
sodium saccharin, sorbitol solution, citric acid anhydrous,
natural and artificial raspberry flavor and an artificial bitterness
modifier.
Each AMICAR (aminocaproic acid) Tablet, for oral administration
contains 500 mg or 1000 mg of aminocaproic acid and the
following inactive ingredients: povidone, crospovidone, stearic
acid, and magnesium stearate.
CLINICAL PHARMACOLOGY
The fibrinolysis-inhibitory effects of AMICAR appear to be
exerted principally via inhibition of plasminogen activators and
to a lesser degree through antiplasmin activity.
In adult s, oral absorption appears to be a zero-order process
with an absorption rate of 5.2 g/hr. The mean lag time in
absorption is 10 minutes. After a single oral dose of 5 g,
absorption was complete (F=1). Mean ± SD peak plasma
concentrations (164 ± 28 mcg/mL) were reached within 1.2 ±
0.45 hours.
After oral administration, the apparent volume of distribution
was estimated to be 23.1 ± 6.6 L (mean ± SD). Correspondingly,
the volume of distribution after intravenous administration
has been reported to be 30.0 ± 8.2 L. After prolonged
administration, AMICAR has been found to distribute throughout
extravascular and intravascular compartments of the body,
penetrating human red blood cells as well as other tissue cells.
Renal excretion is the primary route of elimination. Sixty-five
percent of the dose is recovered in the urine as unchanged
drug and 11% of the dose appears as the metabolite adipic
acid. Renal clearance (116 mL/min) approximates endogenous
creatinine clearance. The total body clearance is 169 mL/min.
The terminal elimination half-life for AMICAR is approximately
2 hours.
INDICATIONS AND USAGE
AMICAR is useful in enhancing hemostasis when fibrinolysis
contributes to bleeding. In life-threatening situations,
transfusion of appropriate blood products and other emergency
measures may be required.
Fibrinolytic bleeding may frequently be associated with surgical
complications following heart surgery (with or without cardiac
bypass procedures) and portacaval shunt; hematological
disorders such as amegakaryocytic thrombocytopenia
(accompanying aplastic anemia); acute and life-threatening
abruptio placentae; hepatic cirrhosis; and neoplastic disease
such as carcinoma of the prostate, lung, stomach, and cervix.
Urinary fibrinolysis, usually a normal physiological phenomenon,
may contribute to excessive urinary tract fibrinolytic bleeding
associated with surgical hematuria (following prostatectomy
and nephrectomy) or nonsurgical hematuria (accompanying
polycystic or neoplastic diseases of the genitourinary system).
(See WARNlNGS.)
CONTRAINDICATIONS
AMICAR should not be used when there is evidence of an
active intravascular clotting process. When there is uncertainty
as to whether the cause of bleeding is primary fibrinolysis or
disseminated intravascular coagulation (DIC), this distinction
must be made before administering AMICAR.
The following tests can be applied to differentiate the two
conditions: Platelet count is usually decreased in DIC but
normal in primary fibrinolysis. Protamine paracoagulation test
is positive in DIC; a precipitate forms when protamine sulfate
is dropped into citrated plasma. The test is negative in the
presence of primary fibrinolysis. The euglobulin clot Iysis test is
abnormal in primary fibrinolysis but normal in DIC.
AMICAR must not be used in the presence of DIC without
concomitant heparin.
WARNINGS
In patients with upper urinary tract bleeding, AMICAR
administration has been known to cause intrarenal obstruction
in the form of glomerular capillary thrombosis or clots in the
renal pelvis and ureters. For this reason, AMICAR should not
be used in hematuria of upper urinary tract origin, unless the
possible benefits outweigh the risk.
Subendocardial hemorrhages have been observed in dogs
given intravenous infusions of 0.2 times the maximum human
therapeutic dose of AMICAR and in monkeys given 8 times the
maximum human therapeutic dose of AMICAR.
Fatty degeneration of the myocardium has been reported in
dogs given intravenous doses of AMICAR at 0.8 to 3.3 times
for transaminitis once it developed.
Twelve patients who developed
grade ≥2 transaminitis were rechallenged with idelalisib after it was
held for a median of 21 days (range
= 10-43 days); the incidence of
recurrent hepatotoxicity was lower
if patients were receiving steroids
at the time of reintroduction of the
study drug, the authors noted.
Fifty percent of patients experienced any type of grade 3 AE, and
the maximum human therapeutic dose and in monkeys given
intravenous doses of AMICAR at 6 times the maximum human
therapeutic dose.
Rarely, skeletal muscle weakness with necrosis of muscle fibers
has been reported following prolonged administration. Clinical
presentation may range from mild myalgias with weakness and
fatigue to a severe proximal myopathy with rhabdomyolysis,
myoglobinuria, and acute renal failure. Muscle enzymes, especially
creatine phosphokinase (CPK) are elevated. CPK levels should be
monitored in patients on long-term therapy. AMICAR administration
should be stopped if a rise in CPK is noted. Resolution follows
discontinuation of AMICAR; however, the syndrome may recur if
AMICAR is restarted.
The possibility of cardiac muscle damage should also be
considered when skeletal myopathy occurs. One case of cardiac
and hepatic lesions observed in man has been reported. The
patient received 2 g of aminocaproic acid every 6 hours for a
total dose of 26 g. Death was due to continued cerebrovascular
hemorrhage. Necrotic changes in the heart and liver were noted
at autopsy.
PRECAUTIONS
General
AMICAR inhibits both the action of plasminogen activators and
to a lesser degree, plasmin activity. The drug should NOT be
administered without a definite diagnosis and/or laboratory finding
indicative of hyperfibrinolysis (hyperplasminemia). Inhibition
of fibrinolysis by aminocaproic acid may theoretically result in
clotting or thrombosis. However, there is no definite evidence that
administration of aminocaproic acid has been responsible for the
few reported cases of intravascular clotting which followed this
treatment. Rather, it appears that such intravascular clotting was
most likely due to the patient’s preexisting clinical condition, e.g.,
the presence of DIC. It has been postulated that extravascular
clots formed in vivo may not undergo spontaneous Iysis as do
normal clots.
Reports have appeared in the literature of an increased
incidence of certain neurological deficits such as hydrocephalus,
cerebral ischemia, or cerebral vasospasm associated with the
use of antifibrinolytic agents in the treatment of subarachnoid
hemorrhage ( SAH). All of these events have also been described
as part of the natural course of SAH, or as a consequence of
diagnostic procedures such as angiography. Drug relatedness
remains unclear.
Aminocaproic acid should not be administered with Factor IX
Complex concentrates or Anti-Inhibitor Coagulant concentrates,
as the risk of thrombosis may be increased.
Laboratory Tests
The use of AMICAR should be accompanied by tests designed to
determine the amount of fibrinolysis present. There are presently
available: (a) general tests such as those for the determination of
the Iysis of a clot of blood or plasma; and (b) more specific tests
for the study of various phases of the fibrinolytic mechanisms.
These latter tests include both semiquantitative and quantitative
techniques for the determination of profibrinolysin, fibrinolysin,
and antifibrinolysin.
Drug Laboratory Test Interactions
Prolongation of the template bleeding time has been reported
during continuous intravenous infusion of AMICAR at dosages
exceeding 24 g/day. Platelet function studies in these patients
have not demonstrated any significant platelet dysfunction.
However, in vitro studies have shown that at high concentrations
(7.4 mMol/L or 0.97 mg/mL and greater) aminocaproic acid
inhibits ADP and collagen-induced platelet aggregation, the
release of ATP and serotonin, and the binding of fibrinogen to the
platelets in a concentration-response manner. Following a 10 g
bolus of AMICAR, transient peak plasma concentrations of 4.6
mMol/L or 0.60 mg/mL have been obtained. The concentration
of AMICAR necessary to maintain inhibition of fibrinolysis is
0.99 mMol/L or 0.13 mg/mL. Administration of a 5 g bolus
followed by 1 to 1.25 g/hr should achieve and sustain plasma
levels of 0.13 mg/mL.Thus, concentrations which have been
obtained in vivo clinically in patients with normal renal function
are considerably lower than the in vitro concentrations found to
induce abnormalities in platelet function tests. However, higher
plasma concentrations of AMICAR may occur in patients with
severe renal failure.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate the carcinogenic
potential of AMICAR and studies to evaluate its mutagenic
potential have not been conducted. Dietary administration of an
equivalent of the maximum human therapeutic dose of AMICAR
to rats of both sexes impaired fertility as evidenced by decreased
implantations, litter sizes and number of pups born.
Pregnancy
Pregnancy Category C. Animal reproduction studies have not
been conducted with AMICAR. It is also not known whether
AMICAR can cause fetal harm when administered to a pregnant
woman or can affect reproduction capacity. AMICAR should be
given to a pregnant woman only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should
be exercised when AMICAR is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been
established.
ADVERSE REACTIONS
AMICAR is generally well tolerated. The following adverse
experiences have been reported:
38 percent experienced any type
of grade 4 AE. No deaths were
recorded during follow-up.
Four patients tolerated idelalisib and remained on therapy for
more than a year without experiencing any known severe AEs
associated with the drug (transaminitis, pneumonitis, or colitis).
Younger patients also had a
higher risk of developing early hepatotoxicity: the median age of patients
General: Edema, headache, malaise.
Hypersensitivity Reactions: Allergic and anaphylactoid
reactions, anaphylaxis.
Cardiovascular: Bradycardia, hypotension, peripheral ischemia,
thrombosis.
Gastrointestinal: Abdominal pain, diarrhea, nausea, vomiting.
Hematologic: Agranulocytosis, coagulation disorder,
leukopenia, thrombocytopenia.
Musculoskeletal: CPK increased, muscle weakness, myalgia,
myopathy (see WARNINGS), myositis, rhabdomyolysis.
Neurologic: Confusion, convulsions, delirium, dizziness,
hallucinations, intracranial hypertension, stroke, syncope.
Respiratory: Dyspnea, nasal congestion, pulmonary embolism.
Skin: Pruritis, rash.
Special Senses: Tinnitus, vision decreased, watery eyes.
Urogenital: BUN increased renal failure. There have been
some reports of dry ejaculation during the period of AMICAR
treatment. These have been reported to date only in hemophilia
patients who received the drug after undergoing dental surgical
procedures. However, this symptom resolved in all patients
within 24 to 48 hours of completion of therapy.
OVERDOSAGE
A few cases of acute overdosage with AMICAR administered
intravenously have been reported. The effects have ranged from
no reaction to transient hypotension to severe acute renal failure
leading to death. One patient with a history of brain tumor
and seizures experienced seizures after receiving an 8 gram
bolus injection of AMICAR. The single dose of AMICAR causing
symptoms of overdosage or considered to be life-threatening is
unknown. Patients have tolerated doses as high as 100 grams
while acute renal failure has been reported following a dose of
12 grams.
The intravenous and oral LD50 of AMICAR were 3.0 and
12.0 g/kg, respectively, in the mouse and 3.2 and 16.4 g/kg,
respectively, in the rat. An intravenous infusion dose of 2.3 g/
kg was lethal in the dog. On intravenous administration, tonicclonic convulsions were observed in dogs and mice.
No treatment for overdosage is known, although evidence exists
that AMICAR is removed by hemodialysis and may be removed
by peritoneal dialysis. Pharmacokinetic studies have shown
that total body clearance of AMICAR is markedly decreased in
patients with severe renal failure.
DOSAGE AND ADMINISTRATION
An identical dosage regimen may be followed by administering
AMICAR Tablets or AMICAR Oral Solution as follows:
For the treatment of acute bleeding syndromes due to elevated
fibrinolytic activity, it is suggested that 5 AMICAR 1000 mg
Tablets or 10 AMICAR 500 mg Tablets (5 g) or 20 milliliters of
AMICAR Oral Solution (5 g) be administered during the fir st
hour of treatment, followed by a continuing rate of 1 AMICAR
1000 mg Tablet or 2 AMICAR 500 mg Tablets (1 g) or 5 milliliters
of AMICAR Oral Solution (1.25 g) per hour. This method of
treatment would ordinarily be continued for about 8 hours or
until the bleeding situation has been controlled.
HOW SUPPLIED:
AMICAR®
(aminocaproic acid)
AMICAR Oral Solution, 0.25 g/mL
Each mL of raspberry-flavored oral solution contains 0.25 g/mL
of aminocaproic acid.
8 Fl. Oz. (236.5 mL) Bottle – NDC 49411-052-08
Store at 20°-25°C (68°-77°F)[see USP Controlled Room
Temperature]; Dispense in Tight Containers; Do Not Freeze.
AMICAR 500 mg Tablets
Each round, white tablet, engraved with XP on one side and
scored on the other with A to the left of the score and 10 on the
right, contains 500 mg of aminocaproic acid.
Bottle of 30 – NDC 49411-050-30
Store at 20°-25°C (68°-77°F)[see USP Controlled Room
Temperature]; Dispense in Tight Containers; Do Not Freeze.
AMICAR 1000 mg Tablets
Each oblong, white tablet, engraved with XP on one side and
scored on the other with A to the left of the score and 20 on the
right, contains 1000 mg of aminocaproic acid.
Bottle of 30 – NDC 49411-051-30
Store at 20°-25°C (68°-77°F)[see USP Controlled Room
Temperature]; Dispense in Tight Containers; Do Not Freeze.
REFERENCE
1
Stefanini M, Dameshek W: The Hemorrhagic Disorders, Ed. 2,
New York, Grune and Stratton; 1962: 510-514.
Marketed by:
Marietta, GA 30062
Code 900B00
Rev. 05/15
who developed hepatotoxicity was
61 years, compared with 72 years
among those who did not (p=0.02).
In addition, all patients younger than
65 years required systemic steroids
for immune-mediated toxicities at
some point during the study.
IGHV mutation status was also
a predictor of hepatotoxicity: 75
percent of patients with IGHVmutated disease experienced early
hepatotoxicity, compared with 25
percent of those without the mutation (p=0.039).
In an effort to understand the
cause of the hepatotoxicity, the
researchers biopsied the liver of
two patients who developed severe
transaminitis and compared them
with specimens taken from a normal liver and the liver of an otherwise healthy CLL patient. Biopsies
from the CLL patients experiencing
idelalisib-associated transaminitis
revealed an increased infiltrate of
CD8+ cytotoxic T cells that also
stained positive for perforin, indicating an activated state.
“The association between
IGHV mutation status and early
hepatotoxicity may reflect a unique
interaction between mutated
IGHV neoplastic cells and T-cell
subsets,” Dr. Lampson and colleagues concluded. “Multiple lines
of evidence point to an autoimmune mechanism as the cause of
the hepatotoxicity seen. … A better understanding of the pathogenesis of these adverse events may
facilitate treatment or avoidance
of them.”
The authors also noted that
while the study’s manuscript was in
production, the drug’s manufacturer
closed seven randomized trials of
idelalisib in B-cell malignancies due
to infectious deaths that occurred in
excess. As other drugs in the class
are developed, they wrote, patients
will need to be closely monitored for
infection and transaminitis based on
the likely immune-mediated origin
of this toxicity.
The small patient population is
a limitation of the study, as is the
small number of samples available
for correlative studies. In addition,
the study focused on the characteristics of early hepatotoxicity,
and, therefore, may not be applicable to other toxicities that are
associated with idelalisib (including enterocolitis, pneumonitis, and
delayed hepatotoxicity occurring
around 130 days).
REFERENCE
Lampson BL, Kasar SN, Matos TR, et al. Idelalisib given
front-line for treatment of chronic lymphocytic leukemia
causes frequent immune-mediated hepatotoxicity. Blood.
2016 May 31. [Epub ahead of print]
August 2016