NICOUMALONE
PHARMACOLOGY : Nicoumalone [ACITROM] reduces the concentration of
prothrombin in blood and increases the prothrombin time by inhibiting the
formation of prothrombin in the liver. The drug also interferes with the
production of factors VII, IX, X, as well as protein C, and its cofactor Protein S so their concentration in the blood is lowered during therapy.
Coumarin derivatives are vitamin K antagonists. They inhibit the
GAMA-carboxylation of certain glutamic acid molecules which are located at several sites near the amino terminal end of vitamin K dependent coagulation factors.
Gama-carboxylation has a significant bearing on the interaction of the coagulation factors with calcium ions. Without this reaction, blood clotting cannot be initiated. Precisely how coumarin derivatives prevent vitamin K from bringing about y carboxylation of the glutamic acid molecules in the coagulation factors has not yet been determined.
Depending on the size of the initial dose, maximal effect on prothrombin time is
usually achieved within 36 to 48 hrs. Following a single therapeutic dose or
cessation of therapy, the prothrombin time usually returns to normal within
48hrs.
Nicoumalone [ACITROM] is rapidly absorbed by the oral route. At least 60% of
the dose is systemically available. Peak plasma concentrations are generally
attained within I to 3 hours of oral administration, with levels of 0.3 Β± 0.05
(micro gm /mL observed following a single 10 mg dose. The peak plasma
concentrations and the areas under the blood concentration time curve (AUC)
are proportional to the size of the dose over a range of 8 to 16 mg.
No correlation can be established between the plasma concentrations of
nicoumalone [ACITROM] and the apparent prothrombin level due to variation
in plasma concentrations among patients. At any given prothrombin level
patients over 70 years of age generally has higher plasma concentrations than
younger patients.
The bulk of nicoumalone [ACITROM] administered is found in the plasma
fraction of the blood. 98.7% of drug is bound to plasma proteins, notably to
albumin.
The calculated apparent volume of distribution of nicoumalone [ACITROM] is
0.16 to 0.18 L/Kg for the R(+) enantiomer and 0.22 to 0.34 L/Kg for the S (-)
enantiomer.
Nicoumalone [ACITROM] passes in to the breast milk but the quantities are too
small to be detected by the usual analytical methods. The drug also crosses the
placenta) barrier.
Nicoumalone [ACITROM] is extensively metabolised. At least two primary
pathways are involved.
Oxidation of nicoumalone [ACITROM] results in 2 hydroxy metabolites.
Reduction of the Keto group on nicoumalone [ACITROM] forms 2 different
alcohol metabolites. A major portion of the amino metabolite, produced by
reduction of the nitro group, is further transformed to the corresponding
acetamido metabolite. An additional unidentified strongly polar metabolite
fraction was also noted. These metabolites appear to be pharmacologically
inactive in the man.
Nicoumalone [ACITROM] is eliminated from the plasma with a half-life of 8-11
hrs. Only 0.1 % to 0.3% of the dose is excreted unchanged in the urine. Over a
period of one week, the cumulative excretion of metabolites and unchanged
active substance in the urine and feces is 60% and 29% of the dose
respectively.
INDICATIONS : The prophylaxis and treatment of venous thrombosis and its
extension, the treatment of atrial fibrillation with embolization, the prophylaxis
and treatment of pulmonary embolism and as an adjunct in the treatment of
coronary occlusion and transient cerebral ischemic attacks.
CONTRAINDICATIONS : Nicoumalone [ACITROM] is contraindicated in all
pathological states in which the risk of hemorrhage is greater than the possible
clinical benefits, e.g., hemorrhagic blood diathesis and /or blood dyscrasias.
Recent or contemplated surgery of CNS or eye; traumatic surgery resulting in
large open surfaces. Bleeding tendencies associated with active ulceration or
overt bleeding of gastrointestinal, genitourinary or respiratory tracts;
cerebrovascular hemorrhage; aneurysms: cerebral, dissecting aorta;
pericarditis and pericardial effusions; subacute bacterial endocarditis.
Threatened abortion, eclampsia and preeclampsia. Severe hypertension.
Severe parenchymal lesions of the liver and kidneys. Increased fibrinolytic
activity as encountered after operations on the lung, prostate, uterus, etc.
Known hypersensitivity to nicoumalone [ACITROM] and related coumarin
derivatives. 1.M. injections (see Precautions/Warnings). Inadequate laboratory
facilities or lack of patient cooperation (e.g., unsupervised and senile patients,
alcoholics and patients with psychiatric disorders).
PREGNANCY: Nicoumalone [ACITROM] passes through the placental barrier,
and the danger of hemorrhage to the fetus exists to the point of fatal hemorrhage
in utero, even within the accepted therapeutic range of maternal prothrombin
level. There have been reports of birth malformation in children born to
mothers who have been treated with coumarin anticoagulants during the first
trimester of pregnancy. Therefore, nicoumalone [ACITROM] must not be
employed during pregnancy. In women of childbearing age, contraceptive
measures are necesssary during treatment. If the patient becomes pregnant
while taking this drug, she should be apprised of the potential risks to fetus. The
possibility of termination of the pregnancy should be discussed in light of those
risks.
LACTATION : Nicoumalone [ACITROM] passes into the breast milk, but in
quantities so small that no undesirable effects on the infant are to be expected.
As a precaution, however, it is recommended that the infant be given 1 mg of
vitamin K1 per week for prophylactic purposes. Clinical monitoring of the
infant for signs of prothrombin abnormalities is also advised.
MISCELLANEOUS : polyarthritis, ascorbic acid deficiency, major regional
block anesthesia.
PRECAUTIONS : Nicoumalone [ACITROM] is a potent drug and it effects tend
to be cumulative and prolonged. At the earliest sign of bleeding the drug should
be withdrawn.
Treatment of each patient is a highly individualized matter. Dosage can be
controlled only by periodic determination of prothrombin time or other
suitable coagulation test (see Dosage). Determinations of clotting and bleeding
times are not effective measures for control of therapy. It is recommended that
the blood samples for laboratory tests always be taken at the same time of the
day.
Since heparin prolongs the one stage prothrombin time when it is given with
nicoumalone [ACITROM], a period of from 4 to 5 hours after the last i.v. dose
and 12 to 24 hours after the last s/c. dose of heparin should elapse before blood
is drawn, if a valid prothrombin time is to be obtained.
Elderly patients on anticoagulant medication should be monitored with special
care.
Experience with oral anticoagulants, including nicoumalone [ACITROM] in
children remains limited. Caution, and more frequent monitoring of
prothrombin time and I NR are recommended.
Factors which increase or decrease the absorption, storage or utilization of
vitamin K may interfere with anticoagulant dosage. It is important that the diet
not only be adequate but stable from day to day in order to regulate the dosage.
Caution should be used in patients with hepatic dysfunction since the
production of coagulation factors and detoxification of oral anticoagulants can
be affected by diseases of the liver. 2
Patients with impaired renal function do not appear to be subject to unusual
risks. However, caution should be exercised in view of the possibility of a
compromised state of platelet-medicated hemostasis.
Nicoumalone [ACITROM] may show greater activity in certain conditions or
diseases due to reduced protein binding (e.g., thyrotoxicosis, tumors, renal
diseases, infections and inflammation). Strict medical supervision is necessary
in these situations.
Diagnostic or therapeutic interventions (e.g., angiography, lumbar puncture,
minor surgery, tooth extractions, etc.) may require the shortening of
thromboplastin time. This should be done with meticulous care.
During treatment with anticoagulants, i.m. injections may cause hematomas
and are therefore contraindicated. There is no evidence that s.c. or i.v.
injections lead to such complications.
Out-patients should be advised to carry an oral anticoagulant card so that
appropriate actions can be taken i n the event of injuries or accidents.
abrupt cessation of anticoagulant therapy is generally not recommended; taper
dose gradually over 3 to 4 weeks.
administration of anticoagulants in the following conditions will be based
upon clinical judgement in which the risk of hemorrhage due to
anticoagulants is weighed against the risk of thrombosis or embolism in
untreated cases: prolonged dietary deficiency (cachexia, vitamin K); moderate
to severe hepatic or renal insufficiency (see also Contraindications); infectious
diseases or disturbances of intestinal flora (sprue, antibiotic therapy); severe
trauma of head, bones or muscles associated with extreme raw surfaces;
indwelling catheters; spinal punctures; moderate to severe hypertension (see
also Contraindications); miscellaneous: polycythemia vera; vasculitis; severe
diabetes; menometrorrhagia; severe allergic and anaphylactic disorders.
The following factors, alone or in combination, may be responsible for
increased prothrombin time response:
Endogenous : hepatic disorders; vitamin K deficiency (hypoprothrombinemia)
of obstructive jaundice, steatorrhea and infectious hepatitis; poor nutritional
state; diarrhea; elevated temperature; congestive heart failure, carcinoma;
collagen disease.
Exogenous : drug interactions ; carbon tetrachloride; alcohol; dietary
deficiencies in protein, ascorbic acid, choline or cystine; narcotics with
prolonged use; drugs affecting the blood elements; hepatotoxic drugs;
anesthetics; prolonged hot weather, anticoagulant overdosage; unreliable
prothrombin determinations.
The following factors, alone or in combination, may be responsible for
decreased prothrombin time response:
Endogenous : edema; hyperlipemia; diabetes mellitus; hereditary resistance to
coumarin therapy, hypothyroidism.
Exogenous: drug interactions; vitamin K in polyvitamin preparations; diet high
in vitamin K; anticoagulant underdosage; unreliable prothrombin
determinations.
N.B. : A patient may be exposed to a combination of the above factors, some of
which may increase and some decrease his sensitivity to nicoumalone
[ACITROM]. Because the net effect on his prothrombin time response may be
unpredictable under these circumstances, more frequent laboratory monitoring
is advisable.
PRECLINICAL SAFETY DATA:
Toxicity: After a single (acute) oral and/or i.v. dose, nicoumalone [ACITROM]
showed a low degree of toxicity in mice, rats, and rabbits. The dog showed
moderate toxicity. In repeated dose studies, the liver is suggested to be the main
target organ in the toxicity of coumarin derivatives including nicoumalone
[ACITROM]. The administration of these substances at excessive
pharmacological doses can cause haemorrhages.
Teratogenicity : Placental and transplacental interference with vitamin - K
dependent coagulation factors may give rise to embryonic or fetal anomalies,
and neonatal hemorrhages both in animals and in humans.
Mutagenicity: From investigations on bacterial and mammalian cell systems in
vitro, including a DNA repair assay on rat hepatocytes, it can be concluded that
nicoumalone [ACITROM] and /or its metabolite did not exert any mutagenic
effects. An in vitro study on human lymphocytes has shown some mild
mutagenic activity. However, in this experiment, the effective concentrations of
nicoumalone [ACITROM], >188 and >250 ng/mL ( with and without metabolic
activation, respectively), were 500 to 1000 times higher than concentrations
determined in human plasma after medication with nicoumalone [ACITROM].
Carcinogenicity : No lifetime - exposure studies were carried out in animals
with nicoumalone [ACITROM]. Coumarin, at doses clearly exceeding the
maximum tolerated dose ( MTD ), induced an increase in the incidence of liver
tumors in rats, without impact on survival. No such finding was recorded for
mice. The induction of hepatoma seen in rats with anticoagulants of the
coumarin class is not likely to indicate an increased carcinogenic risk in
humans. Hepatotoxicity of coumarin and its derivatives in the rat is understood
to be associated with enzyme induction, and the metabolic pathway of
coumarin and/or its metabolites peculiar to this rodent species.
DRUG INTERACTIONS : Coumarin anticoagulants have been involved in a
number of serious adverse drug interactions. Important mechanisms associated
with these interactions include disturbances of absorption, reduced availability
of vitamin K necessary for y - carboxylation of prothrombin-complex factors,
inhibition or induction of metabolizing enzymes and interference with plasma
protein binding. The anticoagulant effects may be increased or decreased by
drug interactions. It is therefore essential to monitor the patient's response with
additional prothrombin time determinations (e.g. Twice weekly), and adjust
dosage of nicoumalone [ACITROM] appropriately, whenever other
medications are initiated, discontinued or taken haphazardly.
The anticoagulant effect may be potentiated by concurrent treatment with the
following drugs (increased prothrombin time) : acetaminophen, allopurinol,
anabolic steroids, androgens, antiarrhythmic agents (e.g. Amiodarone,
quinidine), antibiotics (e.g., erythromycin, tetracyclines, neomycin,
chloramphenicol), chloral hydrate*, clofibric acid as well as its derivatives and
structural analogues, diazoxide, disulfiram, ethacrynic acid, glucagon,
histamine H2-receptor antagonists (e.g., cimetidine), imidazole derivatives
(e.g., metronidazole and, even when administered locally, miconazole),
mefenamic acid, mercaptopurine, MAO inhibitors, nalidixic acid, oral
hypoglycemics (e.g., tolbutamide), phenyramidol, quinine, sulfonamides
(including co-trimoxazole), sulfinpyrazone, thyroid hormone (including
dextrothyroxine).
* Increased and decreased prothrombin time responses have been reported.
During treatment with drugs, which affect hemostasis, the anticoagulant effect
may be potentiated, thereby increasing the risk of gastrointestinal hemorrhage.
Chief among these drugs are heparin and platelet-aggregation inhibitors such
as salicylic acid and its derivatives (e.g. ASA, paraaminosalicylic acid or PAS,
diflunisal ) and phenylbutazone or other pyrazolone derivatives (e.g.,
sulfinpyrazone). Use of nicoumalone [ACITROM] together with these
substances is therefore highly unadvisable.
Increased risk of hemorrhage has been reported with the combined use of oral
anticoagulants and nonsteroidal anti-inflammatory agents. It is therefore
recommended that more frequent coagulation tests be performed.
The anticoagulant effect may be diminished by concurrent treatment with the
following drugs (decreased prothrombin time) : aminoglutethimide,
barbiturates, carbamazepine, cholestyramine, corticosteriods, diuretics*,
griseofulvin, meprobamate, oral contraceptives, rifampin.
* Increased and decreased prothrombin time responses have been reported.
Cholestyramine reduces intestinal absorption, notably by interrupting the
enterohepatic circulation; for this reason, it can be recommended as treatment
for overdosage of a coumarin derivative.
A two way interaction between nicoumalone [ACITROM] and phenytoin has
been suggested. Phenytoin has been reported to decrease the serum
concentrations of nicoumalone and to increase the plasma prothrombin-
proconvertin concentrations. Presumably, phenytoin acts as a stimulator of
nicoumalone [ACITROM] metabolism. Conversely, nicoumalone [ACITROM]
has been reported to increase the serum concentrations and prolong the serum
half-life of phenytoin by inhibiting its metabolism. Patients receiving
nicoumalone [ACITROM] and phenytoin concurrently should be closely
observed for signs of phenytoin toxicity. Frequent monitoring of the
prothrombin time is also essential. Other hydantoin anticonvulsants may
interact with nicoumalone [ACITROM] in a manner similarto that of phenytoin.
During concomitant treatment with sulfonylurea derivatives, their
hypoglycemic effect may be potentiated.
Since neither the severity nor the early signs of interactions can be predicted,
patients taking nicoumalone [ACITROM], especially if they suffer from hepatic
dysfunction, should refrain from consuming alcohol.
ADVERSE EFFECTS : Depending on the intensity of therapy, the patient's age
and nature of the underlying disease, the complications most frequently with
anticoagulants have been hemorrhages at various site. Prospective studies give
no indication that the incidence of bleeding depends on duration of treatment.
If hemorrhage occurs in a patient whose thromboplastin time is within the
therapeutic range, the case must be clarified diagnostically ( in view such
possibilities as ulceration, tumor and congenital coagulation disorders ).
Predilection sites of hemorrhage include the gastrointestinal tract (melena), the
brain, the urogenital tract ( macroscopic and microscopic hematuria ), the
uterus (metrorrhagia and menorrhagia),the liver and gall bladder (hematobilia),
and the eye. Usually, hemorrhage is evident but the possibility of intestinal
hemorrhage must be considered when a patient has abdominal symptoms.
Gastrointestinal disorders (loss of appetite, nausea, diarrhea, vomiting), allergic
reactions (urticaria, dermatitis and fever) and reversible loss of hair (alopecia)
have rarely been noted with similar coumarin derivatives.
Isolated cases of hemorrhagic skin necrosis have been reported, even when the
prothrombin time was within apparently safe limits. The adverse reaction is
usually associated with congenital protein C deficiency. Isolated cases of liver
damage have also occurred.
OVERDOSE: The patient's individual sensitivity to oral anticoagulants, the size
of the overdosage and the duration of anticoagulant administration have a
decisive bearing on the onset and severity of the effects.
Hemorrhages in the region of various organs are the most prominent clinical
feature. Depending on the size of the dose and the patient's reaction to it,
hemorrhages set in 1 to 5 days after ingestion. Effects of overdosage may take
the form of nose-bleed, hematemesis, hemoptysis, gastrointestinal
hemorrhage, vaginal bleeding, hematuria (with renal colic), cutaneous
hemorrhage, bleeding into the joints and menorrhagia.
Tachycardia, hypotension, and peripheral circulatory disorders due to loss of
blood, as well as nausea, vomiting, diarrhea, and colicky pains in the abdomen
are further signs and symptoms of poisoning.
Laboratory tests reveal an extremely low Quick value (or high INR value),
pronounced prolongation of the recalcification time or thromboplastin time
and disturbed y-carboxylation of factors, II, VII, IX, X.
TREATMENT : Antidote : Phytomenadione (vitamin K1) is capable of
counteracting, within 3 to 5 hours, the inhibitory effect of nicoumalone
[ACITROM] on hepatic y - carboxylation of the vitamin K-dependent
coagulation factors.
If at the time of taking a single overdose the patient's thromboplastin time is
normal, the drug can be partly eliminated by inducing vomiting or gastric
lavage. Administration of activated charcoal or a rapid-acting laxative may also
prevent or reduce absorption of the ingested anticoagulant. Cholestyramine
may increase the drug's elimination.
In the event of clinically insignificant hemorrhages, such as brief nose-bleed or small isolated hematomas, a temporary reduction of the nose of nicoumalone
[ACITROM] is often sufficient.
In cases of mild to severe hemorrhage administer 1 to lO mg vitamin K1 by slow
i.v. infusion ( rate not to exceed l mg/minute ). Vitamin K1 should not be
injected i.m. Additional doses ( up to a maximum of 40mg daily ) should be
administered at 4 hour intervals. It should be noted that doses in excess of 5mg
can cause resistance to oral anticoagulants lasting several days. Should an
anticoagulant prove necessary heparin may be employed as a temporary
measure while resuming oral anticoagulant therapy. Heparin should be
subsequently withdrawn when the therapeutic range has been reached.
Only rarely is whole blood needed. If life-threatening hemorrhage has
occurred, the effect of treatment with nicoumalone [ACITROM] can be
abolished by i.v. infusion of deep-frozen plasma concentrates or fresh whole
blood in order to substitute for the missing coagulation factors 11, VI I, IX and X.
DOSAGE AND ADMINISTRATION : Sensitivity to anticoagulants varies from
patient to patient and may also fluctuate in the course of treatment. It is
therefore essential to carry out regular coagulation tests in adequate facilities for standardized laboratory control and to adapt the dosage accordingly. If this is not possible, nicoumalone [ACITROM] should not be used.
The daily dose should be prescribed as a single dose and always taken at the
same time of day.
Initial Dose: First Day: 8 to 12mg. Second Day: 4 to 8mg. If the thromboplastin
time is initially abnormal, treatment must be commenced with great caution.
Maintenance Therapy and Coagulation Tests: In view of the marked individual
differences encountered, the maintenance dose should be established and
adjusted by reference to the results of periodically performed laboratory tests to
determine the patient's blood coagulation time. The Quick value (or INR value)
should be carefully maintained within the therapeutic range. Such values
should be determined daily from the beginning of treatment until the
maintenance dose is established, then repeated at regular intervals (e.g., Once a
month), so that possible fluctuations outside the therapeutic range can be
avoided. Depending on the Quick value (or INR value), as well as on the
individual patient and nature of the disease, the maintenance dose is usually
between 1 to 8mg daily.
As a routine test procedure, measurement of thromboplastin time yields good
results. For the purpose of standardization, an "International Normalized Ratio"
(INR) has been introduced. International comparability is made possible with
help of calibrated thromboplastins. An International Sensitivity Index value is
determined for the reference thromboplastin time and the normal
thromboplastin time is raised to the power of the specified International
Sensitivity Index value of the reference thromboplastin. As the Quick value
decreases, the thromboplastin time for the patient's blood increases; thus the
INR value increases.
After the withdrawal of nicoumalone [ACITROM], there is generally no danger
of reactive hypercoagulability. It has been found, that in extremely rare cases
and in certain high risk patients (after myocardial infarction) rebound
hypercoagulability may occur. In such patients, withdrawal of anticoagulant
therapy should be gradual.
PRESENTATION : Acitrom, brand of Nicoumalone tablets of 1 mg, 2 mg, 4 mg
i n strips of 10.