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Strokan
COMPOSITION
Each tablet contains Ticlopidine
Hydrochloride 250 mg
DESCRIPTION
STROKAN TABLET is a 9mm round
tablet with marking "d/d" and pink in colour
ACTION AND MODE OR MECHANISMS OF ACTION
Ticlopidine HCI is an inhibitor
of platelet aggregation. When taken orally it causes a time and
dosedependent inhibition of platelet aggregation and release of platelet
factors, as well as a prolongation of bleeding time. The drug has no
significant in vitro activity. The exact mechanism of action is not fully
characterised, but does not involve inhibition of the prostacyclin/thromboxane
pathways. Platelet cyclic AMP does not seem to play a role in the mechanism
of action of Ticlopidine HCI. Ticlopidine HCI interferes with platelet
membrane function by inhibiting ADP induced platelet-fibrinogen binding and
subsequent platelet-platelet interactions. The effect of Ticlopidine HCI on
platelet function is irreversible as shown both by inhibition of fibrinogen
binding after washing and by inhibition of platelet aggregation after
resuspension of platelets in buffered medium. Although it is unclear how
ticlopidine brings about these changes, a suggested mechanism is that it
inhibits ADP-induced exposure of the fibrinogen binding site of the
glycoprotein IIb-IIIa complex.
PHARMACOLOGY
Inhibition of platelet
aggregation is detected within 4 days of administration of a dosage regimen
of 250 mg twice daily. Maximum platelet aggregation inhibition (60 to 70%)
is achieved 8 to 11 days following dosing with 250 mg twice daily. At the
therapeutic dose. ADP-induced platelet aggregation is inhibited by 50 to
70%. Lower total daily doses of 375 mg and 250 mg result in 30 to 60% and 25
to 50% inhibition of platelet aggregation respectively. Template bleeding
time is usually prolonged by two to five-fold of baseline values with the
therapeutic dose of Ticlopidine HCI. Upon discontinuation of Ticlopidine HCI
dosing, bleeding time and other platelet function tests return to normal
within two weeks in the majority of patients. At the recommended therapeutic
doses, Ticlopidine HCI has no known significant pharmacological actions in
man other than inhibition of platelet function.
PHARMACOKINETICS
After oral administration of the
therapeutic dose of Ticlopidine HCI, rapid absorption occurs, with peak
plasma levels occurring at approximately 2 hours after dosing. Absorption is
at least 80% in plasma. Administration of Ticlopidine HCI after meals
results in an increased (20%) level of ticlopidine in plasma. Ticlopidine
hydrochloride displays non-linear pharmacokinetics and clearance decreases
markedly on repeated dosing. In older volunteers the apparent half-life of
ticlopidine after a single 250 mg dose is about 12.6 hours, with repeat
dosing at 250 mg twice daily, the terminal elimination half-life rises to 4
to 5 days and steady state levels of ticlopidine hydrochloride in plasma are
obtained after approximately 14 to 21 days. Ticlopidine binds reversibly
(98%) to plasma proteins, mainly to serum albumins and lipoproteins. The
binding to albumin and lipoproteins is non-saturable over a wide
concentration range. Ticlopidine also binds in a saturable manner to alpha-1
acid glycoprotein At concentrations attained with the recommended dose, only
15% or less ticlopidine is detected in the urine. Following an oral dose of
radioactive ticlopidine hydrochloride administered in solution, 60% of the
radioactivity was recovered in the urine and 23% in the faeces.
Unmetabolised ticlopidine is a minor component in plasma after a single
dose, but at steady state, ticlopidine is the major component. Approximately
40 to 50% of the radioactive metabolites circulating in plasma are
covalently bound to plasma proteins. Clearance of ticlopidine decreases with
age. Steady state trough values in elderly patients (mean age 70 years) are
about twice those in young volunteer populations.
Hepatically impaired patients:
Ticlopidine HCI has been studied in patients with varying degrees of liver
function abnormalities Impaired hepatic function resulted in higher than
normal levels of unchanged ticlopidine following single or multiple doses.
Renally Impaired patients: Patients with mildly (Ccr to to 80 mL/min)
or moderately (Ccr 20 to 50 mL/min) impaired renal function were compared to
normal subjects (Ccr 80 to 150 mL/min) in a study of the pharmacokinetic and
platelet pharmacodymic effects of Ticlopidine HCI (250 mg twice daily) for
11 days. Concentrations of unchanged Ticlopidine HCI were, measured after a
single 250 mg dose and after the final 250 mg dose on Day 11. AUC values of
Ticlopidine increased by 28 and 60% in mild and moderately impaired patients
respectively and plasma clearance decreased by 37 and 52% respectively, but
there were no statistically significant differences in ADP-induced platelet
aggregation. In this small study (26 patients) bleeding times showed
significant prolongation only in the moderately impaired patients.
INDICATIONS
Indicated for the following :-
Maintenance of patency of coronary artery by-pass grafts. Maintenance of
patency of access sites in patients on chronic haemodialysis. Reducing risk
of thrombotic stroke (fatal or non-fatal) in patients who have experienced
stroke precursors and in patients who have had a completed stroke.
CONTRAINDICATIONS
Ticlopidine is contraindicated in
the following cases :
Hypersensitivity to the drug or its excipients.
Presence of haematopoietic disorders such as neutropenia, agranulocytosis
and thrombocytopenia.
Presence of haemostatic disorder or of active pathological bleeding (eg.
bleeding peptic ulcer or intracranial bleeding).
Patients with severe liver
impairment or cholestatic jaundice. Elderly patients (>65 years) with
hepatic impairment.
Patients with renal disease on
haemodialysis.
SIDE EFFECTS/ADVERSE REACTIONS
Adverse reactions were relatively
frequent, with over 50% of patients reporting at least one. Most (30 to 40%)
involved the gastrointestinal tract. Most adverse effects were mild, but 21
% of patients discontinued therapy because of an adverse event, principally
diarrhoea, rash, nausea, vomiting G.I. pain, and neutropenia. Most adverse
effects occur early in the course of treatment but a new onset of adverse
effects can occur after several months.
Gastrointestinal: Ticlopidine HCI therapy has been associated with a
variety of gastrointestinal complaints including diarrhoea and nausea. The
majority of cases are mild, but about 13% of patients discontinued therapy
because of these. They usually occur within 3 months of initiation of
therapy and typically are resolved within 1 to 2 weeks without
discontinuation of therapy. If the effect is severe or persistent therapy
should be discontinued.
Haemorrhagic: Ticlopidine
HCI has been associated with a number of bleeding complications such as
ecchymosis, epistaxis, haematuria, conjunctival haemorrhage,
gastrointestinal bleeding, and perioperative bleeding. Intracerebral
bleeding was rare in clinical trials with Ticlopidine HCI with an incidence
no greater than seen with comparator agents. (Ticlopidine 0.5%, aspirin
0.6%, placebo 0.75%).
Rash: Ticlopidine HCI has been associated with a maculopapular rash
(often with pruritus). Rash usually occurs within 3 months of initiation of
therapy, with a mean onset time of 11 days. If drug is discontinued recovery
should occur within several days Many rashes do not recur on drug
rechallenge. There have been rare reports of more severe rashes.
Less frequent adverse reactions (probably related): Clinical adverse
experiences occurring in 0.5 to 1.0 percent of patients in the controlled
trials include:
Digestive system: G.I. fullness;
Skin and Appendages:
urticaria;
Nervous System:
headache;
Body as a whole:
asthenia, pain;
Haemostatic system:
epistaxis;
Special senses:
tinnitus.
In addition, rarer, relatively serious events have also been reported,
mainly from overseas post marketing experience: Pancytopenia, aplastic
anaemia, haemolytic anaemia with reticulocytosis, allergic pneumonitis,
systemic lupus (positive ANA), peripheral neuropathy, vasculitis, serum
sickness, arthropathy, hepatitis, cholestatic jaundice, angioedema, fever,
nephrotic syndrome, myositis, hyponatraemia, immune thrombocytopenia and
thrombocytopenic thrombotic purpura (TTP).
PRECAUTIONS /WARNINGS
LABORATORY MONITORING: ALL PATIENTS SHOULD HAVE A BASELINE WHOLE
BLOOD COUNT (WBC) WITH WHITE CELL DIFFERENTIAL AND PLATELET COUNTS PERFORMED
PRIOR TO THE START OF TREATMENT AND THEN EVERY 2 WEEKS DURING THE FIRST 4
MONTHS OF THERAPY (MORE FREQUENT MONITORING IS NECESSARY FOR PATIENTS WHOSE
ABSOLUTE NEUTROPHIL COUNTS HAVE BEEN CONSISTENTLY DECLINING OR ARE 30% LESS
THAN THE BASELINE COUNT). THEREAFTER, WBC (INCLUDING PLATELET COUNT) AND
WHITE CELL DIFFERENTIAL COUNT NEED ONLY BE REPEATED FOR SYMPTOMS OR SIGNS
SUGGESTIVE OF NEUTROPENIA OR THROMBOCYTOPENIA SINCE TICLOPIDINE HAS A LONG
PLASMA HALF-LIFE, IT IS RECOMMENDED THAT PATIENTS DISCONTINUING THERAPY FOR
ANY REASON DURING THE FIRST FOUR MONTHS SHOULD HAVE A WBC WHITE CELL
DIFFERENTIAL AND PLATELET COUNT PERFORMED 2 WEEKS AFTER CESSATION OF THERAPY
PERIODIC LIVER FUNCTION TESTS AND MEASUREMENT OF CHOLESTEROL LEVELS SHOULD
ALSO BE CONDUCTED DURING THERAPY WITH TICLOPIDINE HCL.
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