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TICLOPIDINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ticlopidine is a platelet aggregation inhibitor of the thienopyridine family.

Specific Substances

    1) Ticlopidine hydrochloride
    2) 5-((2-chlorophenyl)methyl)4,5,6,7-tetrahydrothieno-(3,2-C)pyridine
    3) CAS 55142-85-3

Available Forms Sources

    A) FORMS
    1) TICLOPIDINE is available for oral administration as 250 mg tablets (Prod Info ticlopidine HCl oral film coated tablets, 2008).
    B) USES
    1) Ticlopidine is a platelet aggregation inhibitor used for prevention of thrombo-embolic disorders such as myocardial infarction, peripheral arterial disease, and stroke. It is also used to prevent thromboembolic occlusion of newly implanted coronary stents. Ticlopidine interferes with platelet membrane function by inhibiting ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet interactions (Prod Info ticlopidine HCl oral film coated tablets, 2008) .

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ticlopidine is used to reduce the risk of thrombotic stroke in patients that have had stroke precursors or completed thrombotic stroke.
    B) PHARMACOLOGY: Ticlopidine, a platelet aggregation inhibitor, interferes with platelet membrane function by inhibiting ADP-induced platelet binding and subsequent platelet-platelet interactions.
    C) EPIDEMIOLOGY: Cases of ticlopidine overdoses are rare.
    D) WITH THERAPEUTIC USE
    1) COMMON ADVERSE EVENTS: Gastrointestinal symptoms including diarrhea, nausea, dyspepsia, GI pain, and vomiting have occurred. Other clinical effects may include maculopapular or urticarial rash, cholestatic jaundice, and elevated liver enzymes.
    2) SEVERE ADVERSE EVENTS: Life-threatening hematologic adverse events can develop suddenly within the first few days to weeks of therapy and may include neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura (TTP), and aplastic anemia. The incidence of TTP usually peaks after 3 to 4 weeks of therapy, neutropenia generally peaks at 4 to 6 weeks, and aplastic anemia peaks at 4 to 8 weeks. Other hematologic events may also include bone-marrow suppression and an increased risk of bleeding including gastrointestinal bleeding. Intracerebral bleeding is rare.
    3) INFREQUENT ADVERSE EVENTS: Urticaria, headache, asthenia, pain, epistaxis and tinnitus may develop.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Agitation, tachycardia, hypotension, hypoxia, metabolic acidosis, and bleeding were described in a 69-year-old man following an intentional ingestion of 10 g of ticlopidine. Following a single 6 g dose a 38-year-old developed an increased bleeding time and SGPT, but no clinical symptoms developed.
    2) SEVERE TOXICITY: Hypotension, hypoxia and mental status changes have been reported. Bleeding complications should be anticipated.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Tachycardia and hypotension have been reported following an overdose.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Ticlopidine-induced pulmonary effects have been reported as adverse reactions.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Agitation, confusion and lethargy have been reported in one human case. Ataxia and seizures have been seen in rodents and baboons given overdoses.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Cholestatic jaundice and elevated liver enzyme levels may occur with therapeutic use of this agent.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Data from the FDA's Medwatch program have indicated that the most common serious ticlopidine-associated toxic effects were hematologic, primarily leukopenia, thrombocytopenia, TTP, agranulocytosis, pancytopenia, and aplastic anemia. Fatal aplastic anemia has occurred. Fatal TTP has been reported.
    B) WITH POISONING/EXPOSURE
    1) Prolonged bleeding time and hemorrhage have been reported in overdose.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Dermatitis was the second most common side effect reported with therapeutic use of this agent.
    0.2.20) REPRODUCTIVE
    A) Ticlopidine is classified as FDA pregnancy category B. Maternal and fetal toxicity was seen in animal studies; however, no teratogenicity was observed.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor CBC with differential, serum electrolytes, renal function and liver enzymes following overdose. Monitor for clinical evidence of bleeding.
    C) Toxic serum blood concentrations have not been established.
    D) Life-threatening hematologic toxicity including thrombotic thrombocytopenic purpura (TTP) agranulocytosis, neutropenia, and aplastic anemia have developed with therapeutic use. Any reduction in hemoglobin or platelet count should be further evaluated for the diagnosis of TTP; the appearance of schistocytes (fragmented RBCs) on a peripheral smear should be treated as potential evidence of TTP.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Limited overdose data. Monitor fluid and electrolyte status in patients with severe gastrointestinal loss; replace fluids and electrolytes as indicated. Monitor for bleeding (ie, gastrointestinal, epistaxis, hematuria and conjunctival hemorrhage).
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treat hypotension with intravenous fluids. Add vasopressors if hypotension persists or transfuse if hypotension persists in the setting of clinical evidence of bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal may be considered following a recent ingestion in a patient that is able to support the airway.
    2) HOSPITAL: Consider activated charcoal following a recent ingestion or if coingestions are suspected.
    D) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary following a minor exposure. Insure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression or seizure activity.
    E) ANTIDOTE
    1) None.
    F) HEMATOLOGIC TOXICITY
    1) Hematologic toxicity has been reported after therapeutic use but not after overdose. Aplastic anemia, neutropenia, and thrombotic thrombocytopenia purpura (TTP) have been reported. NEUTROPENIA: Granulocyte colony-stimulating factor (G-CSF) has been used to treat severe neutropenia/leukopenia associated with ticlopidine therapy. Recommended dose of filgrastim for patients receiving myelosuppressive chemotherapy to decrease granulocytopenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor temperature and CBC with differential until recovery. Patients with severe neutropenia should be in protective isolation. Platelet and red cell transfusions may be necessary.
    G) PLASMAPHERESIS
    1) Based on several retrospective case series it has been suggested that the mortality from ticlopidine-induced thrombotic thrombocytopenic purpura may be reduced by plasma exchange or plasmapheresis.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A minor (1 to 2 tablets) inadvertent dose in a patient currently being treated with ticlopidine can likely be managed at home. An asymptomatic child with an inadvertent exposure (a single dose) can likely be monitored at home, if a responsible adult is present.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients with any evidence of persistent symptoms (ie, anemia, bleeding, myelosuppression or electrolyte imbalance) should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PHARMACOKINETICS
    1) Ticlopidine is a time- and dose-dependent inhibitor of platelet aggregation. It is well absorbed (more than 80%), and is extensively metabolized by the liver. Ticlopidine is reported to reversibly (98%) bind to plasma proteins, mainly to serum albumin and lipoproteins. Approximately 60% of a radiolabeled dose is recoverable in the urine, mainly as metabolites; 23% is excreted in the feces. The elimination half-life of ticlopidine ranges from 4 to 5 days.
    J) PITFALLS
    1) Failure to monitor patient for a sufficient period following exposure due to the long half-life (4 to 5 days) of ticlopidine.

Range Of Toxicity

    A) TOXIC DOSE: Data limited. An adult developed agitation, confusion, tachycardia, lethargy, hypotension, metabolic acidosis and a prolonged bleeding time after ingesting 10 g of ticlopidine; recovery was uneventful. No clinical adverse effects, other than increased bleeding time and an elevated SGPT were reported following an overdose of 6 g in another adult.
    B) THERAPEUTIC DOSE: ADULT: STROKE: 500 mg/day. CORONARY ARTERY STENTING: 500 mg/day with antiplatelet doses of aspirin for up to 30 days following stenting. PEDIATRIC: Safety and efficacy have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Ticlopidine is used to reduce the risk of thrombotic stroke in patients that have had stroke precursors or completed thrombotic stroke.
    B) PHARMACOLOGY: Ticlopidine, a platelet aggregation inhibitor, interferes with platelet membrane function by inhibiting ADP-induced platelet binding and subsequent platelet-platelet interactions.
    C) EPIDEMIOLOGY: Cases of ticlopidine overdoses are rare.
    D) WITH THERAPEUTIC USE
    1) COMMON ADVERSE EVENTS: Gastrointestinal symptoms including diarrhea, nausea, dyspepsia, GI pain, and vomiting have occurred. Other clinical effects may include maculopapular or urticarial rash, cholestatic jaundice, and elevated liver enzymes.
    2) SEVERE ADVERSE EVENTS: Life-threatening hematologic adverse events can develop suddenly within the first few days to weeks of therapy and may include neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura (TTP), and aplastic anemia. The incidence of TTP usually peaks after 3 to 4 weeks of therapy, neutropenia generally peaks at 4 to 6 weeks, and aplastic anemia peaks at 4 to 8 weeks. Other hematologic events may also include bone-marrow suppression and an increased risk of bleeding including gastrointestinal bleeding. Intracerebral bleeding is rare.
    3) INFREQUENT ADVERSE EVENTS: Urticaria, headache, asthenia, pain, epistaxis and tinnitus may develop.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Agitation, tachycardia, hypotension, hypoxia, metabolic acidosis, and bleeding were described in a 69-year-old man following an intentional ingestion of 10 g of ticlopidine. Following a single 6 g dose a 38-year-old developed an increased bleeding time and SGPT, but no clinical symptoms developed.
    2) SEVERE TOXICITY: Hypotension, hypoxia and mental status changes have been reported. Bleeding complications should be anticipated.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachycardia and hypotension have been reported following an overdose.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Initial sinus tachycardia followed by profound hypotension were reported in a 69-year-old man who ingested 10 g of ticlopidine (Horowitz et al, 1993).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Ticlopidine-induced pulmonary effects have been reported as adverse reactions.
    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A case of bronchiolitis obliterans-organizing pneumonia (BO-OP) was reported in a 76-year-old woman following one month of therapy with ticlopidine, 250 mg twice daily, and prednisone. Evidence of BO-OP was seen on chest x-ray and transbronchial biopsy, which revealed widening of the alveolar walls with mixed inflammatory infiltrate, air spaces deformed by organizing connective tissue plugs, and foamy macrophages. Symptoms resolved in 5 months with continuing prednisone and discontinuation of ticlopidine (Alonzo-Martinez et al, 1998).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Agitation, confusion and lethargy have been reported in one human case. Ataxia and seizures have been seen in rodents and baboons given overdoses.
    3.7.2) CLINICAL EFFECTS
    A) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Agitation and confusion followed by lethargy were reported in a 69-year-old man who ingested 10 g of ticlopidine (Horowitz et al, 1993).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ATAXIA
    a) Overdose effects seen in both rodents and baboons include initial hyperactivity followed by hypoactivity, ataxia, and prostration leading to death (Mazue et al, 1984 (Suppl)).
    2) SEIZURES
    a) Seizures developed in rodents and baboons given overdoses (Mazue et al, 1984 (Suppl)).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH THERAPEUTIC USE
    a) Most adverse events with ticlopidine therapy have been associated with the gastrointestinal tract. Nausea (7%) and vomiting (1.9%) have been reported with ticlopidine therapy (Prod Info ticlopidine HCl oral film coated tablets, 2008).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea (12.5%) is the most common adverse event reported with ticlopidine therapy (Prod Info ticlopidine HCl oral film coated tablets, 2008). Chronic diarrhea resulting in weight loss has been reported in patients taking ticlopidine therapeutically (Giardina et al, 1984; Fraga et al, 1996; Mansoor & Aziz, 1997).
    1) Mansoor & Aziz (1997) reported a case of chronic diarrhea, anorexia and weight loss that began 2 years after starting ticlopidine therapy. Diarrhea and anorexia resolved within several days of stopping ticlopidine (Mansoor & Aziz, 1997).
    C) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dyspepsia (7%) has been commonly reported with ticlopidine therapy (Prod Info ticlopidine HCl oral film coated tablets, 2008).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Cholestatic jaundice and elevated liver enzyme levels may occur with therapeutic use of this agent.
    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Reversible cholestatic jaundice (occurring at a reported incidence of 1%) may occur with therapeutic use of this drug (Goyan, 1984; Mazue et al, 1984 (Suppl); Day, 1984; Cassidy et al, 1995; Sossai et al, 1998; Kubin et al, 1999; Wu et al, 2000) and in one case this occurred within 3 weeks of starting ticlopidine (Naschitz et al, 1995) and in another case occurred 6 months after initiation of therapy (Grieco et al, 1998). This reaction, as well as rare hepatocellular damage, appears to be an idiosyncratic reaction.
    b) CASE REPORT: A case of severe ticlopidine-induced cholestatic hepatitis (total bilirubin up to 43 mg/dL) was reported after 6 weeks of therapy in an 86-year-old woman. A liver biopsy confirmed the presence of drug-induced cholestatic hepatitis. The patient died 14 days after hospital admission from sudden cardiac death (not related to liver dysfunction) (Wu et al, 2000).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevated hepatic serum enzymes may uncommonly occur following therapeutic doses, usually noted between 10 days and 12 weeks after starting therapy. These patients develop jaundice, generally without fever, with laboratory tests revealing elevation of transaminase concentrations and/or cholestasis (Martinez Perez-Balsa et al, 1998; Ceylan et al, 1998).
    b) Elevated liver enzymes (AST 45 U/L, ALT 69 U/L, alkaline phosphatase 649 U/L, GGTP 1385 U/L, and total bilirubin 0.7 mg/dL) occurred about 3 months after starting ticlopidine therapy in one patient. Liver function tests returned to baseline within 6 months of discontinuing the drug (Klepser & Jogerst, 1997).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) HEMOLYTIC UREMIC SYNDROME
    1) WITH THERAPEUTIC USE
    a) THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME (TTP-HUS) has uncommonly been associated with therapeutic use of ticlopidine. It is suggested that this is an immune-mediated reaction. High mortality and morbidity is associated with drug-induced TTP-HUS. Plasma exchange therapy appears to be appropriate in this setting due to high morbidity, although its role is uncertain (Medina et al, 2001).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Data from the FDA's Medwatch program have indicated that the most common serious ticlopidine-associated toxic effects were hematologic, primarily leukopenia, thrombocytopenia, TTP, agranulocytosis, pancytopenia, and aplastic anemia. Fatal aplastic anemia has occurred. Fatal TTP has been reported.
    B) WITH POISONING/EXPOSURE
    1) Prolonged bleeding time and hemorrhage have been reported in overdose.
    3.13.2) CLINICAL EFFECTS
    A) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Agranulocytosis may occur alone or with thrombocytopenia and/or anemia (Guerciolini et al, 1985; Goyan, 1984; Gallerani et al, 2000). The manufacturer of ticlopidine has included a warning in its prescribing information concerning life-threatening hematological adverse reactions, including neutropenia/agranulocytosis and thrombotic thrombocytopenic purpura (TTP) which may occur following therapy (Prod Info ticlopidine hcl oral tablets, 2004).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Severe neutropenia and leukopenia have been reported in patients taking ticlopidine therapeutically (Guerciolini et al, 1985a; Neumann et al, 1997; Szto et al, 1999) and may progress to agranulocytosis with sepsis in some cases (Haushofer et al, 1997; (Anon, 1998)).
    b) INCIDENCE: The incidence of neutropenia (less than 1200 neutrophils/mm(3)) was 2.4% in ticlopidine clinical trials; the incidence of neutrophil counts less than 450/mm(3) was 0.8% (Prod Info ticlopidine hcl oral tablets, 2004; (Anon, 1998)). Szto et al (1999) reported an incidence of 1.2% of severe neutropenia following 1 month of ticlopidine therapy (Szto et al, 1999a).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been reported with therapeutic use, usually in the first 3 months of therapy (Gallerani et al, 2000).
    D) THROMBOCYTOPENIC PURPURA
    1) WITH THERAPEUTIC USE
    a) Thrombotic thrombocytopenic purpura (TTP), a potentially life-threatening condition, has been reported as an adverse event in approximately 100 patients between 1992 and 1997, with a possible incidence of 1 case per 2000 to 4000 patients exposed(Prod Info ticlopidine hcl oral tablets, 2004; (Anon, 1998); Venegoni et al, 1999). The manufacturer has included a warning in its prescribing information concerning life-threatening hematological adverse reactions, including neutropenia/agranulocytosis and TTP (Prod Info ticlopidine hcl oral tablets, 2004).
    1) Clinical symptoms include changes in mental status, mild renal dysfunction, and fever. Laboratory findings include severe thrombocytopenia and microangiopathic hemolytic anemia (Steinhubl et al, 1999; Muszkat et al, 1998; Chen et al, 1999; Szto et al, 1999; Bennett et al, 1999). Bennett et al (1999) reported that death occurred in almost 60% of all patients NOT receiving plasmapheresis compared with 21.9% of patients receiving plasmapheresis for stroke prevention and 14.3% of patients receiving plasmapheresis in the stent setting (Bennett et al, 1999).
    2) Steinhubl et al (1999) reported a TTP incidence of 0.02% in a population of 43,322 ticlopidine treated patients (Steinhubl et al, 1999). This adverse event is characterized by a short ticlopidine exposure period of about 3 to 5 weeks and usually less than 8 weeks. Chen et al (1999a) reported a median time from ticlopidine initiation to onset of symptoms was 3 weeks (range, 1 to 16 weeks) in 60 patients (Chen & Sutton, 1999aa).
    b) THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME (TTP-HUS) has uncommonly been associated with therapeutic use of ticlopidine. It is suggested that this is an immune-mediated reaction. High mortality and morbidity is associated with drug-induced TTP-HUS. Plasma exchange therapy appears to be appropriate in this setting due to high morbidity, although its role is uncertain (Medina et al, 2001).
    E) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia has been reported at therapeutic doses (Guerciolini et al, 1985; Prod Info ticlopidine hcl oral tablets, 2004).
    F) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Aplastic anemia has occurred in rare cases following therapeutic use of ticlopidine (Dunn, 1996; Ferrer et al, 1998; Ceylan et al, 1998; Taher et al, 2000).
    b) CASE REPORT: Fatal aplastic anemia developed in an 84-year-old woman taking therapeutic doses of ticlopidine for secondary stroke prevention. After 29 days of taking ticlopidine, the patient's WBC count dropped from a baseline of 6.7 x 10(9)/L to 4.0 x 10(9)/L. Ticlopidine was discontinued. On day 42, the woman was seen in the ED with a fever, weakness, sore throat, and mouth ulcer. WBC count was 0.7 x 10(9)/L, absolute neutrophil count 0, hemoglobin 10.4 g/L, and platelets 237 x 10(9)/L. Results of a bone marrow biopsy revealed severe hypoplasia with agranulocytosis (Mallet & Mallet, 1994).
    c) CASE REPORT: A 65-year-old man was admitted to the hospital 11 days after stopping ticlopidine (250 mg twice/day), with a recent history of fever, petechiae, and epistaxis. The patient had concurrently taken aspirin and isosorbide mononitrate. Laboratory values were reported as: WBC, 0.7 x 10(9)/L (3% neutrophils, 95% lymphocytes, 2% monocytes); hemoglobin, 11.8 g/dL; and platelets, 14 x 10(9)/L. E. coli grew from blood cultures. A classic histological pattern of aplastic anemia was seen on bone marrow aspirate and trephine biopsy (Ferrer et al, 1998).
    d) CASE REPORT: Ticlopidine-induced aplastic anemia was reported in an 83-year-old woman 7 weeks after initiation of therapy (250 mg twice daily). Quick bone marrow recovery (within 3 weeks) was reported with G-CSF therapy (Taher et al, 2000).
    G) COAG./BLEEDING TESTS ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Prolonged bleeding time (greater than 15 minutes) developed in a 69-year-old man who ingested 10 g of ticlopidine. Clinical manifestations included ecchymosis, hematuria, guaiac positive stools, epistaxis, and a 2.7 g drop in hemoglobin over 12 days. Bleeding time corrected 8 days postingestion (Horowitz et al, 1993).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dermatitis was the second most common side effect reported with therapeutic use of this agent.
    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Skin rashes are the second most common side effect seen with this agent. They have usually been either urticarial or maculopapular (Goyan, 1984). Dermatitis reactions were reported to occur in 6.9% of 145 patients in a retrospective, observational study (Whetsel & Bell, 1999). Rashes usually cover the trunk and sometimes spread to the arms and may be severe.

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) ARTHRITIS
    1) WITH THERAPEUTIC USE
    a) A case of acute symmetrical polyarthritis has been reported, probably associated with the therapeutic use of ticlopidine (250 mg twice daily for 5 days previous to arthritis symptoms). Treatment with ticlopidine was stopped and a NSAID was given for 10 days. Symptoms resolved within 2 weeks. Laboratory findings and symptoms suggested a drug induced hypersensitivity vasculitis (Dakik et al, 2002).

Reproductive

    3.20.1) SUMMARY
    A) Ticlopidine is classified as FDA pregnancy category B. Maternal and fetal toxicity was seen in animal studies; however, no teratogenicity was observed.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Ticlopidine is listed as FDA pregnancy category B (Prod Info ticlopidine HCl oral film coated tablets, 2008).
    B) LACK OF EFFECT
    1) Initial studies done on rodents showed no adverse effects on fertility, and no teratogenicity or negative prenatal or postnatal maternal effects (Mazue et al, 1984 (Suppl); Mazue et al, 1984 (Suppl)).
    C) ANIMAL STUDIES
    1) Maternal and fetal toxicity was seen in doses of 400 mg/kg in rats, 200 mg/kg/day in mice, and 100 mg/kg in rabbits. No teratogenicity was observed (Prod Info ticlopidine HCl oral film coated tablets, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Ticlopidine has been shown to be excreted in the milk of lactating rats. It is not known if it is excreted in human breast milk (Prod Info ticlopidine HCl oral film coated tablets, 2008).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) No effect on male or female fertility was observed in rats administered ticlopidine doses up to 400 mg/kg/day (Prod Info ticlopidine HCl oral film coated tablets, 2008).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS55142-85-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS53885-35-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Studies carried out in rats and mice indicated ticlopidine is not carcinogenic to animals.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor CBC with differential, serum electrolytes, renal function and liver enzymes following overdose. Monitor for clinical evidence of bleeding.
    C) Toxic serum blood concentrations have not been established.
    D) Life-threatening hematologic toxicity including thrombotic thrombocytopenic purpura (TTP) agranulocytosis, neutropenia, and aplastic anemia have developed with therapeutic use. Any reduction in hemoglobin or platelet count should be further evaluated for the diagnosis of TTP; the appearance of schistocytes (fragmented RBCs) on a peripheral smear should be treated as potential evidence of TTP.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Toxic serum levels have not been established.
    B) BLOOD/SERUM CHEMISTRY
    1) Serum hepatic enzyme elevations have been seen with therapeutic doses. Monitor liver function tests following overdose.
    2) Following severe vomiting and/or diarrhea monitor fluid and electrolyte status.
    C) HEMATOLOGIC
    1) Significant overdose may result in prolonged bleeding. Life-threatening hematologic toxicity including thrombotic thrombocytopenic purpura (TTP), agranulocytosis, neutropenia, and aplastic anemia have developed with therapeutic use. Monitor CBC with differential following an overdose.
    a) Based on clinical use, the incidence of TTP usually peaks after 3 to 4 weeks of therapy, neutropenia generally peaks at 4 to 6 weeks, and aplastic anemia peaks at 4 to 8 weeks (Prod Info ticlopidine HCl oral film coated tablets, 2008)
    2) Any reduction in hemoglobin or platelet count should be further evaluated for the diagnosis of TTP; the appearance of schistocytes (fragmented RBCs) on peripheral smear should be treated as potential evidence of TTP (Prod Info ticlopidine HCl oral film coated tablets, 2008).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with any evidence of persistent symptoms (ie, anemia, bleeding, myelosuppression or electrolyte imbalance) should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A minor (1 to 2 tablets) inadvertent dose in a patient currently being treated with ticlopidine can likely be managed at home. An asymptomatic child with an inadvertent exposure (a single dose) can likely be monitored at home, if a responsible adult is present.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor CBC with differential, serum electrolytes, renal function and liver enzymes following overdose. Monitor for clinical evidence of bleeding.
    C) Toxic serum blood concentrations have not been established.
    D) Life-threatening hematologic toxicity including thrombotic thrombocytopenic purpura (TTP) agranulocytosis, neutropenia, and aplastic anemia have developed with therapeutic use. Any reduction in hemoglobin or platelet count should be further evaluated for the diagnosis of TTP; the appearance of schistocytes (fragmented RBCs) on a peripheral smear should be treated as potential evidence of TTP.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. Human overdose data are limited. Based on animal studies, patients should be observed for CNS depression and seizures. Monitor liver enzymes and serum electrolytes. Monitor for clinical evidence of bleeding.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Monitor CBC with differential, serum electrolytes, renal function and liver enzymes following overdose. Monitor for clinical evidence of bleeding.
    3) Toxic serum blood concentrations have not been established.
    4) Life-threatening hematologic toxicity including thrombotic thrombocytopenic purpura (TTP) agranulocytosis, neutropenia, and aplastic anemia have developed with therapeutic use. Any reduction in hemoglobin or platelet count should be further evaluated for the diagnosis of TTP; the appearance of schistocytes (fragmented RBCs) on a peripheral smear should be treated as potential evidence of TTP (Prod Info ticlopidine HCl oral film coated tablets, 2008).
    C) SEIZURE
    1) Seizures or altered mental status may be one of the symptoms associated with thrombotic thrombocytopenia purpura due to clot formation. Additional signs and symptoms of TTP include fever, weakness, difficulty speaking, jaundice, dark or bloody urine, pallor or petechiae (Prod Info ticlopidine HCl oral film coated tablets, 2008).
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) FLUID/ELECTROLYTE BALANCE REGULATION
    1) If diarrhea or vomiting become severe, monitor fluid and electrolytes and replace as indicated.
    E) MYELOSUPPRESSION
    1) Granulocyte colony-stimulating factor (G-CSF) has been used to treat severe neutropenia/leukopenia associated with ticlopidine therapy (Ferrer et al, 1998; Dunn, 1996).
    2) The recommended dose of G-CSF (filgrastim) for patients receiving myelosuppressive chemotherapy is 5 to 10 mcg/kg/day given by a single daily injection or by continuous infusion (Prod Info Neupogen(R), filgrastim, 1998; Ferrer et al, 1998).
    3) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    4) CASE REPORT: Bone marrow recovery occurred quickly following G-CSF therapy for ticlopidine-induced aplastic anemia which developed within 7 weeks of initiation of ticlopidine. G-CSF was administered at a dose of 5 mcg/kg subQ daily for one week, when the WBC returned to normal and platelet count reached 93 x 10(9)/L (Taher et al, 2000).

Enhanced Elimination

    A) PLASMAPHERESIS
    1) Several retrospective case series have suggested that the mortality from ticlopidine-induced thrombotic thrombocytopenic purpura may be reduced by plasma exchange or plasmapheresis (Chen et al, 1999; Steinhubl et al, 1999).
    2) A 50% (11/22) mortality rate was reported in patients who did NOT receive plasma exchange therapy compared with 24% (9/38) in patients receiving plasma exchange therapy for ticlopidine-induced TTP (Chen & Sutton, 1999a).

Abstracts

Case Reports

    A) ADULT
    1) A 69-year-old man developed agitation, confusion, and tachycardia after ingesting 10 g of ticlopidine. Three hours after admission he became lethargic and developed hypotension (79/60), hypoxia, and metabolic acidosis. During hospitalization he developed ecchymosis, hematuria, epistaxis and guaiac positive stools. Bleeding time was prolonged, greater than 15 minutes, until 8 days postingestion (Horowitz et al, 1993).

Range Of Toxicity

Summary

    A) TOXIC DOSE: Data limited. An adult developed agitation, confusion, tachycardia, lethargy, hypotension, metabolic acidosis and a prolonged bleeding time after ingesting 10 g of ticlopidine; recovery was uneventful. No clinical adverse effects, other than increased bleeding time and an elevated SGPT were reported following an overdose of 6 g in another adult.
    B) THERAPEUTIC DOSE: ADULT: STROKE: 500 mg/day. CORONARY ARTERY STENTING: 500 mg/day with antiplatelet doses of aspirin for up to 30 days following stenting. PEDIATRIC: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) STROKE
    1) 250 mg orally twice daily with food to minimize GI discomfort (Prod Info ticlopidine HCl oral film coated tablets, 2013).
    B) CORONARY ARTERY STENTING
    1) 250 mg orally twice daily with food along with antiplatelet doses of aspirin for up to 30 days following successful stent implantation (Prod Info ticlopidine HCl oral film coated tablets, 2013).
    7.2.2) PEDIATRIC
    A) Safety and efficacy of ticlopidine have not been established in children (Prod Info ticlopidine HCl oral film coated tablets, 2013).

Minimum Lethal Exposure

    A) ANIMAL DATA
    1) Single, acute lethal doses of 1600 or 500 mg/kg in rats and mice, respectively, induced toxic symptoms of GI hemorrhage, seizures, hypothermia, dyspnea, loss of equilibrium and abnormal gait (Prod Info ticlopidine HCl oral film coated tablets, 2008).

Maximum Tolerated Exposure

    A) A 69-year-old man developed agitation, confusion, and tachycardia after ingesting 10 g of ticlopidine. Three hours after admission he became lethargic and developed hypotension (79/60), hypoxia, and metabolic acidosis. During his admission, he developed ecchymosis, hematuria, epistaxis and guaiac positive stools. Bleeding time was prolonged, greater than 15 minutes, until 8 days postingestion (Horowitz et al, 1993).
    B) Following a single intentional overdose of 6000 mg (24 standard 250 mg tablets), increased bleeding time and elevated SGPT were the only reported abnormalities in a 38-year-old man. The patient was observed and recovered without sequelae (Prod Info ticlopidine HCl oral film coated tablets, 2008).

Workplace Standards

    A) ACGIH TLV Values for CAS55142-85-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS53885-35-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS55142-85-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS53885-35-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS55142-85-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS53885-35-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS55142-85-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS53885-35-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 1250 mg/kg (RTECS, 2001)
    B) LD50- (ORAL)MOUSE:
    1) 600 mg/kg (RTECS, 2001)
    C) LD50- (ORAL)RAT:
    1) 1780 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ticlopidine is a time- and dose-dependent inhibitor of platelet aggregation and release of platelet granule constituents, as well as causing prolongation of bleeding time. It differs from aspirin in that it has a direct effect unrelated to prostaglandin metabolism inhibition (Khurmi et al, 1986). This drug selectively inhibits the binding of adenosine diphosphate (ADP) to the platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thus inhibiting platelet aggregation (Prod Info Ticlid(R), ticlopidine, 1999) . Effect on platelet function is irreversible for the life of the platelet (Prod Info Ticlid(R), ticlopidine, 1999).
    B) Ticlopidine is an inhibitor of energy transduction (done in isolated rat mitochondria). In concentrations less than 100 nmoles/mg of mitochondrial protein, it stimulates state 4 oxidation, inhibits state 3 oxidation, decreases ADP-O ratio and respiratory control, and promotes latent ATPase activity (Leblondel & Allain, 1978).

Toxicologic Mechanism

    A) Thrombotic thrombocytopenic purpura (TTP) is generally a result of insults to the vascular endothelium. It has been suggested that ticlopidine, directly or indirectly, may damage endothelial cells and cause the release of ultralarge vWF multimers into the circulation. vWF multimers in susceptible patients may be processed abnormally and initiate intravascular platelet clumping (Chen et al, 1999).

Physicochemical

Physical Characteristics

    A) Ticlopidine hydrochloride: White crystalline solid which is freely soluble in water and self-buffers to a pH of 3.6. It is also freely soluble in methanol (Budavari, 1996; Prod Info Ticlid(R), ticlopidine, 1999).

Molecular Weight

    A) Ticlopidine: 263.78 (Budavari, 1996)
    B) Ticlopidine Hydrochloride Salt: 300.25 (Prod Info Ticlid(R), ticlopidine, 1999)

References

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