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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Trientine is used as a copper chelator, and as a curing component for epoxy resins.

Specific Substances

    1) 1,2-ethanediamine, N1N1-bis(2-aminoethyl)
    2) 1,4,7,10-tetraazadecane
    3) 3,6-diazaoctane-1,8-diamine
    4) Ethylenediamine, N1N1-bis(2-aminoethyl)
    5) N,N'-bis(2-aminoethyl)ethanediamine
    6) TECZA
    7) TETA
    8) Trien
    9) Triethylenetetramine
    10) UPDT 8107
    11) CAS 112-24-3(trientine)
    12) CAS 38260-01-4(trientine hydrochloride)
    13) TECH
    14) TETH
    1.2.1) MOLECULAR FORMULA
    1) C6-H18-N4

Available Forms Sources

    A) FORMS
    1) Trientine is available in the US as 250 mg capsules for oral administration (Prod Info Syprine(R), 2001).
    B) SOURCES
    1) Cuprid(R) is trientine dihydrochloride, marketed as an orphan drug by Merck, Sharp & Dohme in 250 mg capsules prior to 1991 (p 12).
    C) USES
    1) Trientine hydrochloride is used to treat patients with Wilson's disease who are intolerant of penicillamine (Prod Info Syprine(R), 2001).
    2) Trientine is used as a copper chelator and as a curing agent in the making of epoxy resins. Some of the unreacted chemical may be encountered by handling epoxy resins.

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: Trientine, a chelating compound, is used for the treatment of Wilson's disease to remove excess copper from the body; it is indicated in patients who are intolerant to penicillamine. It is also used as a curing agent in the making of epoxy resins. Some of the unreacted chemical may be encountered by handling epoxy resins.
    B) PHARMACOLOGY: Trientine is a chelating agent that can remove excess copper from the body. It is a strong irritant and corrosive with an alkaline pH of 14.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Based on limited clinical use, iron deficiency, systemic lupus erythematosus, dystonia, muscular spasm and myasthenia gravis have been reported in one clinical study. In a study of 4 patients treated with trientine for biliary cirrhosis (not clinically indicated), the following potentially serious gastrointestinal events were reported in one or more patients: heartburn, epigastric pain and tenderness, abdominal pain, anorexia, melena, aphthoid ulcers, and acute gastritis. Other events included: thickening, fissuring of the skin, hypochromic microcytic anemia, malaise, cramps, muscle pain, weakness and rhabdomyolysis. A causal relationship has not been established.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Based on limited data, symptoms are anticipated to be similar to adverse events and may include gastrointestinal events (ie, heartburn, epigastric pain and tenderness, abdominal pain, anorexia, melena, ulcers, gastritis). Other events may include muscle pain/spasm, weakness, and malaise. TOPICAL: Splash contact has resulted in dermal excoriations, vesicles, and bullae. INHALATION: Exposure to hot vapors has caused facial itching, erythema, swelling, and respiratory tract irritation.
    2) SEVERE TOXICITY: Limited data. No adverse events were reported in a woman after ingesting 30 g of trientine.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Facial itching, erythema, and swelling have been reported after exposure to hot trientine vapor.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Irritation of the respiratory tract has been reported after exposure to the hot vapor.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Anorexia, epigastric pain, tenderness, dyspepsia, gastritis, melena stools, and aphthoid ulcers have been reported following trientine therapy.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Anemia was reported in one patient taking this medication for primary biliary cirrhosis. Thrombocytopenia has also been reported.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Various rashes and allergic skin sensitization have been seen with this agent.
    B) WITH POISONING/EXPOSURE
    1) Various rashes and allergic skin sensitization have been seen with this agent.
    0.2.20) REPRODUCTIVE
    A) Trientine is classified as FDA pregnancy category C. Numerous malformations and fetal anomalies have been reported with trientine use in animals. Some reports suggest the copper supplementation may lessen the effects of trientine. Data are not available to assess the potential effects of exposure to trientine during human lactation.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of triethylenetetramine in humans.

Laboratory Monitoring

    A) No routine laboratory studies are indicated; obtain a baseline CBC with differential and a basic metabolic panel in symptomatic patients.
    B) No toxic levels have been established. Trientine may decrease trace metals (this includes zinc, copper, calcium, and iron).

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) ORAL: Limited data. Treatment is symptomatic and supportive. Monitor for gastrointestinal symptoms. Obtain a baseline CBC with differential and monitor trace minerals in patients at risk. DERMAL: The industrial formulation of this agent can act as a strong sensitizer and primary irritant. Remove clothing and wash the exposed skin with soap and water. INHALATION: Exposure to the hot vapor (chemical formulation) has produced pulmonary irritation. Move patient to fresh air; administer 100% humidified supplemental oxygen. Monitor airway.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) ORAL: Treatment is symptomatic and supportive. DERMAL: The industrial formulation of this agent can act as a strong sensitizer and primary irritant. Remove contaminated clothing and wash the exposed skin copiously with soap and water. INHALATION: Exposure to the hot vapor (chemical formulation) has produced pulmonary irritation. Move patient to fresh air. Administer 100% humidified supplemental oxygen. Inhaled beta adrenergic agonists may be needed, if bronchospasm develops. Perform endotracheal intubation and provide assisted ventilation as necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: ORAL: Decontamination is unlikely to be necessary following a minor exposure of the drug. Irritation may occur if the industrial chemical were to be ingested; immediately dilute with 4 to 8 ounces (120 to 240 mL) of water or milk (not to exceed 4 ounces or 120 mL in a child). DERMAL: The industrial formulation of this agent can act as a strong sensitizer and primary irritant. Remove contaminated clothing and wash the exposed skin copiously with soap and water.
    2) HOSPITAL: ORAL: Consider administration of activated charcoal as an aqueous slurry in patients who are awake and able to protect their airway if a large amount of the drug is ingested. DILUTION: Irritation may occur if the industrial chemical were to be ingested; immediately dilute with 4 to 8 ounces (120 to 240 mL) of water or milk (not to exceed 4 ounces or 120 mL in a child). DERMAL: The industrial formulation of this agent can act as a strong sensitizer and primary irritant. Remove contaminated clothing and wash the exposed skin copiously with soap and water.
    D) ANTIDOTE
    1) None.
    E) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following an oral exposure. Exposure to the hot vapor (chemical formulation) has produced pulmonary irritation. Administer supplemental oxygen, administer inhaled beta agonists for bronchospasm, and perform endotracheal intubation and provide assisted ventilation, as necessary.
    F) ENHANCED ELIMINATION
    1) It is unknown whether enhanced elimination would be useful.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic adult or child with an inadvertent minor exposure (eg, a single dose) may be monitored at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with gastrointestinal or hematologic alterations should be monitored until symptoms resolve. Patients may be discharged to home once symptoms have resolved and laboratory studies are within normal limits.
    3) ADMISSION CRITERIA: Patients with persistent symptoms should be admitted for further treatment.
    4) CONSULT CRITERIA: Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    H) PHARMACOKINETICS
    1) According to the manufacturer of trientine, data on the pharmacokinetics are not available.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. No adverse effects were reported in an adult woman after ingesting 30 g of trientine.
    B) THERAPEUTIC DOSE: ADULT: The recommended initial dose is 750 to 1250 mg/day given in divided doses 2, 3, or 4 times daily; maximum: 2000 mg/day. PEDIATRIC: The recommended initial dose is 500 to 750 mg/day given in divided doses 2, 3, or 4 times daily for pediatric patients age 12 years or under; maximum: 1500 mg/day
    C) ANIMAL DATA: An animal study stated that undiluted trientine produced a severe skin burn while a 10% solution was not harmful.

Clinical Effects

Summary Of Exposure

    A) USES: Trientine, a chelating compound, is used for the treatment of Wilson's disease to remove excess copper from the body; it is indicated in patients who are intolerant to penicillamine. It is also used as a curing agent in the making of epoxy resins. Some of the unreacted chemical may be encountered by handling epoxy resins.
    B) PHARMACOLOGY: Trientine is a chelating agent that can remove excess copper from the body. It is a strong irritant and corrosive with an alkaline pH of 14.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Based on limited clinical use, iron deficiency, systemic lupus erythematosus, dystonia, muscular spasm and myasthenia gravis have been reported in one clinical study. In a study of 4 patients treated with trientine for biliary cirrhosis (not clinically indicated), the following potentially serious gastrointestinal events were reported in one or more patients: heartburn, epigastric pain and tenderness, abdominal pain, anorexia, melena, aphthoid ulcers, and acute gastritis. Other events included: thickening, fissuring of the skin, hypochromic microcytic anemia, malaise, cramps, muscle pain, weakness and rhabdomyolysis. A causal relationship has not been established.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Based on limited data, symptoms are anticipated to be similar to adverse events and may include gastrointestinal events (ie, heartburn, epigastric pain and tenderness, abdominal pain, anorexia, melena, ulcers, gastritis). Other events may include muscle pain/spasm, weakness, and malaise. TOPICAL: Splash contact has resulted in dermal excoriations, vesicles, and bullae. INHALATION: Exposure to hot vapors has caused facial itching, erythema, swelling, and respiratory tract irritation.
    2) SEVERE TOXICITY: Limited data. No adverse events were reported in a woman after ingesting 30 g of trientine.

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Facial itching, erythema, and swelling have been reported after exposure to hot trientine vapor.
    3.4.2) HEAD
    A) WITH POISONING/EXPOSURE
    1) ITCHING of the face, erythema, and swelling have been reported after exposure to the hot vapor of trientine used in industry (Bourne et al, 1959).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Irritation of the respiratory tract has been reported after exposure to the hot vapor.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) WITH POISONING/EXPOSURE
    a) Irritation of the respiratory tract has been reported after exposure to the hot vapor (Bingham et al, 2001).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Anorexia, epigastric pain, tenderness, dyspepsia, gastritis, melena stools, and aphthoid ulcers have been reported following trientine therapy.
    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Anorexia, epigastric pain, tenderness, dyspepsia, gastritis, melena stools, and aphthoid ulcers have been reported following trientine therapy (Prod Info SYPRINE(R) oral capsules, 2008).
    b) Heartburn, gastritis, anorexia, and dyspepsia were reported in patients who had been on trientine for 2 to 3 weeks (Epstein & Sherlock, 1980).

Genitourinary

    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) URINE ABNORMAL
    a) One animal study demonstrated an enhanced urinary excretion of endogenous calcium, copper, iron, and zinc when trientine was used in therapeutic doses as a chelator. Overdose or chronic use may decrease these essential metals (Tandon et al, 1984).
    b) Imbalances of essential trace metals or minerals may occur. Overdose or chronic use of trientine may further decrease the elements (Tandon et al, 1984).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Anemia was reported in one patient taking this medication for primary biliary cirrhosis. Thrombocytopenia has also been reported.
    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) HYPOCHROMIC MICROCYTIC anemia was reported in a patient treated for primary biliary cirrhosis (Prod Info SYPRINE(R) oral capsules, 2008; Epstein & Sherlock, 1980).
    b) Iron deficiency, especially in female patients, may occur after chronic chelation therapy (Prod Info SYPRINE(R) oral capsules, 2008) (Walshe, 1982).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia was reported with therapeutic doses. No overt symptoms developed (Dubois et al, 1990).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Various rashes and allergic skin sensitization have been seen with this agent.
    B) WITH POISONING/EXPOSURE
    1) Various rashes and allergic skin sensitization have been seen with this agent.
    3.14.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH POISONING/EXPOSURE
    a) Allergic skin sensitization has been reported. Trientine is a strong primary sensitizer (Bingham et al, 2001; van Putten et al, 1984).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Thickening, scaling, and fissuring of the skin of the hands has been reported in a patient who was being treated chronically for primary biliary cirrhosis (Prod Info SYPRINE(R) oral capsules, 2008; Epstein & Sherlock, 1980).
    2) WITH POISONING/EXPOSURE
    a) Various rashes have been reported due to the primary irritation of trientine (Krajewska & Rudzki, 1976).
    b) MANIFESTATIONS: Itching and redness first appear, which often become minimal or disappear. Re-exposure within hours or days may cause a more severe reaction with generalized erythema. Excoriations, vesicles, and bullae have been reported after splash contact. Paronychia may occur due to contamination of the fingernail areas (Bourne et al, 1959).
    c) RISK FACTORS: Perspiration increases the risk and severity of symptoms (Bourne et al, 1959).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: One case of rhabdomyolysis has been reported within the first 48 hours of taking trientine. This was not observed in the few other patients taking this agent for Wilson's disease (Epstein & Sherlock, 1980).
    B) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) Weakness was reported in a patient being treated for primary biliary cirrhosis (Prod Info SYPRINE(R) oral capsules, 2008; Epstein & Sherlock, 1980).
    C) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Muscle pain has been reported following trientine therapy (Prod Info SYPRINE(R) oral capsules, 2008).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) WITH THERAPEUTIC USE
    a) Systemic lupus erythematosus (SLE) has been reported as a potential adverse effect of trientine (Prod Info SYPRINE(R) oral capsules, 2008). One case of recurrent systemic lupus erythematosus (SLE) that originally developed during penicillamine therapy was seen during trientine use (p 12).

Reproductive

    3.20.1) SUMMARY
    A) Trientine is classified as FDA pregnancy category C. Numerous malformations and fetal anomalies have been reported with trientine use in animals. Some reports suggest the copper supplementation may lessen the effects of trientine. Data are not available to assess the potential effects of exposure to trientine during human lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) In a study of 7 patients (11 pregnancies) with Wilson's disease taking trientine, no morphological abnormalities were seen, and no significant fetal copper depletion was observed (Walshe, 1986).
    2) One study revealed no evidence of teratogenicity either in six patients or in animals who became pregnant during trientine therapy. All infants born during the study had normal development (Walshe, 1982).
    B) ANIMAL STUDIES
    1) CONGENITAL ANOMALY
    a) RATS - Trientine hydrochloride was teratogenic to rats in doses similar to that used in humans. Trientine hydrochloride given in the maternal diets of rats resulted in increased frequencies of resorption and fetal abnormalities, including hemorrhage and edema, and decreased fetal copper levels (Prod Info SYPRINE(R) oral capsules, 2001) .
    b) Malformations, massive hemorrhage, and edema were directly related to copper level decrease (Anon, 1991).
    c) Maternal administration of triethylenetetramine to mice throughout pregnancy resulted in fetal brain abnormalities, including hemorrhages, delayed ossification in the cranium, hydrocephaly, exencephaly, and microcephaly. The frequency of these abnormalities appeared to be dose-dependent (Tanaka et al, 1993).
    d) Increased resorptions, decreased viability, and abnormalities in the brain occurred in fetuses of mice receiving 12,000 parts per million triethylenetetramine (TETA) in the drinking water, but some maternal toxicity (evidenced by decreased weight) was present in this high-level exposure group. Fetal body and cerebral weights were lower in animals receiving 6000 parts per million Fetal concentrations of copper were lower in the liver and cerebrum, while that in maternal serum was not affected (Tanaka et al, 1992). Hydrocephaly, delayed cranial ossification, and microscopic brain abnormalities were reported in fetuses of mice receiving 6000 parts per million in the diet. Exencephaly, microcephaly, delayed cranial ossification and more significant microscopic brain abnormalities were found in the fetuses of a 12,000 parts per million maternal dose group. Information concerning possible maternal toxicity was not provided in these studies (Tanaka et al, 1993).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified trientine as FDA pregnancy category C (Prod Info SYPRINE(R) oral capsules, 2001).
    B) LACK OF EFFECT
    1) One report described 6 pregnancies in 4 female patients; in these 6 pregnancies, there were no miscarriages and no fetal abnormalities. All 6 children had normal development with the oldest child being followed for 5 years (Walshe, 1982). Another study reported the birth of a normal child to a woman who took trientine prior to and during pregnancy (Devesa et al, 1995).
    C) ANIMAL STUDIES
    1) Triethylenetetramine (TETA) produced necrotic changes in the placenta of guinea pigs following dermal application, and also caused miscarriages and fetal death (Clayton & Clayton, 1982). In rats, it increased resorptions and produced bleeding and swelling in the offspring (Keen, 1983), effects which were reduced by copper supplementation (Cohen, 1983).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) SUMMARY
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info SYPRINE(R) oral capsules, 2001).
    3.20.5) FERTILITY
    A) SUMMARY
    1) At the time of this review, no data were available to assess the effects of trientine on fertility in humans (Prod Info SYPRINE(R) oral capsules, 2001).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS112-24-3 (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
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of triethylenetetramine in humans.

Genotoxicity

    A) TETA was mutagenic in the Ames Salmonella microsome assay.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No routine laboratory studies are indicated; obtain a baseline CBC with differential and a basic metabolic panel in symptomatic patients.
    B) No toxic levels have been established. Trientine may decrease trace metals (this includes zinc, copper, calcium, and iron).
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) No toxic levels have been established.
    B) BLOOD/SERUM CHEMISTRY
    1) TRACE METALS: Trientine will decrease trace metal and mineral levels in the body. This includes zinc, copper, calcium, and iron. Iron levels should be monitored in patients on chronic therapy, especially female patients.

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 persistent symptoms should be admitted for further treatment.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic adult or child with an inadvertent minor exposure (eg, a single dose) may be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with gastrointestinal or hematologic alterations should be monitored until symptoms resolve. Patients may be discharged to home once symptoms have resolved and laboratory studies are within normal limits.

Monitoring

    A) No routine laboratory studies are indicated; obtain a baseline CBC with differential and a basic metabolic panel in symptomatic patients.
    B) No toxic levels have been established. Trientine may decrease trace metals (this includes zinc, copper, calcium, and iron).

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) DILUTION
    1) Trientine is an irritant or alkaline corrosive. In its encapsulated, salt form, the irritation is minor, but if the industrial chemical were to be ingested, moderate irritation may exist.
    2) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    B) ACTIVATED CHARCOAL
    1) Consider prehospital administration of activated charcoal as an aqueous slurry in patients who are awake and able to protect their airway if more than the maximum daily dose (2000 mg) was ingested.
    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) DILUTION
    1) Trientine is an irritant or alkaline corrosive. In its encapsulated, salt form, the irritation is minor, but if the industrial chemical were to be ingested, moderate irritation may exist.
    2) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    B) ACTIVATED CHARCOAL
    1) Consider administration of activated charcoal as an aqueous slurry in patients who are awake and able to protect their airway if a large amount of the drug has been ingested.
    2) 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.
    3) 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) MONITORING OF PATIENT
    1) Monitor iron and hemoglobin levels for possible reductions. Women who have had iron deficiencies caused by chronic therapy were able to remedy the situation by taking iron supplements.
    2) Consider monitoring other minerals and metals as well, such as copper, zinc, and calcium.
    3) Rhabdomyolysis and SLE have been rare complications implicated with the use of trientine. Patients should be monitored for these possible, but rare, complications.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) IRRITATION
    1) Exposure to the hot vapor of trientine caused pulmonary irritation, but pulmonary edema was not mentioned.
    2) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    3) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    4) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) This material is alkaline, and might cause mild to moderate alkaline irritation depending upon the concentration and duration of contact with the eye.
    B) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) SUMMARY
    1) This agent is a strong sensitizer and primary irritant. Besides normal decontamination procedures, the patient should be cautioned that reexposure over the next several hours to days may cause a more serious reaction.
    2) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. No adverse effects were reported in an adult woman after ingesting 30 g of trientine.
    B) THERAPEUTIC DOSE: ADULT: The recommended initial dose is 750 to 1250 mg/day given in divided doses 2, 3, or 4 times daily; maximum: 2000 mg/day. PEDIATRIC: The recommended initial dose is 500 to 750 mg/day given in divided doses 2, 3, or 4 times daily for pediatric patients age 12 years or under; maximum: 1500 mg/day
    C) ANIMAL DATA: An animal study stated that undiluted trientine produced a severe skin burn while a 10% solution was not harmful.

Therapeutic Dose

    7.2.1) ADULT
    A) INITIAL DOSE: 750 to 1250 mg/day given in divided doses 2, 3, or 4 times daily, increase only if free serum copper is persistently above 20 mcg/dL; MAX: 2000 mg/day./day. Swallow whole with water on an empty stomach at least one hour before or 2 hours after a meal and one hour before or after all drugs. Capsules should NOT be opened or chewed (Prod Info SYPRINE(R) oral capsules, 2014).
    7.2.2) PEDIATRIC
    A) CHILDREN 12 TO 17 YEARS: 750 to 1250 mg/day given in divided doses 2, 3, or 4 times daily, increase only if free serum copper is persistently above 20 mcg/dL; MAX: 2000 mg/day. Swallow whole with water on an empty stomach at least one hour before or 2 hours after a meal and one hour before or after all drugs. Capsules should not be opened or chewed (Prod Info SYPRINE(R) oral capsules, 2014).
    B) CHILDREN 12 YEARS OR YOUNGER: 500 to 750 mg/day given in 2, 3, or 4 divided doses, increase only if free serum copper is persistently above 20 mcg/dL; MAX: 1500 mg/day. Swallow whole with water on an empty stomach at least one hour before or 2 hours after a meal and one hour before or after all drugs. Capsules should not be opened or chewed (Prod Info SYPRINE(R) oral capsules, 2014).

Maximum Tolerated Exposure

    A) CASE REPORT: An adult woman ingested 30 g of trientine hydrochloride did not experience any adverse effects (Prod Info SYPRINE(R) oral capsules, 2008).
    B) ANIMAL DATA
    1) One animal study stated that undiluted trientine on the belly skin of rabbits produced a severe corrosive effect, while a 10 percent solution was not harmful (Bourne et al, 1959).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) No toxic dose has yet been established.

Workplace Standards

    A) ACGIH TLV Values for CAS112-24-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS112-24-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS112-24-3 :
    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

    D) OSHA PEL Values for CAS112-24-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 468 mg/kg ((RTECS, 2001))
    B) LD50- (ORAL)MOUSE:
    1) 1600 mg/kg ((RTECS, 2001))
    C) LD50- (ORAL)RAT:
    1) 2500 mg/kg ((RTECS, 2001))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Trientine is a copper chelator. After administration, serum levels of copper will actually increase for a short period of time, unlike penicillamine which immediately decreases serum levels.
    1) Because of this, it is thought that the trientine site of action is different from that of penicillamine.

Toxicologic Mechanism

    A) Trientine is an irritant/corrosive depending on concentration and duration of exposure.

Physicochemical

Physical Characteristics

    A) TRIENTINE DIHYDROCHLORIDE: White or pale yellow crystalline, hygroscopic powder (Prod Info, 1990)

Ph

    A) TRIENTINE: 14.0 (Budavari, 1996)

Molecular Weight

    A) TRIENTINE DIHYDROCHLORIDE: 219.2 (Prod Info, 1990)
    B) TRIENTINE: 146.2 (Budavari, 1996)

Other

    A) ODOR THRESHOLD
    1) Currently not available (CHRIS , 2002)

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