Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

KETOTIFEN

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ketotifen fumarate, a selective, noncompetitive histamine antagonist (H1-receptor) and mast cell stabilizer.

Specific Substances

    1) Ketotifen fumarate
    2) HC-20511
    3) CAS 34580-13-7

Available Forms Sources

    A) FORMS
    1) Ketotifen is available as 0.025% ophthalmic solution (Prod Info ketotifen fumarate ophthalmic solution, 2005).
    2) Ketotifen is available as 1 mg tablet and 1 mg/5 mL syrup (250 mL bottles) in some countries outside the United States (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).
    B) USES
    1) Ketotifen fumarate ophthalmic solution is indicated for the temporary prevention of itching of the eye due to allergic conjunctivitis (Prod Info ketotifen fumarate ophthalmic solution, 2005).
    2) In some countries outside the United States (eg, Canada - Zaditen(R)), ketotifen 1 mg tablet and 1 mg/5 mL syrup are used for the chronic treatment of mild atopic asthma in children (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).

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: Ketotifen fumarate ophthalmic solution is indicated for the temporary prevention of itching of the eye due to allergic conjunctivitis. In some countries outside the United States (eg, Canada - Zaditen(R)), ketotifen 1 mg tablet and 1 mg/5 mL syrup are used for the chronic treatment of mild atopic asthma in children.
    B) PHARMACOLOGY: Ketotifen fumarate, a selective, non-competitive histamine antagonist (H1-receptor) and mast cell stabilizer, that acts by inhibiting the release of mediators from cells involved in hypersensitivity reactions and also prevents chemotaxis and activation of eosinophils.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) OPHTHALMIC: The following ocular symptoms have been reported with the therapeutic use of ketotifen fumarate eye solution: allergic reaction, burning or stinging, conjunctivitis, discharge, dry eyes, eye pain, eyelid disorder, itching, keratitis, lacrimation disorder, mydriasis, rhinitis, rash, and photophobia.
    2) ORAL: Rash, dry mouth, sedation, mild dizziness, and CNS stimulation (eg, excitation, irritability, insomnia, and nervousness). RARE: Erythema multiform, Stevens-Johnson syndrome, cystitis, elevated liver enzymes, hepatitis.
    E) WITH POISONING/EXPOSURE
    1) OPHTHALMIC: An ingestion of the contents of one 5 mL ophthalmic solution bottle would be equivalent to 1.725 mg of ketotifen fumarate, acute overdose is unlikely to result in clinically significant adverse events.
    2) ORAL: Clinical effects of overdose following ketotifen doses up to 120 mg have included:
    a) MILD TO MODERATE TOXICITY: Drowsiness, disorientation, confusion, abdominal pain, headache, nystagmus, hypotension.
    b) SEVERE TOXICITY: Hypotension, bradycardia, tachycardia, dyspnea, seizures, coma, respiratory depression.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, and liver enzymes following significant overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is not expected after an overdose of ophthalmic solution. Manage mild hypotension with IV fluids. Transient bradycardia usually does not require intervention.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is not expected after an overdose of ophthalmic solution. Treat severe hypotension with IV fluids, dopamine, or norepinephrine. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: OPHTHALMIC: Because of limited expected toxicity of ophthalmic solution, gastrointestinal decontamination is not routinely recommended. An ingestion of the contents of one 5 mL ophthalmic solution bottle would be equivalent to 1.725 mg of ketotifen fumarate, acute overdose is unlikely to result in clinically significant adverse events. ORAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, large, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS and/or respiratory depression.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are unlikely to be of value because of the large volume of distribution.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with significant CNS or respiratory depression should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Oral absorption: nearly complete. Bioavailability: approximately 50% due to first-pass effect in the liver. Tmax: 2 to 4 hours. Protein binding: 75%. Vd: 56 L/kg. Excretion: 60% to 70% excreted within 48 hours. Elimination half-life: biphasic with a T1/2 alpha of 3 to 5 hours and a T1/2 beta of 21 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes overdose ingestions of other antihistamines or CNS infection.

Range Of Toxicity

    A) TOXICITY: OPHTHALMIC: In the United States, Ketotifen is only available in small 1 to 5 mL bottles. An ingestion of the contents of one 5 mL ophthalmic solution bottle would be equivalent to 1.725 mg of ketotifen fumarate, and would not be expected to result in significant toxicity even in a young child. ORAL: ADULTS: One patient developed drowsiness, disorientation, nystagmus, tachypnea, tachycardia after the ingestion of ketotifen 10 mg. Seizures, hypotension, and coma developed in adults ingesting over 20 mg. Drowsiness, seizures, respiratory depression, and tachycardia developed in one patient after ingesting 25 mg of ketotifen. A 21-year-old developed abdominal pain and headache after ingesting 120 mg of ketotifen. CHILDREN: Eight children (age range, 2 to 10 years) ingested 2 to 20 mg of ketotifen. Effects included sleepiness, tachypnea, cyanosis, dyspnea, fever, dry nose, nystagmus and tachycardia. Two children ingested up to 10 mg of ketotifen and developed no clinical symptoms.
    B) THERAPEUTIC DOSES: ADULTS: Ophthalmic solution: One drop (0.025% ketotifen fumarate solution/5 mL) in affected eye(s) twice daily, every 8 to 12 hr. CHILDREN: 3 years and older: Ophthalmic solution: One drop (0.025% ketotifen fumarate solution/5 mL) in affected eye(s) twice daily, every 8 to 12 hr. Older than 3 years: Oral tablets and syrups: 1 mg twice daily. 6 months to 3 years: 0.05 mg (equal to 0.25 mL of syrup) per kilogram body weight given twice daily.

Clinical Effects

Summary Of Exposure

    A) USES: Ketotifen fumarate ophthalmic solution is indicated for the temporary prevention of itching of the eye due to allergic conjunctivitis. In some countries outside the United States (eg, Canada - Zaditen(R)), ketotifen 1 mg tablet and 1 mg/5 mL syrup are used for the chronic treatment of mild atopic asthma in children.
    B) PHARMACOLOGY: Ketotifen fumarate, a selective, non-competitive histamine antagonist (H1-receptor) and mast cell stabilizer, that acts by inhibiting the release of mediators from cells involved in hypersensitivity reactions and also prevents chemotaxis and activation of eosinophils.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) OPHTHALMIC: The following ocular symptoms have been reported with the therapeutic use of ketotifen fumarate eye solution: allergic reaction, burning or stinging, conjunctivitis, discharge, dry eyes, eye pain, eyelid disorder, itching, keratitis, lacrimation disorder, mydriasis, rhinitis, rash, and photophobia.
    2) ORAL: Rash, dry mouth, sedation, mild dizziness, and CNS stimulation (eg, excitation, irritability, insomnia, and nervousness). RARE: Erythema multiform, Stevens-Johnson syndrome, cystitis, elevated liver enzymes, hepatitis.
    E) WITH POISONING/EXPOSURE
    1) OPHTHALMIC: An ingestion of the contents of one 5 mL ophthalmic solution bottle would be equivalent to 1.725 mg of ketotifen fumarate, acute overdose is unlikely to result in clinically significant adverse events.
    2) ORAL: Clinical effects of overdose following ketotifen doses up to 120 mg have included:
    a) MILD TO MODERATE TOXICITY: Drowsiness, disorientation, confusion, abdominal pain, headache, nystagmus, hypotension.
    b) SEVERE TOXICITY: Hypotension, bradycardia, tachycardia, dyspnea, seizures, coma, respiratory depression.

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Both tachypnea and bradypnea have been reported in several cases of overdose (Jefferys & Volans, 1981; Le Blaye et al, 1992).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Hypotension has been reported in 1 case of overdose (Le Blaye et al, 1992).
    a) CASE REPORT: Systolic blood pressure dropped from 130 to 70 mm Hg in an 80-year-old man following ingestion of 20 mg of ketotifen (Le Blaye et al, 1992).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Both tachycardia and bradycardia have occurred with overdose.
    a) Among 21 reported cases of overdose, tachycardia or bradycardia each occurred in 4 cases (Jefferys & Volans, 1981; Le Blaye et al, 1992).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) OPHTHALMIC SOLUTION: The following ocular symptoms have been reported with the therapeutic use of ketotifen fumarate eye solution: allergic reaction, burning or stinging, conjunctivitis, discharge, dry eyes, eye pain, eyelid disorder, itching, keratitis, lacrimation disorder, mydriasis, and photophobia (Prod Info ketotifen fumarate ophthalmic solution, 2005).
    B) WITH POISONING/EXPOSURE
    1) NYSTAGMUS has been reported in both adult and pediatric ingestions (Jefferys & Volans, 1981; Le Blaye et al, 1992).
    2) CASE REPORTS: One patient developed drowsiness, disorientation, nystagmus, tachypnea, tachycardia after the ingestion of ketotifen 10 mg (Jefferys & Volans, 1981).
    3) In several case reports, ingestions of 20 mg to 60 mg of ketotifen resulted in drowsiness, confusion, bradycardia, nystagmus, and tachypnea (Jefferys & Volans, 1981).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Rhinitis has been reported in up to 10% to 25% of patients during controlled trials with ketotifen fumarate solution (Prod Info ketotifen fumarate ophthalmic solution, 2005). Symptoms were described as mild.
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Pharyngitis has been reported with ophthalmic use of ketotifen fumarate solution (Prod Info ketotifen fumarate ophthalmic solution, 2005).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An 80-year-old man ingested 20 mg and experienced hypotension. Vasopressor treatment was initiated. Recovery was complete with no dysrhythmias reported (Le Blaye et al, 1992).
    B) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Five of 21 cases developed bradycardia with doses of 10 mg or greater (Le Blaye et al, 1992).
    b) In several case reports, ingestions of 20 mg to 60 mg of ketotifen resulted in drowsiness, confusion, bradycardia, nystagmus, and tachypnea (Jefferys & Volans, 1981).
    C) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Drowsiness, seizures, respiratory depression, and tachycardia developed in one patient after ingesting 25 mg of ketotifen (Jefferys & Volans, 1981).
    b) CASE REPORTS: One patient developed drowsiness, disorientation, nystagmus, tachypnea, tachycardia after the ingestion of ketotifen 10 mg (Jefferys & Volans, 1981).
    c) CASE SERIES: Five other cases (n=21) developed tachycardia with doses of 10 mg or greater (Le Blaye et al, 1992).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Respiratory depression has occurred with overdose (Jefferys & Volans, 1981; Le Blaye et al, 1992).
    b) CASE REPORTS: Drowsiness, seizures, respiratory depression, and tachycardia developed in one patient after ingesting 25 mg of ketotifen (Jefferys & Volans, 1981).
    B) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: One 3-year-old child became dyspneic following ingestion of 4 mg (Le Blaye et al, 1992).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: Two 4-month-old boys developed infantile spasms 8 to 10 days after a therapeutic dose of ketotifen (Yasuhara et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Seizures, hypotension, and coma have been reported in adults ingesting over 20 mg (Le Blaye et al, 1992).
    b) CASE REPORTS: Drowsiness, seizures, respiratory depression, and tachycardia developed in one patient after ingesting 25 mg of ketotifen (Jefferys & Volans, 1981).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) ORAL: Sedation and mild dizziness have been reported with oral ketotifen (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).
    2) WITH POISONING/EXPOSURE
    a) CNS depression ranging from confusion to sedation or coma may occur after overdose (Le Blaye et al, 1992; Jefferys & Volans, 1981).
    b) CASE SERIES: Fourteen of 21 overdoses developed decreasing mental status, sleepiness, disorientation or confusion. One patient was comatose. CNS depression has been reported at doses as low as 10 mg in adults and 2 mg to 4 mg in children (Le Blaye et al, 1992; Jefferys & Volans, 1981).
    c) One patient developed drowsiness, disorientation, nystagmus, tachypnea, tachycardia after the ingestion of ketotifen 10 mg (Jefferys & Volans, 1981).
    d) CASE REPORTS: Seizures, hypotension, and coma have been reported in adults ingesting over 20 mg (Le Blaye et al, 1992).
    e) CASE REPORTS: Drowsiness, seizures, respiratory depression, and tachycardia developed in one patient after ingesting 25 mg of ketotifen (Jefferys & Volans, 1981).
    f) In several case reports, ingestions of 20 mg to 60 mg of ketotifen resulted in drowsiness, confusion, bradycardia, nystagmus, and tachypnea. One patient became unconsciousness after ingesting 50 mg of ketotifen. Recovery occurred within 2 hours (Jefferys & Volans, 1981).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches were reported in 10% to 25% of patients in controlled trials following the use of ketotifen fumarate ophthalmic solution (Prod Info ketotifen fumarate ophthalmic solution, 2005). Symptoms were generally mild.
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Headache occurred in one case following ingestion of 120 mg (Jefferys & Volans, 1981).
    D) CENTRAL NERVOUS SYSTEM STIMULATION
    1) WITH THERAPEUTIC USE
    a) ORAL: CNS stimulation, such as excitation, irritability, insomnia, and nervousness have been reported in patients, particularly in children, taking ketotifen 1 mg tablets or 1 mg/5 mL syrup (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 21-year-old woman complained of mild abdominal pain and headache following ingestion of 120 mg (Jefferys & Volans, 1981).
    B) APTYALISM
    1) WITH THERAPEUTIC USE
    a) ORAL: Dry mouth has rarely been reported in patients taking ketotifen 1 mg tablet or 1 mg/5 mL syrup (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) ORAL: Elevated liver enzymes has rarely been reported in patients taking ketotifen 1 mg tablet or 1 mg/5 mL syrup (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).
    B) INFLAMMATORY DISEASE OF LIVER
    1) WITH THERAPEUTIC USE
    a) ORAL: Hepatitis has rarely been reported in patients taking ketotifen 1 mg tablet or 1 mg/5 mL syrup (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) CYSTITIS
    1) WITH THERAPEUTIC USE
    a) ORAL: Cystitis has rarely been reported in patients taking ketotifen 1 mg tablet or 1 mg/5 mL syrup (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Rash has been reported following ketotifen ophthalmic solution (Prod Info ketotifen fumarate ophthalmic solution, 2005) and tablet (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).
    b) CASE REPORT: A patient developed contact dermatitis after treatment with ketotifen ophthalmic drops (Niizeki et al, 1994).
    c) CASE REPORT: A 4-year-old girl developed a skin eruption similar to pityriasis rosea following the use of ketotifen; it was confirmed by a positive MIF test and mast cell test (Wolf et al, 1985).
    B) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) ORAL: Erythema multiforme has rarely been reported in patients taking ketotifen 1 mg tablet or 1 mg/5 mL syrup (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).
    C) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) ORAL: Stevens-Johnson syndrome has rarely been reported in patients taking ketotifen 1 mg tablet or 1 mg/5 mL syrup (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, and liver enzymes following significant overdose.

Methods

    A) CHROMATOGRAPHY
    1) Mass spectrometry after gas chromatographic separation has been used (Jefferys & Volans, 1981).
    B) SPECTROMETRY
    1) Atomic absorption spectrometry and colorimetric methods have been developed for the determination and quantification of ketotifen in pharmaceutical preparations (El-Kousy & Bebawy, 1999).

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 significant CNS or respiratory depression should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, and liver enzymes following significant overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) OPHTHALMIC: Because of limited expected toxicity of ophthalmic solution, gastrointestinal decontamination is not routinely recommended. An ingestion of the contents of one 5 mL ophthalmic solution bottle would be equivalent to 1.725 mg of ketotifen fumarate, acute overdose is unlikely to result in clinically significant adverse events. ORAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    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) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs, mental status, and liver enzymes following significant overdose.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    C) SEIZURE
    1) 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).
    2) 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 .
    3) 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).
    4) 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).
    5) 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).
    6) 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) BRADYCARDIA
    1) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    2) ISOPROTERENOL INDICATIONS
    a) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
    b) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
    c) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis and hemoperfusion are unlikely to be of value because of the large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: OPHTHALMIC: In the United States, Ketotifen is only available in small 1 to 5 mL bottles. An ingestion of the contents of one 5 mL ophthalmic solution bottle would be equivalent to 1.725 mg of ketotifen fumarate, and would not be expected to result in significant toxicity even in a young child. ORAL: ADULTS: One patient developed drowsiness, disorientation, nystagmus, tachypnea, tachycardia after the ingestion of ketotifen 10 mg. Seizures, hypotension, and coma developed in adults ingesting over 20 mg. Drowsiness, seizures, respiratory depression, and tachycardia developed in one patient after ingesting 25 mg of ketotifen. A 21-year-old developed abdominal pain and headache after ingesting 120 mg of ketotifen. CHILDREN: Eight children (age range, 2 to 10 years) ingested 2 to 20 mg of ketotifen. Effects included sleepiness, tachypnea, cyanosis, dyspnea, fever, dry nose, nystagmus and tachycardia. Two children ingested up to 10 mg of ketotifen and developed no clinical symptoms.
    B) THERAPEUTIC DOSES: ADULTS: Ophthalmic solution: One drop (0.025% ketotifen fumarate solution/5 mL) in affected eye(s) twice daily, every 8 to 12 hr. CHILDREN: 3 years and older: Ophthalmic solution: One drop (0.025% ketotifen fumarate solution/5 mL) in affected eye(s) twice daily, every 8 to 12 hr. Older than 3 years: Oral tablets and syrups: 1 mg twice daily. 6 months to 3 years: 0.05 mg (equal to 0.25 mL of syrup) per kilogram body weight given twice daily.

Therapeutic Dose

    7.2.1) ADULT
    A) OPHTHALMIC: One drop (0.025% ketotifen fumarate solution/5 mL) in affected eye(s) twice daily, every 8 to 12 hr (Prod Info ketotifen fumarate ophthalmic solution, 2005)
    7.2.2) PEDIATRIC
    A) OPHTHALMIC
    1) AGES 3 YEARS AND OLDER: One drop (0.025% ketotifen fumarate solution/5 mL) in affected eye(s) twice daily, every 8 to 12 hr (Prod Info ketotifen fumarate ophthalmic solution, 2005)
    2) Safety and effectiveness in children below 3 years of age not established (Prod Info ketotifen fumarate ophthalmic solution, 2005).
    B) ORAL
    1) OLDER THAN 3 YEARS: Oral tablets and syrups (1 mg/5 mL): 1 mg twice daily (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).
    2) 6 MONTHS TO 3 YEARS: 0.05 mg (equal to 0.25 mL of syrup) per kilogram body weight given twice daily (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).

Maximum Tolerated Exposure

    A) An ingestion of the contents of one 5 mL ophthalmic solution bottle would be equivalent to 1.725 mg of ketotifen fumarate (Prod Info ketotifen fumarate ophthalmic solution, 2005).
    B) No serious toxic effects have been reported after the ingestion of up to 20 mg of ketotifen fumarate (Prod Info ketotifen fumarate ophthalmic solution, 2005; Le Blaye et al, 1992).
    C) CHILDREN: Eight children (age range, 2 to 10 years) ingested 2 to 20 mg of ketotifen. Effects included sleepiness, tachypnea, cyanosis, dyspnea, fever, dry nose, nystagmus and tachycardia. One 10-year-old child who had ingested 10 mg (serum level 16 mcg/L) developed no clinical symptoms. One 4-year-old child who had ingested 6 to 8 mg of ketotifen developed no clinical symptoms (Jefferys & Volans, 1981; Le Blaye et al, 1992).
    D) CASE REPORTS
    1) One patient developed drowsiness, disorientation, nystagmus, tachypnea, tachycardia after the ingestion of ketotifen 10 mg (Jefferys & Volans, 1981).
    2) In several case reports, ingestions of 20 mg to 60 mg of ketotifen resulted in drowsiness, confusion, bradycardia, nystagmus, and tachypnea. One patient became unconsciousness after ingesting 50 mg of ketotifen. Recovery occurred within 2 hours (Jefferys & Volans, 1981).
    3) Seizures, hypotension, and coma developed in adults ingesting over 20 mg (Le Blaye et al, 1992).
    4) Drowsiness, seizures, respiratory depression, and tachycardia developed in one patient after ingesting 25 mg of ketotifen (Jefferys & Volans, 1981).
    5) A 21-year-old developed abdominal pain and headache after ingesting 120 mg of ketotifen (Le Blaye et al, 1992; Jefferys & Volans, 1981).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) The therapeutic plasma level is 1 to 4 mcg/mL (Jefferys & Volans, 1981).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) The following effects were associated with serum ketotifen concentrations (Jefferys & Volans, 1981):
    1) 21-year-old woman: Mild abdominal pain, headache; 122 mg/L 20 hours after an ingestion of 120 mg of ketotifen.
    2) 34-year-old man: Drowsy, bradycardia, confusion; 5 mg/L 2 hours after an ingestion of 40 mg of ketotifen.
    3) 6-year-old girl: Drowsy, disoriented, nystagmus, tachypnea, tachycardia; 16 mg/L 5 hours after an ingestion of 10 mg of ketotifen.
    4) 21-year-old man: Unconscious at time of admission (regained consciousness 2 hours later); 54 mg/L 3 hours after an ingestion of 50 mg of ketotifen.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 108 mg/kg ((RTECS, 2000))
    2) LD50- (ORAL)MOUSE:
    a) 179 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ketotifen fumarate, a selective, non-competitive histamine antagonist (H1-receptor) and mast cell stabilizer, that acts by inhibiting the release of mediators from cells involved in hypersensitivity reactions and also prevents chemotaxis and activation of eosinophils (Prod Info Zaditen(R) oral tablets, oral syrup, 2010).

Physicochemical

Physical Characteristics

    A) 0.345 mg ketotifen fumarate is equivalent to 0.25 mg ketotifen (Prod Info Zaditor(TM), 1999).

Molecular Weight

    A) KETOTIFEN: 309.43 (Budavari, 1996)
    B) KETOTIFEN FUMARATE: 425.5 (Prod Info Zaditor(TM), 1999)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    3) Budavari S: The Merck Index, 12th ed, Merck & Co, Inc, Whitehouse, NJ, 1996.
    4) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    5) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    6) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    7) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    8) Craps L: Prophylaxis of asthma with ketotifen in children and adolescents: a review. Pharmatherapeutica 1983; 3:314-326.
    9) El-Kousy N & Bebawy LI: Determination of some antihistaminic drugs by atomic absorption spectrometry and colorimetric methods. J Pharm Biomed Analy 1999; 20:671-679.
    10) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    11) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    12) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    13) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    14) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    15) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    16) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    17) Jefferys DB & Volans GN: Ketotifen overdose: surveillance of the toxicity of a new drug. Br Med J 1981; 282:1755-1756.
    18) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    19) Le Blaye I, Donatini B, & Hall M: Acute ketotifen overdosage. A review of present clinical experience. Drug Safety 1992; 7:387-392.
    20) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    21) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    22) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    23) Niizeki H, Inamoto N, & Nakamura K: Contact dermatitis from ketotifen fumerate eyedrops. Contact Dermatitis 1994; 31:266.
    24) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    25) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    26) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    27) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    28) Product Information: Zaditen(R) oral tablets, oral syrup, ketotifen fumarate oral tablets, oral syrup. Teva Canada Limited (Per manufacturer), Toronto, Canada, 2010.
    29) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    30) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    31) Product Information: ketotifen fumarate ophthalmic solution, ketotifen fumarate ophthalmic solution. Apotex Inc, Toronto, ON, 2005.
    32) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    33) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    34) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    35) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    36) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    37) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    38) Wolf R, Wolf D, & Livni E: Pityriasis rosea and ketotifen. Dermatologica 1985; 171:355-356.
    39) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.