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Ketotifen (Systemic)


VA CLASSIFICATION
Primary: RE190

Commonly used brand name(s): Apo-Ketotifen; Novo-Ketotifen; Zaditen.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.



Category:


Asthma prophylactic, systemic —

Antiallergic, systemic—

Indications

Accepted

Asthma, atopic (prophylaxis)—Oral ketotifen is indicated as an add-on medication in the chronic treatment of mild atopic asthmatic children. Ketotifen is a prophylactic agent to be used on a continuous basis and is not effective in the acute prevention or treatment of acute asthma attacks. {01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Ketotifen fumarate: 425.5{01}

pKa—
    Ka I = 8.43 ± 0.11{01}

Solubility
    In the form of hydrogen fumarate it is readily soluble in water. Ketotifen is stable in slightly acidic solution. {01}

Partition coefficient
    Chloroform/hydrochloric acid 0.1 N 1.2:1{01}
    n-Octanol/hydrochloric acid 0.1 N 0.7:1{01}
    Chloroform/phosphate buffer pH 6.8, 0.05 M >100:1{01}
    n-Octanol/phosphate buffer pH 6.8, 0.05 M >100:1{01}

Mechanism of action/Effect:

Ketotifen is a non-bronchodilator antiasthmatic drug which inhibits the effects of certain endogenous substances known to be inflammatory mediators, and thereby exerts antiallergic activity. Ketotifen possesses a powerful and sustained non-competitive histamine (H 1) blocking property. Ketotifen's antihistamine (H 1) effect seems to be distinct from its antiallergic properties. Properties of ketotifen which may contribute to its antiallergic activity and its ability to affect the underlying pathology of asthma include: In Vivo results: Inhibition of the development of airway hyperreactivity associated with activation of platelets by PAF (Platelet Activating Factor) or caused by neural activation following the use of sympathomimetic drugs or the exposure to allergen; inhibition of PAF-induced accumulation of eosinophils and platelets in the airways; suppression of the priming of eosinophils by human recombinant cytokines and thereby suppression of the influx of eosinophils into inflammatory loci; antagonism of bronchoconstriction due to leukotrienes. In Vitro results: Inhibition of the release of allergic mediators such as histamine, leukotrienes C4and D 4(SRS-A) and PAF. {01}

Absorption:

Following oral administration absorption is at least 60%, and possibly even greater. The rate of absorption is rapid with an absorption half-life of 1 hour. Bioavailability is about 50% due to a large first pass effect.{01}

Bioavailability is not affected by the intake of food. {01}

Protein binding:

High (75%){01}

The percentage of protein binding is concentration-independent. {01}

Biotransformation:

Ketotifen undergoes a large first pass effect in the liver (approximately 50%). {01}

The main metabolite found in both plasma and urine is the inactive ketotifen-N-glucuronide. Nor-ketotifen, the N-demethylated metabolite, and the 10–hydroxyl derivative are the only other metabolites detectable in human urine. Both the 10–hydroxyl derivative and N-glucuronide conjugate may reform the intact product by in vivo reversibility. {01}

The pattern of metabolism in children over the age of 3 years is the same as in adults, but the clearance is higher in children.{01}

Half-life:

Distribution—3 to 5 hours. {01}

Elimination— 21 hours.{01}

Onset of action:

Clinical improvements have been observed in some cases within the first week of treatment and generally reach statistical significance after ten weeks. {01}

Time to peak concentration:

2 to 4 hours.{01}

Time to steady-state concentration

Less than 4 days.{01}

Elimination:
    Within 48 hours, urinary excretion amounts to 1% as unchanged drug and 60% to 70% as metabolites.{01}
    Clearance is higher in children.{01}


Precautions to Consider

Pregnancy/Reproduction
Fertility—
In female rats treated orally with ketotifen fumarate at doses of 2, 10, and 50 mg/kg for two weeks, subsequent mating with untreated males showed no adverse effects on the fertility of the females at any dose level. In male rats treated orally for 70 days with 2, 10, and 50 mg/kg of ketotifen fumarate, no adverse effects were observed on fertility up to the dose of 10 mg/kg. In the 50 mg/kg group, a decreased copulation and fertility index was seen. {01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. {01}

Following oral or intravenous administration in rats, ketotifen passes the maternal/fetal barrier; however, only low levels were found in the fetal tissues.{01}

No teratogenic or embryolethal effects were seen when ketotifen was given to female rats in doses of 10, 30, 56, and 100 mg/kg/day between the sixth and fifteenth day of pregnancy. Maternal weight gain and total body weight were decreased at the 56 and 100 mg/kg/day dose levels. The 100 mg/kg dose was lethal to some of the adult animals. In rabbits, no teratogenic or embryolethal effects were seen following ketotifen treatment by gavage at daily doses of 5, 15, and 45 mg/kg between the sixth and eighteenth day of pregnancy.{01}

In male rats treated orally for seventy days with 2, 10, and 50 mg/kg of ketotifen, no adverse effects were observed on the development of the offspring up to the dose of 10 mg/kg. In the 50 mg/kg group, an increased pre and postnatal mortality of the offspring was seen. However, high mortality occurred in males in the 10 and 50 mg/kg groups.{01}

In female rats treated orally with ketotifen at doses of 2, 10, and 50 mg/kg for two weeks, subsequent mating with untreated males showed no adverse effects on the development of their offspring at any dose level. Impairment of weight gain and increased mortality was seen in mothers treated with 10 and 50 mg/kg.{01}

In female rats treated orally with 2, 10, and 50 mg/kg of ketotifen from day fifteen postcoitum to day twenty-one postpartum, no adverse effects on the pre and postnatal development of the offspring were found in the two lower dose groups. However, the 50 mg/kg dose produced mortality in 10% of the mothers as well as an increase loss of pups, resulting in slightly decreased litter size and reduced weight gain during the first four days. {01}

Postpartum——
In female rats treated orally with 2, 10, and 50 mg/kg of ketotifen from day fifteen postcoitum to day twenty-one postpartum, no adverse effects on the pre and postnatal development of the offspring were found in the two lower dose groups. However, the 50 mg/kg dose produced mortality in 10% of the mothers as well as an increase loss of pups, resulting in slightly decreased litter size and reduced weight gain during the first four days. {01}

Breast-feeding

Ketotifen is distributed into the milk of rats and may be distributed into human breast milk. Women who take this medication should not breast-feed.{01}

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of ketotifen in children.


Geriatrics


No information is available on the relationship of age to the effects of ketotifen in geriatric patients{01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Antidiabetic agents, oral{01}    (concomitant use with ketotifen may result in reversible thrombocytopenia; platelet counts are recommended during concurrent use{01})


» Alcohol or
» Antihistamines or
» Hypnotics or
» Sedatives    (concurrent use with ketotifen may potentiate the CNS depressant effects of these medications{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Liver enzymes    ( elevated values were seen during clinical trials; however, no causal relationship could be established{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to ketotifen or to any other component of the formulations, including benzoate compounds which are only present in the syrup {01}.
Risk-benefit should be considered when the following medical problems exist
» Diabetes mellitus{01}    (carbohydrate content of the syrup (5 mL = 4 grams carbohydrate) should be taken into consideration; use ketotifen with caution if taking an oral antidiabetic agent{01})


» Epilepsy{01}    (ketotifen may lower the seizure threshold{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Platelet count {01}    (recommended in patients taking oral antidiabetic agents concomitantly{01})




Side/Adverse Effects

Note: In one clinical trial, there was a relatively low incidence of adverse reactions reported. Adverse reactions were similar in both the ketotifen and placebo treated groups of patients. {01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Flu {01}(chills; cough; diarrhea; fever; general feeling of discomfort or illness; headache; joint pain; loss of appetite; muscle aches and pains; nausea; runny nose; shivering; sore throat; sweating; trouble sleeping; unusual tiredness or weakness; vomiting)
    
respiratory infection {01}(cough; fever; sore throat)

Incidence rare
    
Cystitis {01}(bloody or cloudy urine; difficult, burning, or painful urination; frequent urge to urinate)
    
erythema multiforme {01}(blistering, itching, peeling, or redness of skin; joint pain; muscle pain; unusual tiredness or weakness)
    
hepatitis {01}(abdominal or stomach pain; chills; clay-colored stools; dark urine; diarrhea ; dizziness; fever; headache ; itching; loss of appetite; nausea; rash; unpleasant breath odor; unusual tiredness or weakness; vomiting of blood ; yellow eyes or skin)
    
seizures {01}(convulsions; muscle spasm or jerking of all extremities; sudden loss of consciousness )



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Weight gain {01}

Incidence less frequent or rare
    
Abdominal pain {01}(stomach or abdomen pain)
    
central nervous system (CNS) stimulation {01}(excitation; irritability; insomnia; nervousness)—particularly in children
    
dizziness {01}
    
dryness of mouth {01}
    
epistaxis {01}(bloody nose; unexplained nosebleeds)
    
increased appetite {01}
    
sedation ( drowsiness){01}
    
skin rash {01}
    
sleep disturbance {01}( trouble sleeping)
    
swelling of eyelids {01}

Note: Dizziness, dryness of mouth, and sedation may occur at the beginning of ketotifen treatment but usually disappear with continued use.{01}






Overdose
For specific information on the agents used in the management of ketotifen toxicity or overdose, see:    • Barbiturates (Systemic) monograph; and/or
   • Benzodiazepines (Systemic) monograph; and/or
   • Charcoal, Activated (Oral-Local) monograph; and/or
   • Physostigmine (Systemic)monograph.

For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
coma {01}(loss of consciousness)—reversible
    
confusion {01}(disorientation)
    
convulsions {01}(seizures)—especially in children
    
hyperexcitability {01}—in children
    
hypotension {01}(blurred vision; confusion; dizziness; faintness, or lightheadedness when getting up from a lying or sitting position; sweating; unusual tiredness or weakness)
    
sedation {01}( drowsiness)—mild to severe
    
tachycardia {01}( fainting; fast, pounding, or irregular heartbeat or pulse ; palpitations)


Treatment of overdose
Treatment is generally symptomatic and supportive{01} , possibly including:


To decrease absorption:
If ingestion is very recent, emptying of the stomach may be considered. Administration of activated charcoal may be beneficial.{01} See the package insert or Charcoal, Activated (Oral-Local) for specific dosing guidelines for use of this product.



Specific treatment:
If necessary, specific or symptomatic treatment and monitoring of the cardiovascular system and physostigmine for anticholinergic effects are recommended.{01} See the package insert or Physostigmine (Systemic) for specific dosing guidelines for use of this product.

If excitation or convulsions are present, short-acting barbiturates or benzodiazepine may be given. {01} See the specific package inserts or Barbiturates (Systemic) or Benzodiazepines (Systemic) for specific dosing guidelines for use of these products.



Monitoring:
Monitor the cardiovascular system. {01}



Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ketotifen (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to ketotifen or to any other component of the formulations, including benzoate compounds which are only present in the syrup. {01}





Breast-feeding— May be distributed into human breast milk; women taking ketotifen should not breast-feed
Other medications, especially antidiabetic agents (oral), alcohol, antihistamines, hypnotics, or sedatives{01}
Other medical problems, especially diabetes mellitus or epilepsy {01}

Proper use of this medication
» Helps prevent, but does not relieve, acute asthma attacks

» Ketotifen must be used continuously to be effective

Continuing current asthma medications unless otherwise directed by physician

» Ketotifen may be taken with or without food

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

Proper storage

Precautions while using this medication
» Regular visits to physician to check progress during therapy

» Since drowsiness and, rarely, slight dizziness may occur in the early stages of therapy caution is advised; not driving, using machines, or doing anything else that requires alertness while taking ketotifen

» Occasionally, symptoms of central nervous system (CNS) stimulation, such as excitation, irritability, insomnia, and nervousness have been observed, particularly in children

» For patients with diabetes: Recognizing that ketotifen syrup contains 4 grams of carbohydrate in every 5 mL; glucose concentrations may be affected


Side/adverse effects
Signs of potential side effects, especially flu, respiratory infection, cystitis, erythema multiforme, hepatitis, and seizures


General Dosing Information
Ketotifen must be taken continuously to be effective. Clinical effectiveness is generally reached after 10 weeks of treatment. For patients not adequately responding within a few weeks, treatment should be maintained for a minimum of 2 to 3 months. Continuous use may reduce the frequency, severity, and duration of asthmatic symptoms or attacks, and lead to a reduction in daily requirements of concomitant antiasthmatic medication. If it is necessary to withdraw ketotifen , this should be done progressively over a period of 2 to 4 weeks.{01}

To minimize initial sedation, a slow increase in dosage is recommended during the first week of treatment commencing with one half the daily recommended dosage given in two divided doses or in a single dose given in the evening, followed within 5 days, by an increase to the full therapeutic dose. {01}

Existing asthma therapy should be maintained. A progressive reduction in dosage of other asthma drugs, where clinically indicated, should be attempted only after 6 to 12 weeks of ketotifen therapy. Reduction in the dosage of corticosteroids and/or ACTH should be completed in a gradual manner according to accepted and recommended methods. Patients should be monitored carefully during the dosage reduction period. If symptoms recur during the period of dosage reduction, the daily dose of the drug(s) should be raised immediately.{01}

Diet/Nutrition
Ketotifen may be taken with or without food.{01}


Oral Dosage Forms

KETOTIFEN FUMARATE SYRUP

Usual adult and adolescent dose
Asthma, atopic (prophylaxis)
Oral, 5 mL (1 mg) twice daily, in the morning and evening.{01}


Usual pediatric dose
Asthma, atopic (prophylaxis)
Infants and children 6 months to 3 years of age: Oral, 0.25 mL (50 mcg or 0.05 mg) per kg of body weight twice daily, in the morning and evening. {01}

Children older than 3 years of age: See Usual adult and adolescent dose.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mg per 5 mL (Rx) [Apo-Ketotifen (artificial strawberry flavor) (citric acid) ( glycerin) (purified water) ( methylparaben) (propylparaben) ( sodium citrate) (sorbitol) ( sucrose){02}] [Novo-Ketotifen (alcohol) (citric acid) (strawberry flavor) (methyl p-hydroxybenzoate) (propyl-p-hydroxybenzoate ) (sodium phosphate) ( sorbitol solution) (sucrose) ( water){03}] [Zaditen (alcohol ) (citric acid) (propyl-p-hydroxybenzoate ) (sodium phosphate) ( methyl p-hydroxybenzoate) (sorbitol solution) (sucrose) (strawberry flavor) (water){01}]

Packaging and storage:
Store at temperatures not exceeding 25 °C (77 °F).{01}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • For oral use.


Caution:
Patients who are sensitive to benzoate compounds should not use benzoate-containing brands of ketotifen syrup.{01}


KETOTIFEN FUMARATE TABLETS

Usual adult and adolescent Dose
Asthma, atopic (prophylaxis)
Oral, 1 mg twice daily in the morning and evening. {01}


Usual Pediatric Dose
Asthma, atopic (prophylaxis)


Children older than 3 years of age:
See Usual adult and adolescent dose



Infants and children from 6 months to 3 years of age:
See Ketotifen Fumarate Syrup.



Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mg (Rx) [Novo-Ketotifen (cornstarch) (lactose) (magnesium stearate) (water){03}] [Zaditen{01} (scored) ( calcium hydrogen phosphate, magnesium stearate, maize starch)]{01}

Packaging and storage:
Store at temperatures not exceeding 25 °C (77 °F), in a dry place.{01}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Swallow tablet whole.



Developed: 08/02/2000



References
  1. Product Information: Zaditen(R), ketotifen fumarate. Novartis Pharmaceuticals, Dorval, Quebec, Canada, (PI revised 9/1998) reviewed 7/2000.
  1. Ketotifen fumarate (Apo-Ketotifen, Apotex). In: Welbanks L, editor. CPS Compendium of pharmaceuticals and specialties. 35th ed. Ottawa: Canadian Pharmacists Association; 2000. p. 114.
  1. Ketotifen fumarate (Novo-Ketotifen, Novpharm). In: Welbanks L, editor. CPS Compendium of pharmaceuticals and specialties. 35th ed. Ottawa: Canadian Pharmacists Association; 2000. p. 1099.
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