Professional Drug Information > Cetirizine Hydrochloride and Pseudoephedrine Hydrochloride

Cetirizine and Pseudoephedrine (Systemic)

VA CLASSIFICATION
Primary: RE501

Commonly used brand name(s): Zyrtec-D 12 Hour.

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

^†Not commercially available in Canada.

Category:


Antihistaminic, H₁-receptor-decongestant—

Indications

Accepted

Rhinitis, seasonal allergic (treatment) or
Rhinitis, perennial allergic (treatment)—Cetirizine and pseudoephedrine combination is indicated for symptomatic relief of seasonal or perennial allergic rhinitis in adults and children 12 years of age and older when both the antihistaminic and decongestant effects are desired.^{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—


Cetirizine hydrochloride:
    Piperazine derivative. Cetirizine is a metabolite of hydroxyzine.^{01}

Molecular weight—


Cetirizine hydrochloride:
    461.82^{01}



Pseudoephedrine hydrochloride:
    201.70^{01}


Solubility


Cetirizine hydrochloride:
    Water soluble.^{01}



Pseudoephedrine hydrochloride:
    Very soluble in water, freely soluble in alcohol, and sparingly soluble in chloroform.^{01}


Mechanism of action/Effect:


Cetirizine:

The selective inhibition of H₁ receptors resulting in antihistaminic effects documented in both animal and human models.^{01}



Pseudoephedrine:

A sympathomimetic amine that has a decongestant effect on the nasal mucosa. Its peripheral effects are similar to those of ephedrine and its central effects are similar to, but less intense than, those of amphetamines.^{01}



Other actions/effects:


Cetirizine:

In animal models it has been shown that cetirizine has negligible anticholinergic and antiserotonergic activity. However, in clinical studies, dry mouth was more common with cetirizine than with placebo. Ex-vivo experiments in mice have shown that cetirizine does not significantly occupy cerebral H₁ receptors.^{01}



Pseudoephedrine:

Pseudoephedrine has the potential for excitatory side effects.^{01}


Absorption:

Bioavailability of cetirizine and pseudoephedrine from the combination formulation is similar to that observed with administration as single agents. Food had no significant effect on the extent of cetirizine absorption (AUC), but Tmax was delayed by 1.8 hours and the Cmax was decreased by 30%. Pseudoephedrine absorption was not affected by food.^{01}

Distribution:


Cetirizine:

Cetirizine has been shown to be distributed into human breast milk^{01}

In animal studies, it was shown that 3% of an oral dose of cetirizine was distributed into breast milk.^{01}



Pseudoephedrine:

The apparent volume of distribution of pseudoephedrine is 2.6 to 3.3 L per kg.^{01}

In humans, it was shown that 0.4 to 0.7% of an oral dose is distributed into breast milk. The milk to plasma drug concentration showed that pseudoephedrine concentrations in milk were 2 to 3 fold higher than those in plasma.^{01}


Protein binding:


Cetirizine—:

Very high (93%) plasma protein binding^{01}{02}



Pseudoephedrine—:

No plasma protein binding data in humans available^{01}.


Biotransformation:


Cetirizine:

Oxidative dealkylation is the method responsible for the limited metabolism of cetirizine resulting in a metabolite with negligible antihistaminic activity^{01}



Pseudoephedrine:

Hepatic, about 25 to 45% of an administered dose is metabolized in the liver^{01}. N-demethylation of pseudoephedrine results in 1 to 7% of a single oral dose being metabolized to norpseudoephedrine^{01} .


Half-life:


Elimination—:



Cetirizine—:

Mean elimination half-life is 7.9 hours^{01}.



Pseudoephedrine—:

Mean elimination half-life is 6.0 hours.^{01}


Onset of action:


Cetirizine (antihistaminic effect)—:

Within 1 hour^{01}.



Pseudoephedrine (decongestant effect)—:

30 minutes ^{03}{04}{05}.


Time to peak concentration:


Plasma:



Cetirizine:

2.2 hours following a single dose.^{01}



Pseudoephedrine:

4.4 hours following a single dose.^{01}


Peak plasma concentration:


Cetirizine:

114 ng per mL following a single dose^{01}.



Pseudoephedrine:

309 ng per mL following a single dose^{01}.


Duration of action:


Cetirizine (antihistaminic effect)—:

At least 24 hours^{01}.



Pseudoephedrine (decongestant effect)—:

8–12 hours ^{03}{04}{05}.


Elimination:


Cetirizine—
        Renal — Of the 70% of the total dose found in the urine, approximately 50% is unchanged drug; 10% recovered in the feces.^{01}



Pseudoephedrine—
        Renal — 55 to 75% is excreted unchanged in the urine^{01}



In dialysis—
        Less than 10% of the administered dose of cetirizine was removed during a single dialysis session^{01}



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to hydroxyzine may also be sensitive to cetirizine, and patient sensitive to other adrenergic agents may also be sensitive to pseudoephedrine^{01}

Carcinogenicity

There are no carcinogenicity studies of cetirizine and pseudoephedrine in combination.^{01}



Cetirizine—:

In a 2–year animal study, cetirizine was not carcinogenic at up to 20 mg per kg dose which is approximately 15 times the maximum recommended daily dose in adults^{01}.



Pseudoephedrine—:

A 2–year animal study demonstrated no evidence of carcinogenic potential with ephedrine sulfate, a structurally related drug with pharmacological properties similar to pseudoephedrine, at doses 10 and 27 mg per kg which is 1/3 to 1/2 the maximum recommended daily dose of pseudoephedrine in adults^{01}.


Tumorigenicity


Cetirizine—

In animal studies no increase in liver tumors was observed with doses of 4 mg per kg, which is 2 times the maximum recommended daily dose in adults, but with doses 6 times the maximum (16 mg per kg), there was an increase in benign liver tumors^{01}.


Mutagenicity

The combination of cetirizine and pseudoephedrine in a 1:24 ratio was not mutagenic or clastogenic in the Ames test, the mouse lymphoma test or the human lymphocyte test. However, the Ames and mouse lymphoma assays did not strictly adhere to test standards.^{01}



Cetirizine:

There was no evidence of mutagenicity in the Ames test or mouse lymphoma test. Cetirizine was not clastogenic in human lymphocyte assay or the in-vivorodent micronucleus test.^{01}


Pregnancy/Reproduction
Fertility—
Reproductive toxicity studies in animals showed no effects on fertility when oral doses of 6 mg per kg of cetirizine and 154 mg per kg of pseudoephedrine were given in combination, which is approximately 5 times the maximum recommended daily dose in adults.^{01}

Pregnancy—
Adequate and well-controlled studies in pregnant women have not been done using the combination of cetirizine and pseudoephedrine.^{01}

In animal studies using rats, the combination of cetirizine and pseudoephedrine caused developmental toxicity when administered orally at approximately 5 times the maximum recommended daily dose in adults. When the animals were dosed throughout pregnancy at those same doses, there was an increase in the number of fetal skeletal malformations and variants. In studies in rabbits the same doses resulted in no embryofetal toxicity.^{01}

Since there are no adequate and well-controlled studies in pregnant women, cetirizine and pseudoephedrine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus^{01}

FDA Pregnancy Category C.^{01}

Breast-feeding

Because cetirizine and pseudoephedrine are distributed into breast milk, its use in nursing mothers is not recommended.^{01}

When cetirizine was administered alone, in animal studies it was reported that approximately 3% of the dose is distributed into breast milk.^{01}

When pseudoephedrine was administered alone, 0.4 to 0.7% of the dose has been reported to be distributed into human breast milk.^{01}

In animal studies with rats, when dosing of 6 mg per kg of cetirizine and 154 mg per kg of pseudoephedrine combined, which is approximately 5 times the maximum recommended daily dose in adults, was continued throughout lactation, the viability and weight gain of the offspring decreased. This effect was not found when doses equivalent to maximum recommended daily doses in adults where given^{01}.

Pediatrics


Cetirizine and pseudoephedrine:

No information is available since appropriate studies in have not been performed on the relationship of age to the effects of the combination of cetirizine and pseudoephedrine in the pediatric population in children up to 12 years of age. Safety and efficacy have not been established.^{01}



Pseudoephedrine:

The dose of pseudoephedrine in the combination exceeds the recommended dose for pediatric patients under 12 years of age and therefore its use is not recommended^{01}



Geriatrics


Insufficient information is available on the relationship of age to the effects of cetirizine and pseudoephedrine in geriatric patients. However, elderly patients are more likely to have age-related hepatic, renal, or cardiac function conditions, concomitant disease, or other drug therapy which may require cautious use.^{01}

Note:  In a study conducted on adult subjects with a mean age of 77, following a single 10 mg oral dose of cetirizine, the elimination half-life was prolonged by 50% and the apparent total body clearance was 40% lower. The decrease in cetirizine clearance may be related to decreased renal function^{01}


Insufficient information is available on the relationship of age to the effects of pseudoephedrine in geriatric patients. However the elderly are more likely to have adverse reactions to sympathomimetic amines.^{01}


Pharmacogenetics

The effects of race and gender on cetirizine or pseudoephedrine pharmacokinetics have not been adequately studied.^{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.

» Alcohol or
» CNS depression–producing medications, other (see Appendix II)    (Alcohol or other central nervous system depressants including tricyclic antidepressants should be avoided due to the potentiation of reductions in alertness and CNS performance^{01})


Antihypertensives that interfere with sympathomimetic activity, such as:
Mecamylamine,
Methyldopa, or
Reserpine    (concurrent administration with pseudoephedrine may lead to reduced antihypertensive effects^{01})


» Digitalis glycosides    (concurrent administration with pseudoephedrine can result in increased ectopic pacemaker activity.^{01})


» Monoamine oxidase (MAO) inhibitors     (concurrent use with pseudoephedrine is contraindicated; pseudoephedrine should not be administered during and for 14 days after stopping use of MAO inhibitors^{01})


Sympathomimetics, other    (concurrent use may increase the cardiovascular effects of either the other sympathomimetics or pseudoephedrine and the potential for side effects.^{01})


Theophylline    (concurrent administration of theophylline (400 mg once a day for 3 days) with cetirizine has resulted in a 16% decrease in cetirizine clearance^{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
Transaminase and
bilirubin     (reversible hepatic transaminase elevations and elevated bilirubin has been associated with the use of cetirizine^{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 cetirizine, hydroxyzine, pseudoephedrine or other sympathomimetic amines.^{01}
For pseudoephedrine:
» Glaucoma, narrow-angle
» Urinary retention
» Hypertension, severe
» Coronary artery disease, severe    (conditions may be exacerbated due to sympathomimetic activity of pseudoephedrine^{01})


Risk-benefit should be considered when the following medical problems exist
» Renal Impairment    (patients with moderate renal impairment or on hemodialysis can expect a 3 fold increase in cetirizine half-life and a 70% decrease in clearance. Pseudoephedrine may accumulate in patients with renal insufficiency.^{01}. )


For cetirizine:
» Hepatic impairment, such as: hepatocellular, cholestatic, and biliary cirrhosis    (hepatic impairment results in a 50% increase in half-life of cetirizine along with a corresponding 40% decrease in clearance^{01})


For pseudoephedrine:
Diabetes mellitus,
» Hypertension
Hyperthyroidism
» Intraocular pressure, increased
Ischemic heart disease, or
Prostatic hypertrophy    (conditions may be exacerbated.^{01})






Side/Adverse Effects

Note: Pseudoephedrine alone may cause mild CNS stimulation in hypersensitive patients, including nervousness, excitability, restlessness, dizziness, weakness, or insomnia. Other effects include headache, nausea, drowsiness, tachycardia, palpitation, pressor activity, and cardiac arrhythmias. Arrhythmias, dizziness, insomnia, tremor and weakness may be manifestations of patient idiosyncrasy to adrenergic agents. Possible adverse effects of sympathomimetic amines include CNS stimulation with convulsions or cardiovascular collapse and accompanying hypotension. Sympathomimetic medications have also been associated with fear, anxiety, tremor, hallucinations, seizures, pallor, respiratory difficulty, dysuria, and cardiovascular collapse.^{01}


Note: Other side effects have been reported in patients receiving cetirizine in U.S. clinical trials, but a causal relationship of these infrequent events with cetirizine has not been established.^{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:

For cetirizine—
Those indicating need for medical attention
Incidence rare—Observed during clinical practice
    
Anaphylaxis (skin rash or hives; troubled breathing; swollen mouth or throat)
    
cholestasis ( stomach pain; light-colored stools; dark urine; diarrhea; fever; vomiting of blood; yellow eyes or skin)
    
glomerulonephritis (bloody or cloudy urine; increased blood pressure; sudden decrease in amount of urine; swelling of face, fingers, feet, and/or lower legs; rapid weight gain)
    
hemolytic anemia (back, leg, or stomach pains; bleeding gums; dark urine; fatigue; fever; general body swelling; nosebleeds; pale or yellow skin or eyes)
    
hepatitis
    
hypotension, severe ( blurred vision; confusion; dizziness, faintness, or lightheadedness when getting up from a lying or sitting position; sudden sweating; unusual tiredness or weakness )
    
orofacial dyskinesia (twitching, twisting, or uncontrolled repetitive movements of face)
    
stillbirth
    
thrombocytopenia (black, tarry stools; chest pain; chills; swollen glands; unusual bleeding or bruising)
^{01}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (> 5%)
    
Somnolence (sleepiness or unusual drowsiness; extreme tiredness)
^{01}
Incidence less frequent (1–5%)
    
Dry mouth
    
fatigue (weakness)
^{01}
Incidence rare (< 1%)
    
Dizziness
    
pharyngitis ( soreness of throat)
^{01}





Overdose
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:
Cetirizine
    
Somnolence (sleepiness or unusual drowsiness)
    
restlessness
    
irritability
^{01}
Pseudoephedrine

Note: Pseudoephedrine overdose information is limited to marketing history and the information concerning overdose of sympathomimetics in general.^{01}

    
Anxiety
    
arrhythmias or circulatory collapse (dizziness; fainting; fast, slow, or irregular heartbeat)
    
coma
    
convulsions
    
giddiness
    
headache
    
insomnia ( sleeplessness; trouble sleeping)
    
micturition, difficulty in (difficulty in urination)
    
muscular weakness and tenseness
    
nausea
    
palpitations or tachycardia ( fast, irregular, pounding, or racing heartbeat or pulse)
    
precordial pain (chest and/or abdominal pain)
    
respiratory failure (difficult or troubled breathing; irregular, fast or slow, or shallow breathing; shortness of breath)
    
restlessness
    
sweating
    
thirst
    
toxic psychosis with delusions and hallucination (changes in mood; confusion; irrational behavior; depersonalization hallucinations)
    
vomiting

^{01}
Treatment of overdose
There is no known specific antidote to cetirizine^{01}

Cetirizine is not effectively removed by dialysis.^{01}

Supportive care—Symptomatic and supportive treatment is recommended^{01}

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, Cetirizine and Pseudoephedrine (Systemic)
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to cetirizine, hydroxyzine, pseudoephedrine or other sympathomimetic amines

Pregnancy—Studies in animals have shown that cetirizine and pseudoephedrine causes skeletal malformities and variants.





Breast-feeding—Cetirizine and pseudoephedrine are distributed into breast milk. Its use in nursing mothers is not recommended.




Use in children——Safety and efficacy have not been established in children up to 12 years of age.

Other medications, especially alcohol or CNS depression-producing medications, digitalis glycosides, and monoamine oxidase inhibitors
Other medical problems, especially narrow-angle glaucoma, urinary retention, hepatic impairment, renal impairment, severe coronary artery disease, severe hypertension, or increased intraocular pressure

Proper use of this medication

Proper administration technique for extended-release tablets
Swallowing tablet whole; not breaking, crushing, or chewing before swallowing

» 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
» Avoiding use of alcohol or other CNS depressants including tricyclic antidepressants.

» Caution if dizziness or drowsiness occurs; not driving, using machines, or doing anything else that requires alertness while taking cetirizine and pseudoephedrine combination and for 24 hours after discontinuing it

Possible dryness of mouth; using sugarless candy or gum, ice or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks

» Taking last dose of medicine for each day a few hours before bedtime to avoid insomnia


Side/adverse effects
Signs of potential side effects, especially anaphylaxis, cholestasis, glomerulonephritis, hemolytic anemia, hepatitis, severe hypotension, orofacial dyskinesia, stillbirth, or thrombocytopenia


General Dosing Information

Diet/Nutrition
Cetirizine and pseudoephedrine may be given with or without food.^{01}


Oral Dosage Forms

CETIRIZINE HYDROCHLORIDE AND PSEUDOEPHEDRINE HYDROCHLORIDE EXTENDED-RELEASE TABLETS

Usual adult and adolescent dose
Seasonal or perennial allergic rhinitis (treatment)
Oral, one tablet (5 mg cetirizine and 120 mg pseudoephedrine) two times a day.^{01}


Note: In renally impaired patients (creatinine clearance 11 to 31 mL per min), patients on hemodialysis (creatine clearance less than 7 mL per min) and in hepatically impaired patients, a dose of one tablet once a day is recommended.^{01}


Usual pediatric dose
Seasonal or perennial allergic rhinitis (treatment)
Children younger than 12 years of age: Use is not recommended; the dosage limits of pseudoephedrine are exceeded in the extended-release formulation.^{01}

Children 12 years of age and over: See Usual adult and adolescent dose^{01}.


Usual geriatric dose
See Usual adult and adolescent dose^{01}.

Note: In general, dosing in the elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function. The elderly are more likely to have adverse reactions to sympathomimetic amines.^{01}


Strength(s) usually available
U.S.—


5 mg of cetirizine hydrochloride and 120 mg of pseudoephedrine hydrochloride (Rx) [Zyrtec-D 12 Hour ( The bilayer tablet enables the cetirizine component to be immediately released and the pseudoephedrine component to be extended released) (colloidal silicon dioxide) (croscarmellose sodium) (hydroxypropyl methylcellulose) (lactose monohydrate) (magnesium stearate ) (microcrystalline cellulose)]

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F); excursions permitted between 15 and 30 °C (59 and 86 °F)^{01}.

Auxiliary labeling:
   • May cause drowsiness. Be careful while driving or operating machinery.
   • Avoid alcoholic beverages.
   • Swallow tablet whole. Do not crush, break, or chew.^{02}
{01}

Developed: 10/23/2001
Revised: 01/24/2002

References

1. Product information: Zyrtec-D 12 hour™, cetirizine and pseudoephedrine. Pfizer, New York, New York (PI written 07/2001) reviewed 10/2001.
   

2. Expert Committee comment, 12/01.
   

3. Expert Committee comment, 12/01.
   

4. Novafed package insert (Lakeside/Merrell Dow—US), Rec 5/86.
   

5. Sudafed 12 hour extended release caplets package insert (BW—US), Rec 7/93.
   

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