Continuing Education Activity

Cetirizine is a medication used in the treatment of allergic rhinitis and urticaria. It is a second-generation antihistamine. Cetirizine was FDA-approved in the United States as a prescription-only product in 1995, and later in 2007, it got approval as an over-the-counter medication. This activity reviews the indications, action, and contraindications for cetirizine as a valuable agent in treating rhinitis and urticaria. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the treatment of patients using cetirizine.

Objectives:

• Summarize the mechanism of action of cetirizine.
• Outline the adverse effects of cetirizine.
• Review the monitoring of cetirizine.
• Explain how healthcare professionals should educate patients on the potential adverse effects of cetirizine, such as drowsiness and fatigue.

Indications

Cetirizine was FDA-approved in the United States as a prescription-only product in 1995, and later in 2007, it got approval as an over-the-counter medication. Derived from the first-generation antihistamine hydroxyzine, cetirizine does not cross the blood-brain barrier to the extent of its first-generation counterparts; as a result, cetirizine is an effective treatment of allergic rhinitis that simultaneously minimizes the possibility of adverse sedative effects. In addition, cetirizine is a second-generation antihistamine that effectively relieves sneezing, rhinorrhea, and watery eyes associated with seasonal allergies and allergic rhinitis due to allergens such as dust mites and molds. In addition, cetirizine is available as a prescription-only ophthalmic formulation to treat allergic conjunctivitis.

• Cetirizine is an FDA-approved medication for the relief and treatment of allergic rhinitis and chronic urticaria.[1][2] 
• Cetirizine also effectively reduces hives' severity and pruritus in patients with idiopathic urticaria.[3]
• Cetirizine is safe to treat perennial allergic rhinitis and urticaria in adults and children over the age of 6 months; it is indicated for treating seasonal allergies in adults and children two years and older.
• Cetirizine is also safe to use in the geriatric population.
• The ophthalmic formulation of cetirizine is FDA-approved to treat allergic conjunctivitis.[4]
• Cetirizine is used as an adjunct to epinephrine (off-label) for the management of anaphylaxis. (The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) guidelines).[5]
• Second-generation antihistamines like cetirizine are safe and effective treatment options in patients with chronic urticaria and are considered first-line agents by the AAAAI and ACAAI guidelines.[6]

Mechanism of Action

Cetirizine is a fast-acting, highly selective antagonist of the peripheral histamine H1 receptor. The H1-receptors inhibited by cetirizine are primarily on respiratory smooth muscle cells, vascular endothelial cells, immune cells, and the gastrointestinal tract. Unlike first-generation antihistamines such as diphenhydramine and doxylamine, cetirizine does not cross the blood-brain barrier to a large extent, avoiding the neurons of the central nervous system. As a result, cetirizine produces minimal sedation compared to many first-generation antihistamines.[7]

Given its antagonism with histamine H1-receptors, cetirizine effectively reverses many of the effects of histamine. Like other second-generation antihistamines, cetirizine decreases vascular permeability, decreasing fluid escaping to tissues from capillaries. Cetirizine is also an inhibitor of histamine-induced bronchospasm.[8]

Cetirizine has been found to exert significant anti-inflammatory activity, reducing the infiltration of inflammatory cells in the setting of allergic rhinitis.[9] Specifically, research has found that cetirizine minimizes the migration of neutrophils and eosinophils.[10]

Pharmacokinetics

Absorption: Cetirizine is absorbed rapidly in the gastrointestinal tract and undergoes substantial excretion by the kidney. Cetirizine reaches peak plasma concentration after approximately one hour. Its effects typically begin after 20 to 60 minutes and persist for at least 24 hours. Food does not affect the extent of exposure (AUC) of cetirizine, but the time to attain peak concentration is delayed by 1.7 hours.

Distribution: The mean plasma protein binding of cetirizine is 93%.

Metabolism: Cetirizine undergoes oxidative O-dealkylation to a metabolite with negligible antihistaminic activity. Cetirizine is not a substrate of the CYP450 system.[11][12] Evidence indicates that cetirizine is a P-glycoprotein substrate, which should be considered in the concurrent use of cetirizine with P-gp inhibitors.[13]

Excretion: The elimination half-life of cetirizine is 8.3 hours. Cetirizine is primarily excreted through the kidney.[14]

Administration

Cetirizine is available as tablets, capsules, solutions, and orally disintegrating tablets. The dosing of cetirizine depends on the patient's age. In adults and children 12 years or older, the recommended dose is 5 or 10 mg per day orally, depending on symptom severity.[15] It is available in 5 mg and 10 mg tablets and 5 mg/ 5 ml oral solution and elixir. The ophthalmic formulation is available as 0.24% cetirizine hydrochloride eye drops in 5 mL and 7.5 mL bottles.

• In children 6 to 11 years old, 5 or 10 mg (1 or 2 teaspoons) once daily in syrup form is recommended depending on symptom severity.[16]
• In children 2 to 5 years old, the recommended dose is 2.5 mg (half a teaspoon) in syrup form once daily.
• In children six months to 23 months old, the recommended dose is 2.5 mg (half teaspoon) in syrup form once daily.
• One drop (0.24% cetirizine hydrochloride ophthalmic solution) is instilled in the affected eye twice daily for patients with allergic conjunctivitis.

Use in Specific Patient Population

Breastfeeding Considerations: Occasional and small doses of cetirizine are acceptable while breastfeeding. Prolonged use of larger doses may cause a decrease in the milk supply or drowsiness and other adverse effects in the infant, particularly in combination with pseudoephedrine. The use of an ophthalmic formulation of cetirizine by the mother is hypothesized to have minimal risk to the breastfed infant. Clinicians should advise the mother to apply pressure over the tear duct by the corner of the eye and remove the leftover solution to decrease the amount of drug that reaches the breast milk.[17]

Pregnancy Considerations: Cetirizine is a former US FDA pregnancy category B medicine. The American College of Obstetricians and Gynecologists & the American College of Allergy, Asthma, and Immunology (ACOG-ACAAI) suggests cetirizine for pregnant women who requires antihistamine treatment. Cetirizine should be used in pregnancy only when necessary.[18][19]

Hepatic Impairment: According to manufacturers prescribing information, 12 years and older patients with hepatic impairment should reduce the dose to 5 mg once daily. The manufacturer also recommends lowering the dose for 6 to 11 years old patients with hepatic impairment.

Renal Impairment: According to manufacturers prescribing information, 12 years and older patients with decreased renal function (CrCL 11-31 mL/min) and patients on hemodialysis (CrCL less than 7 mL/min) should reduce the dose to 5 mg once daily. The manufacturer also recommends lowering the dose for 6 to 11 years old patients with renal impairment.

Ophthalmic Formulation: Each bottle of 0.24% cetirizine hydrochloride contains benzalkonium chloride and can be absorbed by contact lenses. Manufacturers advise patients to remove contact lenses before instilling eye drops and wait for 10 min until the reinsertion of lenses. If irritation or redness persists after this precaution, then avoid the use of contact lenses. It is proven safe and effective for pediatric patients two years and above in clinical studies.[20]

Adverse Effects

Cetirizine is safe and relatively well-tolerated for treating allergic rhinitis and urticaria. Although uncommon, its primary adverse effects in adults include somnolence, fatigue, pharyngitis, dizziness, and dry mouth.[1]

Somnolence, as a result of cetirizine, appears to be dose-related. Research indicates that in some patients, cetirizine contributes to daytime sleepiness.[21]

Children taking cetirizine most commonly experience similar side effects as adults taking cetirizine (somnolence, fatigue, and dry mouth). Children, in particular, are more likely than adults to experience headaches while taking cetirizine.[22]

In pediatric patients aged 2 to 11 years, the majority of adverse reactions reported with cetirizine were mild or moderate. Among all, somnolence appeared to be dose-related and abdominal pain was considered treatment-related.

Common adverse drug reactions of cetirizine ophthalmic solution are conjunctival hyperemia and instillation site pain.[4]

While on cetirizine therapy, few cases of transient, reversible hepatic transaminase elevations have been reported in the literature. Some reports exist of hepatitis with elevated bilirubin too. In postmarketing studies, rare, potentially severe adverse events like severe hypotension, anaphylaxis, hemolytic anemia, cholestasis, orofacial dyskinesia, glomerulonephritis, hepatitis, stillbirth, and thrombocytopenia are reported.[23]

Ophthalmic formulation's common adverse reactions are local pain at the instillation site, ocular hyperemia, and decreased visual acuity.

Drug-Drug Interactions

• Patients should be advised not to use cetirizine concurrently with alcohol or other CNS depressants, such as benzodiazepines or opioids, as it may cause dose-related sedation.[24]

• Pitolisant is a histamine-3 receptor competitive antagonist and inverse agonist used in patients with narcolepsy. Concurrent use of pitolisant with antihistamines like cetirizine may diminish the therapeutic efficacy of pitolisant. Avoid combination.[25]

• Cetirizine decreases gabapentin plasma concentrations and reduces systemic exposure to gabapentin. However, gabapentin is a CNS depressant; hence the pharmacodynamic synergism leading to additional CNS depression may also be observed.[26]

• Cetirizine is a substrate of P-glycoprotein, and verapamil is an inhibitor of P-glycoprotein. Concurrent administration of both drugs prevents the efflux of cetirizine from the CNS and increases antihistaminic activity.[13]

• Cetirizine should not be administered with erdafitinib as erdatifinib is also an inhibitor of P-glycoprotein(ABCB1, MDR1).[27]

Contraindications

Cetirizine is contraindicated in anyone with a known hypersensitivity to it or any of its ingredients. Cetirizine is also contraindicated in anyone with a known hypersensitivity to hydroxyzine, as cetirizine is a metabolite of hydroxyzine.[28]

There are few well-controlled human studies on cetirizine in pregnant mothers, although these showed it to be safe during pregnancy in animal studies. First-generation antihistamines, diphenhydramine, and doxylamine are safest to use during pregnancy. However, first-generation antihistamines are more likely than second-generation antihistamines to cause somnolence; clinicians should counsel the patients regarding the potential adverse effects of the medication they choose to take during pregnancy.[18]

Monitoring

Patients taking cetirizine require monitoring for the relief of symptoms. Healthcare team members should also monitor patients for adverse effects such as fatigue and somnolence in adults and headaches in children.

The kidney primarily excretes cetirizine; as a result, the risk of toxicity is typically higher in patients with impaired renal function. Patients with renal impairment should take a lower medication dosage in their age bracket.[29]

Liver function and enzymes should also be closely monitored in patients with hepatic impairment. Healthcare providers should make dosage adjustments as needed for patients with hepatic impairment.[30]

Cetirizine may be confused with sertraline (look-alike-sound-alike drugs). Clinicians and pharmacists should be careful while prescribing and dispensing this drug.[31]

Toxicity

Research showed the minimal lethal dose to be approximately 460 times the maximum recommended daily dose for adults in rats. The primary target of acute toxicity in rodents was the central nervous system. The primary target of multiple-dose toxicity in rodents was the liver. A small number of cases of cetirizine overdose appear in the literature. However, many overdoses of cetirizine in children result from improper medication storage by adults living in the same home. Most overdose incidents in children resolve spontaneously, with drowsiness and sedation being the main adverse effects observed. 

Drug-induced liver damage is common with numerous medications; there are reports of a small number of cases of cetirizine-induced liver damage; in all cases, liver enzyme values returned to normal after cessation of cetirizine.[32]

An adult who overdosed on 150 mg cetirizine had somnolence but did not have abnormal blood chemistry, hematology results, or other clinical signs. An infant overdosed on 180 mg of cetirizine and experienced restlessness and irritability, followed by drowsiness. Several hours after an accidental overdose of cetirizine, the six-year-old child presented with fixed and dilated pupils, tachycardia, agitation, hyperthermia, and hallucinations consistent with anticholinergic toxicity.[33] There is no known specific antidote to cetirizine, and it can not be effectively removed by dialysis. When overdosed on cetirizine, treatment should be supportive and symptomatic, considering any concomitantly ingested medications.[34]

Enhancing Healthcare Team Outcomes

Cetirizine is a relatively safe and effective medication for treating allergic rhinitis, urticaria, and allergic conjunctivitis. As cetirizine is also available over the counter, prescribers should educate patients on possible side effects, such as drowsiness, fatigue, and dry mouth, while dispensing medicine. Healthcare providers should be careful when prescribing cetirizine to patients with impaired renal or hepatic function. Ophthalmologists should educate contact lens wearers to exercise precautions and proper direct use of eye drops. Patients using eye drops should be informed that local pain at the instillation site, ocular hyperemia, and decreased visual acuity are common adverse reactions with the ophthalmic formulation.

Immunologists play a crucial role in the management of refractory urticaria. Nurses should monitor therapeutic success and consult patients not to combine cetirizine with drugs that cause central nervous system depression. Pharmacists should perform thorough medication reconciliation and verify that the patient is not taking any medications or supplements that could exacerbate cetirizine's adverse effects. Clinicians(MD, DO, NP, PA), nurses, and pharmacists who prescribe or recommend cetirizine to patients should also provide information on the safe storage of cetirizine to prevent accidental overdose by children. If the overdose of cetirizine is intentional, a psychiatrist should be consulted. Communication and collaboration among interprofessional teams can achieve the best patient outcomes and reduce healthcare service utilization costs. [Level 5]