Continuing Education Activity

This activity discusses using cetirizine for allergic rhinitis and urticaria, shedding light on its indications, mechanism of action, and contraindications. Initially approved by the FDA in 1995 as a prescription-only medication, cetirizine gained over-the-counter status in 2007. This discussion also navigates the adverse event profile and other critical aspects, including off-label uses, dosing, pharmacokinetics, monitoring, and relevant drug interactions, highlighting the role of the interprofessional healthcare team in overseeing therapy. Understanding cetirizine's pharmacology empowers healthcare professionals to tailor treatment plans to individual patient needs. Equipped with evidence-based medicine, they can make informed decisions and fine-tune dosage regimens while mitigating adverse reactions. By enhancing comprehension of cetirizine's pharmacological nuances, this educational initiative aims to elevate patient outcomes in allergic conditions, emphasizing the collaborative effort of the healthcare team in optimizing treatment strategies.

Objectives:

• Identify the mechanism of action of cetirizine.

• Evaluate the adverse effects of cetirizine.

• Assess the clinical monitoring parameters for cetirizine.

• Implement effective collaboration and communication among interprofessional team members to improve patient outcomes and treatment efficacy while educating about 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. In 2007, it was approved 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. Additionally, cetirizine is available as a prescription-only ophthalmic formulation to treat allergic conjunctivitis.

FDA-Approved Indications

• Cetirizine is an FDA-approved medication for the relief and treatment of allergic rhinitis and chronic urticaria.[1][2] The American Academy of Otolaryngology suggests cetirizine for seasonal and perennial allergic rhinitis.[3]
• Cetirizine effectively reduces the severity of hives and pruritus in patients with idiopathic urticaria.[4] 
• 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.[5]
• Cetirizine is considered safe for perennial allergic rhinitis and urticaria in adults and children older than 6 months; it is indicated for treating seasonal allergies in adults and children 2 years and older.
• The ophthalmic formulation of cetirizine is FDA-approved to treat allergic conjunctivitis.[6]
• The FDA has approved the intravenous formulation of cetirizine for treating acute urticaria.[7]

Off-Label Uses

• 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).[8]
• Cetirizine is effective in infusion-related reactions due to ocrelizumab and non-inferior to diphenhydramine.[9] Research has demonstrated the efficacy of cetirizine as a premedication agent for preventing hypersensitivity reactions induced by chemotherapy.[10] 
• BASCULE syndrome is characterized by Bier anemic spots, cyanosis, and urticaria-like eruption. In a retrospective chart review of patients with BASCULE syndrome, treatment responses to propranolol and high-dose cetirizine were noted.[11] 
• A recent study suggests that topical cetirizine 1% could be a potential treatment for androgenic alopecia, especially for individuals who show poor responsiveness to topical minoxidil. Further research is needed to confirm these findings.[12]

Mechanism of Action

Cetirizine is a fast-acting, highly selective peripheral histamine H1-receptor antagonist. 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.[13]

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.[14]

Cetirizine has demonstrated significant anti-inflammatory activity, reducing the infiltration of inflammatory cells in allergic rhinitis.[15] Specifically, research has found that cetirizine minimizes the migration of neutrophils and eosinophils.[16]

Pharmacokinetics

Absorption: Cetirizine is absorbed rapidly in the gastrointestinal tract and undergoes substantial excretion by the kidney. Cetirizine reaches peak plasma concentration after approximately 1 hour. The effects of cetirizine 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.[17][18] Evidence indicates that cetirizine is a P-glycoprotein substrate, which should be considered in patients using cetirizine concurrently with P-gp inhibitors.[19]

Excretion: The elimination half-life of cetirizine is 8.3 hours. Cetirizine is primarily excreted through the kidney.[20]

Administration

Available Dosage Forms and Strengths

Cetirizine is available as oral 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 to 10 mg/d orally, depending on symptom severity.[21] Cetirizine is available in 5 mg and 10 mg tablets and 5 mg/5 mL oral solution and elixir. The ophthalmic formulation is 0.24% cetirizine hydrochloride eye drops in 5 mL and 7.5 mL bottles. Cetirizine 5 mg combined with pseudoephedrine HCl 120 mg is a nasal decongestant that temporarily relieves sinus congestion and pressure. 

• Children 6 to 11 years old: 5 to 10 mg (1 or 2 teaspoons) once daily in syrup form is recommended, depending on symptom severity.[22]
• Children 2 to 5 years old: 2.5 mg (half a teaspoon) in syrup form once daily.
• Children 6 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.
• The FDA has approved the IV administration of cetirizine 10 mg to treat acute urticaria in adults and adolescents aged 12 and older.

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 when combined with pseudoephedrine. The use of an ophthalmic formulation of cetirizine by the mother is thought 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 drug that reaches the breast milk.[23]

Pregnancy Considerations: Cetirizine is a former U.S. FDA pregnancy category B medicine. The American College of Obstetricians and Gynecologists and the American College of Allergy, Asthma, and Immunology (ACOG-ACAAI) recommend cetirizine for pregnant women who require antihistamine treatment. Cetirizine should be used in pregnancy only when necessary.[24][25]

Hepatic Impairment: According to the manufacturer's prescribing information, the dose for 12-year-old and older patients with hepatic impairment should be reduced to 5 mg daily. The manufacturer also recommends lowering the dose for patients 6 to 11 years old with hepatic impairment. Intravenous administration of cetirizine is intended for short-term use; no dose adjustment is required per the manufacturer's labeling.

Renal Impairment: Manufacturers' prescribing information suggests reducing the dose to 5 mg daily for patients aged 12 years and older with decreased renal function (CrCL 11 to 31 mL/min) and patients on hemodialysis. The manufacturer also recommends lowering the dose for 6 to 11-year-old patients with renal impairment. The IV formulation of cetirizine is intended for short-term use; no dose adjustment is required per the manufacturer's labeling.

Pediatric Patients: According to one meta-analysis, there is moderate to low certainty evidence that cetirizine may improve clinical outcomes and quality of life in children with allergic rhinitis. Cetirizine demonstrates comparable efficacy with other antihistamines and is generally well tolerated, although there is an increased risk of somnolence in the pediatric population.[26] The intravenous formulation is FDA-approved for urticaria in children 6 months and older. For adolescents aged 12 years and older, the recommended intravenous dosage of cetirizine is 10 mg. Children aged 6 to 11 years old may receive either 5 mg to 10 mg, depending on symptom severity. For children aged 6 months to 5 years, the recommended intravenous dosage is 2.5 mg.

Older Patients: Efficacy evaluations did not include an adequate number of patients aged 65 years and older to determine potential divergent response patterns compared to younger patients. Safety assessments of cetirizine in older patients compared to younger adults revealed no significant differences. However, sensitivity to adverse drug reactions in certain older individuals remains a possibility.

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 and wait 10 minutes after administration until the reinsertion of lenses. If irritation or redness persists after this precaution, contact lenses should be avoided. Cetirizine has proven safe and effective for pediatric patients 2 years and older in clinical studies.[27]

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 appears to be a dose-related effect of cetirizine. Research indicates that in some patients, cetirizine contributes to daytime sleepiness.[28]

Children taking cetirizine most commonly experience similar side effects as adults taking cetirizine (eg, somnolence, fatigue, and dry mouth). Children, in particular, are more likely than adults to experience headaches while taking cetirizine.[29]

In pediatric patients aged 2 to 11, the majority of adverse reactions reported with cetirizine were mild or moderate. 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.[6]

A few cases of transient, reversible hepatic transaminase elevations during cetirizine therapy have been reported in the literature. Some reports of hepatitis with elevated bilirubin have also been documented. In postmarketing studies, rare, potentially severe adverse events, including severe hypotension, anaphylaxis, hemolytic anemia, cholestasis, orofacial dyskinesia, glomerulonephritis, hepatitis, stillbirth, and thrombocytopenia, have been reported.[30]

The most common adverse reactions to ophthalmic formulations include 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 this combination may result in dose-related sedation.[31]

• Pitolisant is a histamine-3 receptor competitive antagonist and inverse agonist used in patients with narcolepsy. Concurrent use with antihistamines like cetirizine may diminish the therapeutic efficacy of pitolisant. This combination should be avoided.[32]

• Cetirizine decreases gabapentin plasma concentrations and reduces systemic exposure to gabapentin. However, gabapentin is a CNS depressant. Pharmacodynamic synergism between these 2 drugs may lead to additional and observable CNS depression.[33]

• 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.[19]

• Cetirizine should not be administered with erdafitinib, an inhibitor of P-glycoprotein (ABCB1, MDR1).[34]

Contraindications

Cetirizine is contraindicated in patients 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.[35]

Warnings and Precautions

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.[24]

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.[36]

Liver function and enzymes should be closely monitored in patients with hepatic impairment. Healthcare providers should make dosage adjustments as needed for patients with hepatic impairment.[37]

Cetirizine may be confused with sertraline (look-alike-sound-alike drugs). Clinicians and pharmacists should be careful while prescribing and dispensing this drug.[38]

Toxicity

Animal studies

Studies using rat models have shown the minimal lethal dose of cetirizine to be approximately 460 times the maximum recommended daily dose for adults. 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.

Signs and Symptoms of Overdose

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 cetirizine cessation.[39] 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 6-year-old child presented with fixed and dilated pupils, tachycardia, agitation, hyperthermia, and hallucinations consistent with anticholinergic toxicity.[40] 

Management of Overdose

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.[41]

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 the possible side effects, which include drowsiness, fatigue, and dry mouth. Healthcare providers should be careful when prescribing cetirizine to patients with impaired renal or hepatic function. Ophthalmologists should educate contact lens wearers on proper precautions and 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 regular and thorough medication reconciliation and verify that the patient is not taking any medications or supplements that could exacerbate cetirizine's adverse effects. Clinicians (MDs, DOs, NPs, PAs), 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.