Loratadine

Mechanism of Action

Loratadine is a long-acting, second-generation, non-sedating tricyclic antihistamine (piperidine derivative) with selective antagonistic properties to peripheral histamine H1-receptors. Loratadine selectively inhibits H1-receptors primarily located on respiratory smooth muscle cells, vascular endothelial cells, the gastrointestinal tract, and immune cells. Unlike the first-generation antihistamines such as diphenhydramine, loratadine is a competitive histamine antagonist that does not cross the blood-brain barrier. Therefore, it does not affect the neurons of the central nervous system, thereby preventing daytime somnolence or sedation.[7][8]

Loratadine binds to H1-receptors in different cells and causes a decrease in vascular permeability (prevents edema and flushing), decreases smooth muscle tone (bronchodilation), and decreases the activation of the peripheral nociceptive receptors (decreases pain and pruritus). At high concentrations, second-generation antihistamines such as loratadine can inhibit histamine release from mast cells and basophils, thereby reducing ICAM-1 expression in epithelial cells and inhibiting type 1 hypersensitivity reactions (e.g., hay fever, urticaria, pruritus, edema).[9] There is also evidence of anti-inflammatory properties with second-generation antihistamines.[10]

Loratadine has a rapid onset of action; it works within 1 to 3 hours, its effects peak within 8 to 12 hours, and elimination occurs through the fecal and renal routes. It has a half-life of approximately 8 hours, and the half-life of its active metabolite is 28 hours. Metabolism is primarily in the liver into its active metabolite, descarboethoxy-loratadine, via the CYP450 pathway, specifically, CYP 3A4.

Administration

Loratadine dosing is by tablet (chewable or ODT - orally disintegrating tablet), liquid-filled capsule, or syrup (1 mg/mL solution). The medication can be administered orally with or without meals, although the recommendation is to take the oral medication on an empty stomach. The dispersible tablet is placed in the mouth and allowed to dissolve. The patient may swallow it with or without water. Research is underway for other formulations designed to increase bioavailability.[11]

For allergic rhinitis:

• In adolescents, adults, and geriatrics: 10 mg by mouth daily or 5 mg twice daily; do not exceed 10 mg in 24 hours.
• In pediatrics: age 2 to 5: 5 mg orally every day; over the age of 6: 10 mg orally daily. The ODT formulation is not recommended for younger children.

For urticaria:

• In adolescents, adults, and geriatrics: 10 mg by mouth daily: generally dosing should not exceed 10 mg in 24 hours. However, some patients may benefit from higher doses - clinicians should weigh the risk vs. benefit.
• In pediatrics over the age of 6: 10 mg by mouth daily as needed. 

In both renal and hepatic insufficiency, the recommendation is to increase the dosing interval to 48 hours, as follows:

Patients with renal impairment (GFR of less than 30 mL/min): 

• In adults: 10 mg orally every other day.
• In children age 2 to 6: 5 mg oral dosing every other day.
• In children over the age of 6: 10 mg by mouth every other day.

Patients on peritoneal or hemodialysis should be dosed every 48 hours; no supplemental dose following dialysis.

Patients with hepatic impairment:

• In adults: 10 mg orally every other day.
• In children aged 2 to 6: 5 mg orally every other day.
• In children over the age of 6: 10 mg by mouth every other day.

The drug's half-life increases with the increasing severity of the hepatic disease.

Loratadine is subject to half-life variability in the elderly, and clinicians need to be mindful of this factor when initiating therapy in this age group.

Adverse Effects

Though loratadine is a relatively safe and effective medication for treating allergic rhinitis, its primary adverse effects include headaches, dizziness, and GI distress (diarrhea, abdominal pain, nausea, and vomiting). Loratadine may also cause sedation (rare side effect), mydriasis, and xerostomia. These effects are primarily due to the drug's anticholinergic effects.[12][13] 

Patients should not take loratadine with other CNS depressants such as diphenhydramine, dextromethorphan, or pseudoephedrine as it may cause dose-related sedation. There is no evidence for increased adverse events when combining loratadine and oral contraceptives.

Contraindications

Contraindications to loratadine include patients with documented hypersensitivity to the drug or components of the formulation, with strong contraindications in children under the age of 2 due to its antihistamine properties, which may cause CNS stimulation or seizures in young patients.

This medication requires cautious use in asthmatic or COPD patients due to its anticholinergic effects, which may cause a flare-up.

Though the medication is generally non-sedating, patients who perform activities requiring concentration, such as driving a motor vehicle, should be advised to use caution as it may cause some drowsiness.

Patients diagnosed with phenylketonuria (PKU) should speak with their primary care physician before taking loratadine. Some of its formulations (e.g., orally disintegrating tablets) may contain phenylalanine which may exacerbate the symptoms of PKU. 

While loratadine has no dangerously significant drug-drug interactions, as with any drug, thorough medication reconciliation is necessary. Drugs that affect the CYP450 enzyme system may have interactions that require therapy modification.[14]

Patients with liver disease or hepatic impairment are advised to exercise caution as the liver extensively metabolizes loratadine, and dose adjustments are necessary per healthcare guidelines. Similarly, individuals with kidney failure or renal impairment should be cautious as such patients will have elevated loratadine concentrations, requiring dose adjustments.[15][16]

According to the American College of Obstetricians and Gynecologists, loratadine should be safe for use during pregnancy; the risk of harm to the fetus is not expected based on limited human data; the drug is pregnancy category B. Caution is advised in breastfeeding; nursing mothers may use the medication short-term while breastfeeding; both loratadine and its active metabolite pass readily into breast milk. There is no known risk of infant harm based on the drug's properties and currently limited data in humans.[17][18]

Monitoring

Patients taking loratadine require monitoring regarding symptomatic relief, sedation, and any anticholinergic effects (such as dilated pupils and drying of oral mucosa). 

Renal and hepatic function also requires close monitoring by the primary care physician for patients with kidney or liver impairment, with appropriate dose adjustment of the drug made accordingly. 

Cardiac function should also be monitored in individuals with a history of cardiac arrhythmias to prevent loratadine over-medication. 

Loratadine storage should be in a cool, dry place at a temperature of between 68 to 77 degrees Fahrenheit.[2]

Toxicity

Loratadine-induced cardiotoxicity, including cardiac arrhythmias and prolongation of QT-interval, is possible in patients, especially in the elderly, if taking a higher than the recommended 24-hour dose. Though rare, overdosing on loratadine may cause significant toxicity, including agitation and symptoms of the anticholinergic syndrome. Symptoms include, but are not limited to, mydriasis, urinary retention, tachycardia, and skin flushing.[19][20][21] 

Treatment protocol for loratadine toxicity may involve providing emesis (except for patients with impaired consciousness), supplemental oxygen, and cardiac monitoring. Clinicians may give sodium bicarbonate to treat arrhythmias and prolonged QT intervals in patients with suspected toxicity. Alleviation of agitation can be with benzodiazepines due to their high therapeutic index. Adults with symptoms of anticholinergic poisoning due to loratadine toxicity may receive physostigmine antidote therapy (recommended dose is between 0.5 to 2 mg IV). The recommendation is that only a medical toxicologist should supervise antidote therapy.

There is no evidence of abuse potential or dependency with loratadine.

Enhancing Healthcare Team Outcomes

Loratadine is proven to be an effective and safe medication for alleviating symptoms of allergic rhinitis and treating urticaria. The drug is available as an over-the-counter medication; thus, it is essential to have a pharmacist educate the patient on the therapeutic dose of the drug and check their medication profile for any potential interactions. The primary care clinician (MD, DO, PA, NP) must counsel the patient on the importance of reading labels to avoid taking more than the recommended dose to prevent any drug-related toxicities. While loratadine is a relatively safe drug, healthcare providers should inform patients of all the side effects associated with the medication, and medication reconciliation is necessary as with the addition or discontinuing of any drug.

Healthcare providers should also check liver and kidney function before prescribing the medication to individuals with hepatic and renal impairments. Nurses should take a complete mediation history from the patient at each visit, including OTC agents and supplements, and chart these, so all interprofessional healthcare team members have complete patient information. Nursing can also reinforce counseling to the patient on proper dosing and administration of loratadine and watching for adverse effects and patient compliance. Pharmacists can reinforce dosing and administration parameters and check for drug-drug interactions. All members of the interprofessional team, as cited above, need to practice collaborative communication to ensure the best possible patient outcomes for loratadine therapy. [Level 5]