Desloratadine (Systemic)


VA CLASSIFICATION
Primary: AH102

Commonly used brand name(s): Aerius; Clarinex.

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



Category:


Antihistaminic (H1-receptor)—

Indications

Accepted

Rhinitis, allergic (treatment)—Desloratadine is indicated for the relief of the nasal and non-nasal symptoms of seasonal and perennial allergic rhinitis1{02} in patients 12 years of age and older.{01}{02}

Urticaria, idiopathic, chronic (treatment)—Desloratadine is indicated for the symptomatic relief of pruritus, reduction in the number of hives, and size of hives, in patients with chronic idiopathic urticaria 12 years of age and older.{01}{02}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Metabolite of loratadine.{01}{02}

Chemical group—
    Piperidine antihistamine
Molecular weight—
    310.8{01}{02}

pKa—
    Pyridine functional group: 4.2 {02}
    Piperidine functional group: 9.7.{02}

Solubility
    Slightly soluble in water; Very soluble in ethanol and propylene glycol.{01}.

Note: Canadian product information lists freely soluble in ethanol, methanol, methylene chloride, and octanol; very slightly soluble in water; soluble in 0.1N hydrochloric acid, and dimethyl sulfoxide; slightly soluble in pH 7.4 phosphate buffer; practically insoluble in 0.1 N sodium hydroxide{02}


Partition coefficient

Note: Values expressed as log KO/W.{02}

    n-octanol/0.1 N HCl: -2.27 {02}
    n-octanol/pH 3 buffer: -1.44 {02}
    n-octanol/pH 6 buffer: 0.342 {02}
    n-octanol/pH 7 buffer: 1.02 {02}
    n-octanol/pH 8 buffer: 0.944 {02}

Mechanism of action/Effect:

Desloratadine is a long-acting tricyclic histamine antagonist with selective H1-receptor histamine antagonist activity. Receptor binding data indicates that at a concentration of 2-3 ng/mL (7 nanomolar), desloratadine shows significant interaction with the human histamine H1-receptor. Desloratadine inhibited histamine release from human mast cells in vitro .{01}{02}

Absorption:

The bioavailability of desloratadine is dose proportional over the range of 5 mg to 20 mg.{02} Following 5 mg oral daily doses for 10 days, the AUC (area under the concentration-time curve) is 56.9 ng hr per mL{01} .

In patients with mild or moderate renal impairment (creatine clearance of 34 to 69 mL per min per 1.73 m2), AUC values increased by approximately 1.9-fold. In patients with severe renal impairment, (creatine clearance of 5 to 29 mL per min per 1.73 m 2) or who were hemodialysis dependent, AUC values increased by approximately 2.5-fold. Dosage adjustments are recommended.{01}

In elderly patients over the age of 65, the AUC values were 20% greater than in younger subjects, but require no dosage adjustments.{01}

In patients with mild (n=4), moderate (n=4) and severe (n=4) hepatic impairment had approximately 2.4-fold increase in AUC{01}{02}

Distribution:

Desloratadine is distributed into breast milk. {01}{02}

Protein binding:

Desloratadine: High (82 to 87%)—plasma protein{01}

3-hydroxydesloratadine: High (85 to 89%)—plasma protein{01}

Biotransformation:

Desloratadine is extensively metabolized to 3-hydroxydesloratadine, an active metabolite, which is subsequently glucuronidated. The enzymes responsible for the metabolism have not been identified.{01}{02}.

Note: Data from clinical trials indicate that a subset of the general patient population has a decreased ability to form 3-hydroxydesloratadine, and are slow metabolizers of desloratadine. In pharmacokinetic studies approximately 7% of subjects were slow metabolizers of desloratadine (defined as a subject with an AUC ratio of 3-hydroxydesloratadine to desloratadine less than 0.1, or a subject with a desloratadine half-life exceeding 50 hours). The frequency of slow metabolizers is higher in African-Americans. The median exposure (AUC) to desloratadine in the slow metabolizers was approximately 6-fold greater than the subjects who are not slow metabolizers{01}



Half-life:

Elimination—27 hours in healthy subjects; In patients 65 years of age and older the mean elimination half-life was 33.7 hours. {01}{02}

Mean elimination half-life was increased{01}

Onset of action:

Histamine skin wheal studies—within one hour. {01}

Time to peak concentration:

Following oral administration—approximately 3 hours.{01}{02}

Peak plasma concentration:

4 ng/mL—following a single 5 mg oral dose in normal healthy volunteers once daily for 10 days.

Note: In patients 65 years of age or older the mean C max was 20% greater than in younger patients, but require no changes in dosage.{01}.
In patients with mild or moderate renal impairment (creatine clearance of 34 to 69 mL per min per 1.73 m2), median Cmax values increased by approximately 1.2-fold. In patients with severe renal impairment, (creatine clearance of 5 to 29 mL per min per 1.73 m2) or who were hemodialysis dependent, Cmax values increased by approximately 1.7-fold. Dosage adjustments are recommended.{01}.


Duration of action:

Histamine skin wheal studies—up to 24 hours. {01}

Elimination:


Fecal and Renal—
        Approximately 87% of a 14C-desloratadine dose was equally recovered in urine and feces. {01}{02}
        Desloratadine, and 3-hydroxydesloratadine were not removed by hemodialysis. {02}
        In patients with mild (n=4), moderate (n=4) and severe (n=4) hepatic impairment the apparent oral clearance was 37%, 36%, and 28%, respectively, compared to healthy patients{01}.



Precautions to Consider

Carcinogenicity

Note: The carcinogenic potential of desloratadine was assessed using loratadine studies.


In 18-month and 2 year studies in mice and rats, loratadine was administered in the diet at doses up to 40 mg/kg/day in mice and 25 mg/kg/day in rats. Male mice given 40 mg/kg/day of loratadine had a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) than concurrent controls. In rats a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg/day and in males and females given 25 mg/kg/day. The estimated desloratadine and desloratadine metabolite exposures of rats given 10 mg/kg of loratadine were approximately 7 times the area under the curve in humans at the recommended daily oral dose. {01}

Mutagenicity

Desloratadine showed no genotoxic potential in a reverse mutation assay (Salmonella / E. coli mammalian microsome bacterial mutagenicity assay) or in two assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenicity assay and mouse bone marrow micronucleus assay). {01}{02}

Pregnancy/Reproduction
Fertility—
At desloratadine doses up to 24 mg/kg/day there was no effect on female fertility in rats. A male specific decrease in fertility, demonstrated by reduced female conception rates, decreased sperm numbers and motility, and histopathologic testicular changes, occurred at an oral desloratadine dose of 12 mg/kg in rats. Desloratadine had no effect on fertility in rats at an oral dose of 3 mg/kg/day. {01}{02}

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}{02}

Desloratadine was not teratogenic in rats at doses up to 48 mg/kg/day or in rabbits at doses up to 60 mg/kg/day. In a separate study, an increase in pre-implantation loss and a decreased number of implantations and fetuses were noted in female rats at 24 mg/kg. Reduced body weight and slow righting reflex were reported in pups at doses of 9 mg/kg/day or greater. Desloratadine had no effect on pup development at an oral dose of 3 mg/kg/day. {01}

FDA Pregnancy Category C

Breast-feeding

Desloratadine is distributed into breast milk. {01}{02}

Pediatrics

No information is available on the relationship of age to the effects of desloratadine in children under 12 years of age. Safety and efficacy have not been established. {01}{02}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of desloratadine in the elderly. However, elderly patients are more likely to have age-related impairment of hepatic, or renal function which may require adjustment of dosage in patients receiving desloratadine.{01}{02}

In patients 65 years of age and older, peak plasma concentration and area under the curve values for desloratadine were 20% greater than in younger patients. The mean plasma elimination half-life was approximately 30% longer than in younger patients. This is not relevant clinically and no dosage adjustment is recommended. The oral total body clearance when normalized for body weight was similar between the two age groups. {01}{02}


Pharmacogenetics

Female patients treated for 14 days with desloratadine had peak plasma concentration and area under the curve values for desloratadine that were 10% and 3% higher, respectively, compared with male patients. The 3-hydroxydesloratadine peak plasma concentration and area under the curve values for desloratadine were increased by 45% and 48%, respectively, in females compared with males. This is not relevant clinically and no dosage adjustment is recommended. {01}{02}

African-American patients treated for 14 days with desloratadine had peak plasma concentration and area under the curve values for desloratadine that were 18% and 32% higher, respectively, in African-Americans compared with Caucasian patients. For 3-hydroxydesloratadine there was a corresponding 10% reduction in peak plasma concentration and area under the curve values in African-Americans compared to Caucasian. This is not relevant clinically and no dosage adjustment is recommended.{01}{02}

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 desloratadine or to any of its ingredients, or to loratadine{01}{02}
Risk-benefit should be considered when the following medical problems exist
» Hepatic function impairment    (based upon increases in the values of bioavailability, mean elimination half-life and the area under the curve of desloratadine, dosage adjustment for patients with hepatic function impairment is recommended. {01})


» Renal function impairment    (based upon increases in the values of the peak plasma concentration and the area under of the curve for desloratadine, dosage adjustment for patients with renal function impairment is recommended.{01})


Metabolism of desloratadine, impaired    (patients cannot be prospectively identified as slow metabolizers of desloratadine and may be more susceptible to dose-related adverse events.{01})




Side/Adverse Effects
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 not determined
—Observed during clinical practice, estimates of frequency cannot be determined    
Anaphylaxis {01}(cough; difficulty swallowing; dizziness; fast heartbeat; hives; itching; puffiness or swelling of the eyelids or around the eyes, face, lips or tongue; shortness of breath; skin rash; tightness in chest; unusual tiredness or weakness; wheezing)
    
dyspnea {01}(shortness of breath; difficult or labored breathing; tightness in chest; wheezing)
    
edema {01}(swelling)
    
pruritus {01}(itching skin)
    
rash {01}
    
tachycardia {01}(fast, pounding, or irregular heartbeat or pulse)
    
urticaria {01}(hives or welts; itching; redness of skin; skin rash)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Headache {01}{02}
    
pharyngitis {01}( body aches or pain; congestion; cough; dryness or soreness of throat; fever; hoarseness; runny nose; tender, swollen glands in neck; trouble in swallowing; voice changes)

Incidence less frequent
    
Dizziness {01}
    
dry mouth {01}{02}
    
dysmenorrhea {01}(difficult or painful menstruation )
    
dyspepsia {01}( acid or sour stomach; belching; heartburn; indigestion; stomach discomfort upset or pain)
    
fatigue {01}{02}(unusual tiredness or weakness)
    
myalgia {01}( joint pain; swollen joints; muscle aching or cramping; muscle pains or stiffness; difficulty in moving), somnolence {01}{02}(sleepiness or unusual drowsiness)
    
nausea {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:
    
Somnolence {01}( sleepiness or unusual drowsiness)


Note: Single daily doses of 45 mg were given to normal male and female volunteers for 10 days. All ECGs obtained in this study were manually read in a blinded fashion by a cardiologist. In desloratadine-treated patients, there was an increase in mean heart rate of 9.2 bpm relative to placebo. The QT interval was corrected for heart (QTc) by both the Bazett and Fridericia methods. Using the QT c (Bazett) there was a mean increase of 8.1 msec in desloratadine-treated patients relative to placebo. Using QTc (Fredericia) there was a mean increase of 0.4 msec in desloratadine-treated patients relative to placebo.{01}
Lethality occurred in rats at oral doses of 250 mg/kg or greater (estimated desloratadine and desloratadine metabolite exposures were approximately 120 times the area under the curve in humans at the recommended daily oral dose). The oral median lethal dose in mice was 353 mg/kg (estimated desloratadine exposures were approximately 290 times the human daily oral dose on a mg/m2 basis. No deaths occurred at oral doses up to 250 mg/kg in monkeys (estimated desloratadine exposures were approximately 810 times the human daily oral dose on a mg/m2 basis).{01}


Treatment of overdose

Note: Desloratadine and 3-hydroxydesloratadine are not eliminated by hemodialysis.{01}{02}
It is not known if desloratadine is eliminated by peritoneal dialysis. {02}



Supportive care:
Treat should be symptomatic and supportive{01}{02}

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, Desloratadine (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to desloratadine or any of its ingredients, or to loratadine.





Breast-feeding—Desloratadine is distributed into breast milk.
Other medical problems, especially hepatic or renal function impairment.

Proper use of this medication

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

Proper storage


Side/adverse effects
Signs of potential side effects, especially anaphylaxis, dyspnea, edema, pruritus, rash, tachycardia or urticaria.


General Dosing Information
Desloratadine may be taken with or without food. {01}{02}


Oral Dosage Forms

DESLORATADINE TABLETS

Usual Adult and adolescent dose
Rhinitis, allergic (treatment)
Oral, 5 mg once daily.{01}{02}

Urticaria, idiopathic, chronic (treatment)
Oral, 5 mg once daily.{01}{02}

Note: In patients with liver or renal impairment, U.S. prescribing information recommends a starting dose of 5 mg every other day. {01}



Usual Pediatric Dose
Safety and efficacy have not been established.
{01}{02}
Usual Geriatric Dose
See Usual adult and adolescent dose{01}{02}.

Strength(s) usually available
U.S.—


5 mg (Rx) [Clarinex (dibasic calcium phosphate dihydrate USP) (microcrystalline cellulose NF) (corn starch NF) ( talc USP) (carnauba wax NF) ( white wax NF) (lactose monohydrate) (hydroxypoplyl methylcellulose) (titanium dioxide) (polyethylene glycol) ( FD&C Blue # 2 Aluminum Lake)]{01}

Canada—


5 mg (Rx) [Aerius (carnauba wax ) (microcrystalline cellulose) ( corn starch) (dibasic calcium phosphate dihydrate ) (FD&C Blue # 2 Lake) ( hydroxypropyl methylcellulose) (lactose monohydrate ) (polyethylene glycol) ( talc) (titanium dioxide) ( white beeswax)]{02}

Packaging and storage:
Store between 2 and 25 °C (36 and 77 °F). Heat sensitive. Avoid exposure at or above 30 °C (86 °F). Protect from moisture.{01}

Note: Canadian product information states to store between 15 and 30 °C. {02}


Auxiliary labeling:
   • Do not use if you are breastfeeding. Contact your doctor or pharmacist.



Developed: 09/09/2002
Revised: 01/15/2003



References
  1. Product Information: Clarinex®, desloratadine. Schering, Kenilworth, NJ, (PI issued 2/2002) reviewed 5/2002.
  1. Product Information: Aerius™, desloratadine. Schering Canada,.Pointe-Claire, Quebec, (PI revised 2/2002) reviewed 7/2002.
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