Lorinase-D Extended Release Tablet is indicated for the relief of the nasal and non-nasal symptoms of seasonal allergic rhinitis, including nasal congestion, in adults and adolescents 12 years of age and older. Lorinase-D Extended Release Tablets should be administered when the antihistaminic properties of desloratadine and the nasal decongestant properties of pseudoephedrine are desired.

Administer Lorinase-D Extended Release Tablet by the oral route only. Do not break, chew, or crush the tablet. Swallow the tablet whole.

       Adults and children aged 12 years or more:

The recommended dose of Lorinase-D Extended Release Tablet is 1 tablet twice a day, administered approximately 12 hours apart and with or without a meal. Higher doses or increased dosing frequency of Lorinase-D Extended Release Tablets have not demonstrated increased effectiveness. Do not exceed the recommended dose as desloratadine and pseudoephedrine, the active components of Lorinase-D Extended Release Tablets have been associated with adverse effects at higher doses.

In patients taking digitalis, patients with cardiac arrhythmias, hypertension, myocardial infarction, diabetes, stenosing peptic ulcer, pyloroduodenal obstruction, prostatic hypertrophy or bladder neck obstruction, or bronchospasm in patients with a history of caution. Special caution is required in patients aged 60 years or more, it is for people in this age group are more likely adverse reactions to sympathomimetics. In this case, the dose should be reduced. The dose should be reduced in the case of severe renal insufficiency.

Caution should be exercised in patients treated with other sympathomimetic agents, including decongestants, drugs to reduce appetite or amphetamine-type stimulant medications, antihypertensives, tricyclic antidepressants and other antihistamines.

As with any CNS stimuli are also in pseudoephedrine sulfate reported abuse. Prolonged use can lead to tolerance and therefore increases the risk of over-dosing.

The effect of the results of laboratory test results: Antihistamines should be discontinued approximately 2 days before skin tests because they can prevent or reduce otherwise positive reaction to the skin indicators.

Lorinase-D medicine may affect your test taking doping in athletes.

As with other CNS stimulants, pseudoephedrine sulphate carries the risk of abuse. Increased doses may ultimately produce toxicity. Continuous use can lead to tolerance resulting in an increased risk of overdosing.

There have been rare cases of posterior reversible encephalopathy syndrome (PRES) / reversible cerebral vasoconstriction syndrome (RCVS) reported with sympathomimetic drugs, including pseudoephedrine.

Symptoms reported include sudden onset of severe headache, nausea, vomiting, and visual disturbances. Most cases improved or resolved within a few days following appropriate treatment. Pseudoephedrine should be discontinued, and medical advice sought immediately if signs or symptoms of PRES/RCVS develop.

Pseudoephedrine-containing medicines must not be used in patients with severe or uncontrolled hypertension or severe acute or chronic kidney disease or renal failure, as these are risk factors for developing PRES or RCVS.

Cardiovascular and Central Nervous System Effects

The pseudoephedrine sulfate contained in LORINASE-D Extended Release Tablets, like other sympathomimetic amines, can produce cardiovascular and central nervous system (CNS) effects in some patients such as insomnia, dizziness, weakness, tremor, or arrhythmias. In addition, central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension has been reported. Therefore, LORINASE-D Extended Release Tablets should be used with caution in patients with cardiovascular disorders, and should not be used in patients with severe hypertension or severe coronary artery disease.

Coexisting Conditions

LORINASE-D Extended Release Tablets contain pseudoephedrine sulfate, a sympathomimetic amine, and therefore should be used with caution in patients with diabetes and hyperthyroidism. Also use with caution in patients with prostatic hypertrophy or increased intraocular pressure, as urinary retention and narrow-angle glaucoma may occur [see Contraindications (4.3)].

Co-Administration with Monoamine Oxidase (MAO) Inhibitors

LORINASE-D Extended Release Tablets should not be used in patients receiving monoamine oxidase (MAO) inhibitor therapy or within fourteen (14) days of stopping such treatment as an increase in blood pressure or hypertensive crisis, may occur [see Contraindications (4.3) and Drug Interactions (4.5)].

Hypersensitivity Reactions

Hypersensitivity reactions including rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis have been reported after administration of desloratadine a component of LORINASE-D Extended Release Tablets. If such a reaction occurs, therapy with LORINASE-D Extended Release Tablets should be stopped and alternative treatment should be considered [see Adverse Reactions (4.8)].

Renal Impairment

LORINASE-D Extended Release Tablets should generally be avoided in patients with renal impairment.

Hepatic Impairment

LORINASE-D Extended Release Tablets should generally be avoided in patients with hepatic impairment.

No specific interaction studies have been conducted with LORINASE-D Extended Release Tablets.

Monoamine Oxidase Inhibitors

LORINASE-D Extended Release Tablets should not be used in patients receiving monoamine oxidase (MAO) inhibitor therapy or within fourteen (14) days of stopping such treatment because the action of pseudoephedrine a component of LORINASE-D Extended Release tablets on the vascular system may be potentiated by these agents [see Contraindications (4.3) and Warnings and Precautions (4.4)].

Beta-Adrenergic Blocking Agents

The antihypertensive effects of beta-adrenergic blocking agents, methyldopa, and reserpine, may be reduced by sympathomimetics such as pseudoephedrine. Exercise caution when using LORINASE-D Extended Release Tablets with these agents.

Digitalis

Increased ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis. Exercise caution when using LORINASE-D Extended Release Tablets with these agents.

Inhibitors of Cytochrome P450 3A4

In controlled clinical studies co-administration of desloratadine with ketoconazole, erythromycin, or azithromycin resulted in increased plasma concentrations of desloratadine and 3-hydroxydesloratadine but there were no clinically relevant changes in the safety profile of desloratadine.

Fluoxetine

In controlled clinical studies co-administration of desloratadine with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), resulted in increased plasma concentrations of desloratadine and 3-hydroxydesloratadine but there were no clinically relevant changes in the safety profile of desloratadine.

Cimetidine

In controlled clinical studies co-administration of desloratadine with cimetidine a histamine H2-receptor antagonist resulted in increased plasma concentrations of desloratadine and 3-hydroxydesloratadine but there were no clinically relevant changes in the safety profile of desloratadine.

Desloratadine: Concomitant use of alcohol, Desloratadine does not increase its activities, which are research assessed by measurements of physical and mental fitness.

Following concomitant administration of ketoconazole, erythromycin, or cimetidine in controlled clinical trials reported an increase in plasma concentrations of Desloratadine but without clinically significant changes (including changes in the ECG). Other drugs known to inhibit hepatic metabolism should only be used concurrently with caution until definitive studies are completed drug-drug interactions.

Pseudoephedrine: Sympathomimetics may reduce the antihypertensive effect of drugs affecting the sympathetic system as example. methyldopa, reserpine, and guanethidine, and partially counteract the hypotensive effects of beta blockers. Concomitant use of tablets Lorinase-D with sympathomimetic agents such as, for example: decongestants, drugs used to reduce appetite, amphetamines, tricyclic antidepressants or MAO inhibitors may increase blood pressure. Due to the long-term operation MAO inhibitors, this effect can also be 14 days after discontinuation of treatment (see section 4.3). Concomitant use of furazolidone should be avoided as it may cause a dose-dependent brake MAO. Concomitant use of pseudoephedrine and digitalis may result in increased ectopic activity centers in the heart. Antacids increase the rate of pseudoephedrine absorption, kaolin decreases it.

-       Pediatric Use

LORINASE-D Extended Release Tablets are not indicated for use in pediatric patients under 12 years of age.

-       Geriatric Use

The number of subjects (n=10) ≥65 years old treated with LORINASE-D Extended Release Tablets was too limited to make any formal statistical comparison regarding the efficacy or safety of this drug product in this age group, or to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences between the elderly and younger patients, although the elderly are more likely to have adverse reactions to sympathomimetic amines. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pseudoephedrine, desloratadine, and their metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor the patient for adverse events.

-       Renal Impairment

No studies with LORINASE-D Extended Release Tablets were conducted in subjects with renal impairment. LORINASE-D Extended Release Tablets should generally be avoided in patients with renal impairment [see Warnings and Precautions (4.4)].

-       Hepatic Impairment

No studies with LORINASE-D Extended Release Tablets or pseudoephedrine were conducted in subjects with hepatic impairment. LORINASE-D Extended Release Tablets should generally be avoided in patients with hepatic impairment [see Warnings and Precautions (4.4)].

-       Gender

No clinically significant gender-related differences were observed in the pharmacokinetic parameters of desloratadine, 3-hydroxydesloratadine or pseudoephedrine following administration of LORINASE-D Extended Release Tablets.

-       Race

No studies have been conducted to evaluate the effect of race on the pharmacokinetics of LORINASE-D Extended Release Tablets.

Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies of desloratadine and pseudoephedrine in combination in pregnant women. Neither are there animal reproduction studies conducted with the combination of desloratadine and pseudoephedrine. Desloratadine was not teratogenic in rats or rabbits but affected implantation in rats. Because animal reproduction studies are not always predictive of human response, LORINASE-D Extended Release Tablets should be used during pregnancy only if clearly needed.

Desloratadine was not teratogenic in rats or rabbits at approximately 210 and 230 times, respectively, the AUC in humans at the recommended daily oral dose. An increase in pre-implantation loss and a decreased number of implantations and fetuses were noted, however, in a separate study in female rats at approximately 120 times the AUC in humans at the recommended daily oral dose. Reduced body weight and slow righting reflex were reported in pups at approximately 50 times or greater than the AUC in humans at the recommended daily oral dose. Desloratadine had no effect on pup development at approximately 7 times the AUC in humans at the recommended daily oral dose. The AUCs in comparison referred to the desloratadine exposure in rabbits and the sum of desloratadine and its metabolites exposures in rats, respectively [see Nonclinical Toxicology (13.2)].

Lactation

Desloratadine and pseudoephedrine both pass into breast milk; therefore, a decision should be made whether to discontinue nursing or to discontinue LORINASE-D Extended Release Tablets, taking into account the benefit of the drug to the nursing mother and the possible risk to the child.

At a daily dose of 10 mg of Desloratadine were reported sedating the operation of the product. Attention and reaction time were not reduced. Similarly, it is not known that pseudoephedrine sulfate decreased psychophysical ability.

Reported adverse reactions by system organ class in MedDRA

Very common (≥ 1/10); Common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); Rare (≥ 1/10, 000 to <1/1000); very rare (<1/10, 000)

Metabolism and nutrition disorders

Common: thirst.

Psychiatric disorders

Very common: anorexia, insomnia.

Common: nervousness, somnolence, depression, agitation.

Nervous system disorders

Very common: dry mouth.

Common: dizziness.

Uncommon: confusion, tremors, increased sweating, hot flushes, broken flavor.

Eye Disorders

Uncommon: disorders of lacrimal gland.

Ear and labyrinth disorders

Uncommon: tinnitus

Heart disease

Common: tachycardia

Uncommon: palpitations

Respiratory, thoracic and mediastinal disorders

Common: pharyngitis, rhinitis

Uncommon: epistaxis

Gastrointestinal Disorders

Common: constipation, nausea

Renal and urinary disorders

Uncommon: micturition disorders

Skin and subcutaneous tissue disorders

Common: pruritus

General disorders and administration site conditions

Common: headache, chills.

Other adverse reactions have been reported very rarely during post-marketing are listed below:

Immune system disorders: anaphylaxis

Nervous system disorders: vertigo

Vascular diseases: hypertension

Respiratory, thoracic and mediastinal disorders: cough, bronchospasm

Hepato-biliary disorders: abnormal liver function

Renal and urinary disorders: urinary retention

Skin and subcutaneous tissue disorders: alopecia

The following adverse reactions are discussed in greater detail in other sections of the label:

·       Cardiovascular and Central Nervous System effects [see Warnings and Precautions (4.4)]

·       Increased intraocular pressure [see Warnings and Precautions (4.4)]

·       Urinary retention in patients with prostatic hypertrophy [see Warnings and Precautions (4.4)]

·       Hypersensitivity reactions [see Warnings and Precautions (4.4)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety data described below are from 2 clinical trials with LORINASE-D Extended Release Tablets that included 1248 patients with seasonal allergic rhinitis, of which 414 patients received LORINASE-D Extended Release Tablets twice daily for up to 2 weeks. The majority of patients were between 18 and <65 years of age with a mean age of 35.8 years and were predominantly women (64%). Patient ethnicity was 82% Caucasian, 9% Black, 6% Hispanic and 3% Asian/other ethnicity. The percentage of subjects receiving LORINASE-D Extended Release Tablets and who discontinued from the clinical trials because of an adverse event was 3.6%. Adverse reactions that were reported by ≥2% of subjects receiving LORINASE-D Extended Release Tablets are shown in Table 1.

Table 1: Incidence of Adverse Reactions Reported by ≥2% of Subjects Receiving LORINASE-D Extended Release Tablets

There were no relevant differences in adverse reactions for subgroups of patients as defined by gender, age, or race.

Post-Marketing Experience

In addition to the adverse reactions reported during clinical trials and listed above, adverse events have been identified during post approval use of LORINASE-D Extended Release Tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse events identified from post-marketing surveillance on the use of LORINASE-D Extended Release Tablets include tachycardia, palpitations, dyspnea, rash and pruritus.

In addition to these events, the following spontaneous adverse events have been reported during the marketing of desloratadine as a single ingredient product: headache, somnolence, dizziness and rarely hypersensitivity reactions (such as urticaria, edema and anaphylaxis), psychomotor hyperactivity, movement disorders (including dystonia, tics, and extrapyramidal symptoms), seizures, and elevated liver enzymes including bilirubin and, very rarely, hepatitis.

Other adverse reactions reported during post-marketing only to Desloratadine include increased appetite, redness and gastritis.

-       Pediatric Use

LORINASE-D Extended Release Tablets are not indicated for use in pediatric patients under 12 years of age.

-       Geriatric Use

The number of subjects (n=10) ≥65 years old treated with LORINASE-D Extended Release Tablets was too limited to make any formal statistical comparison regarding the efficacy or safety of this drug product in this age group, or to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences between the elderly and younger patients, although the elderly are more likely to have adverse reactions to sympathomimetic amines. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pseudoephedrine, desloratadine, and their metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor the patient for adverse events.

-       Renal Impairment

No studies with LORINASE-D Extended Release Tablets were conducted in subjects with renal impairment. LORINASE-D Extended Release Tablets should generally be avoided in patients with renal impairment [see Warnings and Precautions (4.4)].

-       Hepatic Impairment

No studies with LORINASE-D Extended Release Tablets or pseudoephedrine were conducted in subjects with hepatic impairment. LORINASE-D Extended Release Tablets should generally be avoided in patients with hepatic impairment [see Warnings and Precautions (4.4)].

-       Gender

No clinically significant gender-related differences were observed in the pharmacokinetic parameters of desloratadine, 3-hydroxydesloratadine or pseudoephedrine following administration of LORINASE-D Extended Release Tablets.

-       Race

No studies have been conducted to evaluate the effect of race on the pharmacokinetics of LORINASE-D Extended Release Tablets.

-       DRUG ABUSE AND DEPENDENCE

There is no information to indicate that abuse or dependency occurs with LORINASE-D or LORINASE-D Extended Release Tablets.

For OMAN:

Department of Pharmacovigilance & Drug Information

Directorate General of Pharmaceutical Affairs & Drug Control

Ministry of Health, Sultanate of Oman

Phone Nos. 22357687 / 22357686

Fax: 22358489

Email: dg-padc@moh.gov.om

Website: www.moh.gov.om

In the event of overdose, consider standard measures to remove any unabsorbed drug. Symptomatic and supportive treatment is recommended. Desloratadine and 3-hydroxydesloratadine are not eliminated by hemodialysis.

Desloratadine

Information regarding acute overdosage with desloratadine is limited to experience from post-marketing adverse event reports and from clinical trials conducted during the development of the LORINASE-D product. In the reported cases of overdose, there were no significant adverse events that were attributed to desloratadine. In a dose-ranging trial, at doses of 10 mg and 20 mg/day, somnolence was reported.

In another study, no clinically relevant adverse events were reported in normal male and female volunteers who were given single daily doses of LORINASE-D 45 mg for 10 days [see Clinical Pharmacology (12.2)].

Lethality occurred in rats at oral doses of 250 mg/kg or greater (estimated desloratadine and desloratadine metabolite exposures were approximately 120 times the AUC in humans at the recommended daily oral dose). The oral median lethal dose in mice was 353 mg/kg (estimated desloratadine exposure was approximately 290 times the human daily oral dose on an mg/m2 basis). No deaths occurred at oral doses up to 250 mg/kg in monkeys (estimated desloratadine exposure was approximately 810 times the human daily oral dose on an mg/m2 basis).

Sympathomimetics

In large doses, sympathomimetics such as pseudoephedrine may give rise to giddiness, headache, nausea, vomiting, sweating, thirst, tachycardia, precordial pain, palpitations, difficulty in micturition, muscle weakness and tenseness, anxiety, restlessness, and insomnia. Many patients can present a toxic psychosis with delusions and hallucinations. Some may develop cardiac arrhythmias, circulatory collapse, convulsions, coma, and respiratory failure.

The probability of CNS stimulation is particularly high in children, and this also applies to signs and symptoms similar to those seen after atropine (dry mouth, dilated pupils unresponsive, flushing, hyperthermia, and gastrointestinal symptoms).

Treatment: The patient vomiting, even if it is already vomited spontaneously. The best way to challenge vomiting using syrup of ipecac. In patients with disorders of consciousness, vomiting should not be induced. Precautions must be taken against aspiration of vomit, especially in children. After vomiting may try to adsorb the remaining amount of drug in the stomach, so that the patient administered the active carbon in the form of a mixture with water.

If vomiting is unsuccessful or contraindicated if it is necessary to carry out gastric lavage. The solution of choice for this purpose is a saline solution, particularly in children, while in adults may be used as drinking water. Before the next instillation should be removed as big as possible intake of medicines.

Salt laxatives pull water into the intestines on the principle of osmosis and therefore may be useful due to the rapid dilution of bowel content.

It is not known, or can be administered to remove by dialysis.

After emergency treatment, the patient continued to remain under medical supervision. Treatment of the signs and symptoms of overdose is symptomatic and supportive. Stimulants (analeptiki) should not be used. Hypertension can be controlled with alpha blockers, tachycardia with beta-blockers. Short-acting barbiturates - diazepam 10 mg i.v. or i.m. (adults) and 0.5 mg / kg intrarectally (children), or paraldehyde - can be used for the control of possible seizures. In hyperpyrexia, especially in children, may require lowering the body temperature by washing with a sponge soaked in lukewarm water, or hypothermic blanket. Apnea is treated with ventilatory support.

Mechanism of Action

Desloratadine is a long acting tricyclic histamine antagonist with selective H1-receptor histamine antagonist activity. Receptor binding data indicate that at a concentration of 2 to 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. Results of a radiolabeled tissue distribution study in rats and a radioligand H1-receptor-binding study in guinea pigs showed that desloratadine does not readily cross the blood brain barrier. The clinical significance of this finding is unknown.

Pseudoephedrine sulfate is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa. Pseudoephedrine sulfate is recognized as an effective agent for the relief of nasal congestion due to allergic rhinitis. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory side effects.

Wheal and Flare: Human histamine skin wheal studies following single and repeated 5 mg doses of desloratadine have shown that the drug exhibits an antihistaminic effect by 1 hour; this activity may persist for as long as 24 hours. There was no evidence of histamine-induced skin wheal tachyphylaxis within the desloratadine 5 mg group over the 28-day treatment period. The clinical relevance of histamine wheal skin testing is unknown.

Effects on QTc: In clinical trials for LORINASE-D Extended Release Tablets, ECGs were recorded at baseline and endpoint within 1 to 3 hours after the last dose. The majority of ECGs were normal at both baseline and endpoint. No clinically meaningful changes were observed following treatment with LORINASE-D Extended Release Tablets for any ECG parameter, including the QTc interval. An increase in the ventricular rate of 7.1 and 6.4 bpm was observed in the LORINASE-D Extended Release Tablets and pseudoephedrine groups, respectively, compared to an increase of 3.2 bpm in subjects receiving desloratadine alone. Single daily doses of LORINASE-D 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 the LORINASE-D-treated subjects, there was a mean increase in the maximum heart rate of 9.2 bpm relative to placebo. The QT interval was corrected for heart rate (QTc) by both Bazett’s and Fridericia methods. Using the QTc (Bazett), there was a mean increase of 8.1 msec in the LORINASE-D-treated subjects relative to placebo. Using QTc (Fridericia) there was a mean increase of 0.4 msec in LORINASE-D-treated subjects relative to placebo. No clinically relevant adverse events were reported.

CLINICAL STUDIES

Seasonal Allergic Rhinitis

The clinical efficacy and safety of LORINASE-D Extended Release Tablets was evaluated in two 2-week multicenter, randomized parallel group clinical trials involving 1248 subjects 12 to 78 years of age with seasonal allergic rhinitis, 414 of whom received LORINASE-D Extended Release Tablets. In the 2 trials, subjects were randomized to receive LORINASE-D Extended Release Tablets twice daily, LORINASE-D Tablets 5 mg once daily, or sustained-release pseudoephedrine tablet 120 mg twice daily for 2 weeks. The majority of patients were between 18 and <65 years of age with a mean age of 35.8 years and were predominantly women (64%). Patient ethnicity was 82% Caucasian, 9% Black, 6% Hispanic and 3% Asian/other ethnicity. Primary efficacy variable was twice-daily reflective patient scoring of 4 nasal symptoms (rhinorrhea, nasal stuffiness/congestion, nasal itching, and sneezing) and four non-nasal symptoms (itching/burning eyes, tearing/watering eyes, redness of eyes, and itching of ears/palate) on a 4 point scale (0=none, 1=mild, 2=moderate, and 3=severe). In both trials, the antihistaminic efficacy of LORINASE-D Extended Release Tablets, as measured by total symptom score excluding nasal congestion, was significantly greater than pseudoephedrine alone over the 2-week treatment period; and the decongestant efficacy of LORINASE-D Extended Release Tablets, as measured by nasal stuffiness/congestion, was significantly greater than LORINASE-D (desloratadine alone) over the 2-week treatment period. Primary efficacy variable results from 1 of 2 trials are shown in Table 3.

Table 3: Changes in Symptoms in a 2-Week Clinical Trial in Subjects With Seasonal Allergic Rhinitis

SEM=Standard Error of the Mean

* To qualify at Baseline, the sum of the twice-daily diary reflective scores for the 3 days prior to Baseline and the morning of the Baseline visit were to total ≥42 for total nasal symptom score (sum of 4 nasal symptoms of rhinorrhea, nasal stuffiness/congestion, nasal itching, and sneezing) and a total of ≥35 for total non-nasal symptoms score (sum of 4 non-nasal symptoms of itching/burning eyes, tearing/watering eyes, redness of eyes, and itching of ears/palate), and a score of ≥14 for each of the individual symptoms of nasal stuffiness/congestion and rhinorrhea. Each symptom was scored on a 4-point severity scale (0=none, 1=mild, 2=moderate, 3=severe).

† Mean reduction in score averaged over the 2-week treatment period.

‡ The comparison of interest is shown bolded.

There were no significant differences in the efficacy of LORINASE-D Extended Release Tablets across subgroups of subjects defined by gender, age, or race.

Absorption: In a single dose pharmacokinetic study, the mean time to maximum plasma concentrations (Tmax) for desloratadine occurred at approximately 4 to 5 hours post dose and mean peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of approximately 1.09 ng/mL and 31.6 nghr/mL, respectively, were observed. In another pharmacokinetic study, food and grapefruit juice had no effect on the bioavailability (Cmax and AUC) of desloratadine.

For pseudoephedrine, the mean Tmax occurred at 6 to 7 hours post dose and mean peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of approximately 263 ng/mL and 4588 nghr/mL, respectively, were observed. Food had no effect on the bioavailability (Cmax and AUC) of pseudoephedrine.

Following oral administration of LORINASE-D Extended Release Tablets twice daily for 14 days in healthy volunteers, steady-state conditions were reached on Day 10 for desloratadine, 3-hydroxydesloratadine and pseudoephedrine. For desloratadine, mean steady-state peak plasma concentrations (Cmax) and area under the concentration-time curve AUC 0-12 hrs of approximately 1.7 ng/mL and 16 ng•hr/mL were observed, respectively. For pseudoephedrine, mean steady-state peak plasma concentrations (Cmax) and AUC 0-12 hrs of 459 ng/mL and 4658 ng•hr/mL were observed.

Distribution: Desloratadine and 3-hydroxydesloratadine are approximately 82% to 87% and 85% to 89%, bound to plasma proteins, respectively. Protein binding of desloratadine and 3-hydroxydesloratadine was unaltered in subjects with impaired renal function.

Metabolism: Desloratadine (a major metabolite of loratadine) is extensively metabolized to 3-hydroxydesloratadine, an active metabolite, which is subsequently glucuronidated. The enzyme(s) responsible for the formation of 3-hydroxydesloratadine have not been identified. Data from clinical trials with desloratadine indicate that a subset of the general population has a decreased ability to form 3-hydroxydesloratadine, and are poor metabolizers of desloratadine. In pharmacokinetic studies (n=3748), approximately 6% of subjects were poor 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). These pharmacokinetic studies included subjects between the ages of 2 and 70 years, including 977 subjects aged 2 to 5 years, 1575 subjects aged 6 to 11 years, and 1196 subjects aged 12 to 70 years. There was no difference in the prevalence of poor metabolizers across age groups. The frequency of poor metabolizers was higher in Blacks (17%, n=988) as compared to Caucasians (2%, n=1462) and Hispanics (2%, n=1063). The median exposure (AUC) to desloratadine in the poor metabolizers was approximately 6-fold greater than in the subjects who are not poor metabolizers. Subjects who are poor metabolizers of desloratadine cannot be prospectively identified and will be exposed to higher levels of desloratadine following dosing with the recommended dose of desloratadine. In multidose clinical safety studies, where metabolizer status was prospectively identified, a total of 94 poor metabolizers and 123 normal metabolizers were enrolled and treated with LORINASE-D Syrup for 15 to 35 days. In these studies, no overall differences in safety were observed between poor metabolizers and normal metabolizers. Although not seen in these studies, an increased risk of exposure-related adverse events in patients who are poor metabolizers cannot be ruled out.

Pseudoephedrine alone is incompletely metabolized (less than 1%) in the liver by N-demethylation to an inactive metabolite. The drug and its metabolite are excreted in the urine. About 55% to 96% of an administered dose of pseudoephedrine hydrochloride is excreted unchanged in the urine.

Elimination: Following single dose administration of LORINASE-D Extended Release Tablets, the mean plasma elimination half-life of desloratadine was approximately 27 hours. In another study, following administration of single oral doses of desloratadine 5 mg, Cmax and AUC values increased in a dose proportional manner following single oral doses between 5 and 20 mg. The degree of accumulation after 14 days of dosing was consistent with the half-life and dosing frequency. A human mass balance study documented a recovery of approximately 87% of the 14C-desloratadine dose, which was equally distributed in urine and feces as metabolic products. Analysis of plasma 3-hydroxydesloratadine showed similar Tmax and half-life values compared to desloratadine.

The mean elimination half-life of pseudoephedrine is dependent on urinary pH. The elimination half-life is approximately 3 to 6 or 9 to 16 hours when the urinary pH is 5 or 8, respectively.

Geriatric Subjects: Following multiple-dose administration of LORINASE-D Tablets, the mean Cmax and AUC values for desloratadine were 20% greater than in younger subjects (˂ 65 years old). The oral total body clearance (CL/F) when normalized for body weight was similar between the 2 age groups. The mean plasma elimination half-life of desloratadine was 33.7 hr in subjects ≥ 65 years old. The pharmacokinetics for 3-hydroxydesloratadine appeared unchanged in older vs. younger subjects. These age-related differences are unlikely to be clinically relevant and no dosage adjustment is recommended in elderly patients.

Pediatric Subjects: LORINASE-D Extended Release Tablets are not an appropriate dosage form for use in pediatric patients below 12 years of age.

Renally Impaired: Following a single dose of desloratadine 7.5 mg, pharmacokinetics were characterized in subjects with mild (n=7; creatinine clearance 51-69 mL/min/1.73 m2), moderate (n=6; creatinine clearance 34-43 mL/min/1.73 m2) and severe (n=6; creatinine clearance 5-29 mL/min/1.73 m2) renal impairment or hemodialysis dependent (n=6) subjects. In subjects with mild and moderate renal impairment, median Cmax and AUC values increased by approximately 1.2-and 1.9-fold, respectively, relative to subjects with normal renal function. In subjects with severe renal impairment or who were hemodialysis dependent, Cmax and AUC values increased by approximately 1.7-and 2.5-fold, respectively. Minimal changes in 3hydroxydesloratadine concentrations were observed. Desloratadine and 3-hydroxydesloratadine were poorly removed by hemodialysis. Plasma protein binding of desloratadine and 3-hydroxydesloratadine was unaltered by renal impairment.

Pseudoephedrine is primarily excreted unchanged in the urine as unchanged drug with the remainder apparently being metabolized in the liver. Therefore, pseudoephedrine may accumulate in patients with renal impairment.

Hepatically Impaired: Following a single oral dose of desloratadine, pharmacokinetics were characterized in subjects with mild (n=4), moderate (n=4) and severe (n=4) hepatic impairment as defined by the Child-Pugh classification of hepatic impairment and 8 subjects with normal hepatic function. Subjects with hepatic impairment, regardless of severity, had approximately a 2.4-fold increase in AUC as compared with normal subjects. The apparent oral clearance of desloratadine in subjects with mild, moderate, and severe hepatic impairment was 37%, 36%, and 28% of that in normal subjects, respectively. An increase in the mean elimination half-life of desloratadine in subjects with hepatic impairment was observed. For 3hydroxydesloratadine, the mean Cmax and AUC values for subjects with hepatic impairment combined were not statistically significantly different from subjects with normal hepatic function.

Gender: Female subjects treated for 14 days with LORINASE-D Tablets had 10% and 3% higher desloratadine Cmax and AUC values, respectively, compared with male subjects. The 3-hydroxydesloratadine Cmax and AUC values were also increased by 45% and 48%, respectively, in females compared with males. However, these apparent differences are not considered to be clinically relevant.

Race: Following 14 days of treatment with LORINASE-D Tablets, the Cmax and AUC values for desloratadine were 18% and 32% higher, respectively in Blacks compared with Caucasians. For 3-hydroxydesloratadine there was a corresponding 10% reduction in Cmax and AUC values in Blacks compared to Caucasians. These differences are not considered to be clinically relevant.

Drug Interaction: In 2 controlled crossover clinical pharmacology studies in healthy male (n=12 in each study) and female (n=12 in each study) subjects, desloratadine 7.5 mg (1.5 times the daily dose) once daily was co-administered with erythromycin 500 mg every 8 hours or ketoconazole 200 mg every 12 hours for 10 days. In 3 separate controlled, parallel group clinical pharmacology studies, desloratadine at the clinical dose of 5 mg has been co-administered with azithromycin 500 mg followed by 250 mg once daily for 4 days (n=18) or with fluoxetine 20 mg once daily for 7 days after a 23-day pretreatment period with fluoxetine (n=18) or with cimetidine 600 mg every 12 hours for 14 days (n=18) under steady state conditions to healthy male and female subjects. Although increased plasma concentrations (Cmax and AUC_0-24 hrs) of desloratadine and 3-hydroxydesloratadine were observed (see Table 2), there were no clinically relevant changes in the safety profile of desloratadine, as assessed by electrocardiographic parameters (including the corrected QT interval), clinical laboratory tests, vital signs and adverse events.

Table 2: Changes in Desloratadine and 3-hydroxydesloratadine Pharmacokinetics in Healthy Male and Female Subjects

5.3.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no animal or laboratory studies on the combination product of desloratadine and pseudoephedrine sulfate to evaluate carcinogenesis, mutagenesis, or impairment of fertility.

Carcinogenicity Studies: The carcinogenic potential of desloratadine was assessed using a loratadine study in rats and a desloratadine study in mice. In a 2-year study in rats, loratadine was administered in the diet at doses up to 25 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 30 times the AUC in humans at the recommended daily oral dose). A significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg/day of loratadine and in males and females given 25 mg/kg/day of loratadine. The estimated desloratadine and desloratadine metabolite exposures in rats given 10 mg/kg of loratadine were approximately 7 times the AUC in humans at the recommended daily oral dose. The clinical significance of these findings during long-term use of desloratadine is not known.

In a 2-year dietary study in mice, males and females given up to 16 mg/kg/day and 32 mg/kg/day desloratadine, respectively, did not show significant increases in the incidence of any tumors. The estimated desloratadine and desloratadine metabolite exposures in mice at these doses were 12 and 27 times, respectively, the AUC in humans at the recommended daily oral dose.

Genotoxicity Studies: In genotoxicity studies with desloratadine, there was no evidence of genotoxic potential in a reverse mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity assay) or in 2 assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenicity assay and mouse bone marrow micronucleus assay).

Impairment of Fertility: There was no effect on female fertility in rats at desloratadine doses up to 24 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 130 times the AUC in humans at the recommended daily oral dose). 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 (estimated desloratadine and desloratadine metabolite exposures were approximately 45 times the AUC in humans at the recommended daily oral dose). Desloratadine had no effect on fertility in rats at an oral dose of 3 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 8 times the AUC in humans at the recommended daily oral dose).

5.3.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies: Desloratadine was not teratogenic in rats at doses up to 48 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 210 times the AUC in humans at the recommended daily oral dose) or in rabbits at doses up to 60 mg/kg/day (estimated desloratadine exposures were approximately 230 times the AUC in humans at the recommended daily oral dose). 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 (estimated desloratadine and desloratadine metabolite exposures were approximately 120 times the AUC in humans at the recommended daily oral dose). Reduced body weight and slow righting reflex were reported in pups at doses of 9 mg/kg/day or greater (estimated desloratadine and desloratadine metabolite exposures were approximately 50 times or greater than the AUC in humans at the recommended daily oral dose). Desloratadine had no effect on pup development at an oral dose of 3 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 7 times the AUC in humans at the recommended daily oral dose).

For PSEUDOEPHEDRINE SULFATE 120 MG BULK

·       Dibasic Calcium Phosphate Dihydrate: 60 mg

·       Avicel PH 102: 44.5 mg

·       Hydroxypropyl Methylcellulose K15M: 105 mg

·       Povidone 30: 12 mg

·       Purified Water BP Q.S.

-       Extragranular Materials

·       Colloidal Silicon Dioxide: 3.5 mg

·       Magnesium Stearate: 5 mg

For DESLORATADINE 2.5 MG BULK

·       Avicel PH 101: 47.6 mg

·       Maize Starch: 30 mg

·       Pregelatinized Starch Dry: 15 mg

·       Spectracol Brilliant Blue LK 815030: 0.75 mg

·       Purified Water BP Q.S.

-       Extragranular Materials

·       Pregelatinized Starch Dry: 15 mg

·       Avicel PH 112: 36.9 mg

·       Colloidal Silicon Dioxide: 1.5 mg

·       Sodium Stearyl Fumarate: 0.75 mg

Not Applicable.

Store below 30°C.

Reel PVC/PE/PVDC 250/25/120, 95MM Clear blister.

Each pack contains 20 tablets in 2 strips, each blister contains 10 tablets.

No Special Disposal