LEVORID D Tablets (Levocetirizine hydrochloride + Phenylephrine hydrochloride)

Table of Content

Composition

Levorid D Tablets

Each tablet contains

Levocetirizine hydrochloride ………....... 2.5 mg

Phenylephrine hydrochloride …... 10 mg

Dosage Form

Oral tablet

Description

Levorid D Tablets are a combination of levocetirizine hydrochloride and phenylephrine hydrochloride.

Levocetirizine hydrochloride is the R-enantiomer of the racemate, cetirizine hydrochloride. Levocetirizine is orally active, potent, selective and long-acting histamine (H1)-receptor antagonist, which has no anticholinergic effects.

Phenylephrine is a relatively selective alpha1-adrenoceptor agonist that is widely used as a constituent of proprietary cough and cold cure preparations for its vasoconstrictor and decongestant properties.

Pharmacology

Pharmacodynamics

Levocetirizine Hydrochloride

Levocetirizine, the R-enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors. Binding studies have revealed that levocetirizine has high affinity for human H1-receptors (Ki = 3.2 nmol/L). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3 nmol/L). Levocetirizine dissociates from H1-receptors with a half-life of 115±38 minutes. After single administration, levocetirizine shows receptor occupancy of 90% at 4 hours and 57% at 24 hours.

The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1 hour post-drug intake in placebo-controlled trials in the model of the allergen challenge chamber.

In vitro studies (Boyden chambers and cell layers techniques) show that levocetirizine inhibits eotaxin-induced eosinophil transendothelial migration through both the dermal and lung cells. A pharmacodynamic experimental study in vivo (skin chamber technique) showed three main inhibitory effects of levocetirizine 5 mg in the first 6 hours of pollen-induced reaction, compared with placebo in 14 adult patients: inhibition of VCAM-1 release, modulation of vascular permeability, and a decrease in eosinophil recruitment.

The efficacy and safety of levocetirizine has been demonstrated in several double-blind, placebo controlled, clinical trials performed in adult patients suffering from seasonal allergic rhinitis, perennial allergic rhinitis, or persistent allergic rhinitis. Levocetirizine has been shown to significantly improve symptoms of allergic rhinitis, including nasal obstruction in some studies.

Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.

The pharmacokinetic/pharmacodynamic relationship of 5 mg levocetirizine provides a similar pattern of inhibition of histamine-induced wheal and flare than 10 mg cetirizine. As for cetirizine, the action on histamine-induced skin reactions was out of phase with the plasma concentrations. The electrocardiographs (ECGs) did not show the relevant effects of levocetirizine on the QT interval.

Phenylephrine Hydrochloride

Phenylephrine is considered a relatively selective alpha1-adrenoceptor agonist. It is reported by some investigators to have weak alpha2-adrenoceptor activity and some activity as a beta-adrenoceptor agonist. Phenylephrine is used as a preferential alpha1-agonist drug, leading to dose- and concentration-dependent vasoconstriction. The alpha1-adrenoceptor action of phenylephrine is slightly stronger on the venous capacitance vessels when compared to the arteriolar resistance vessels. The sympathomimetic effect of phenylephrine produces vasoconstriction which in turn relieves nasal congestion. As a decongestant, it may be administered orally in divided doses of up to 40 mg daily.

Pharmacokinetics

Levocetirizine Hydrochloride

The pharmacokinetics of levocetirizine is linear with dose and time-independent, with low inter-subject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.

Absorption

Levocetirizine is rapidly and extensively absorbed following oral administration. Peak plasma concentrations are achieved 0.9 hours after dosing. Steady state is achieved after 2 days. Peak concentrations are, typically, 270 ng/ml and 308 ng/ml following a single and a repeated 5 mg o.d. dose, respectively. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed. A dose of 5 mg (10ml) of levocetirizine dihydrochloride oral solution is bioequivalent to a 5 mg dose of levocetirizine tablets. Following oral administration of a 5 mg dose of levocetirizine oral solution to healthy adult subjects, the mean peak plasma concentrations were achieved approximately 0.5 hours post-dose.

Distribution

No tissue distribution data are available in humans. Levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is restrictive, as the volume of distribution is 0.4 l/kg.

Biotransformation

The extent of metabolism of levocetirizine in humans is less than 14% of the dose and, therefore, differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O-dealkylation and taurine conjugation. Dealkylation pathways are primarily mediated by cytochrome (CYP) 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose. Due to its low metabolism and the absence of metabolic inhibition potential, the interaction of levocetirizine with other substances or vice-versa, is unlikely.

Elimination

The plasma half-life in adults is 7.9+­1.9 hours. The mean apparent total body clearance is 0.63 ml/kg/min. The major route of excretion of levocetirizine and metabolites is via the urine, accounting for a mean of 85.4% of the dose. Excretion via the faeces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.

Phenylephrine Hydrochloride

Phenylephrine is variably absorbed after oral administration and is also subject to extensive pre-systemic metabolism. As a consequence, systemic bioavailability is only about 40%, with peak plasma concentrations at 1–2 hours. The volume of distribution is between 200 to 500 litres, with a mean plasma half-life of 2–3 hours. Few data are available on the extent of plasma protein binding or on the disposition of the drug. There is probably little penetration into the brain, the drug does not seem to cross the placenta, and excretion in breast milk is not documented.

Phenylephrine undergoes extensive biotransformation in the intestinal wall during absorption. Following absorption, the drug is extensively biotransformed in the liver. Both phenylephrine and its metabolites are excreted in the urine, with only a small amount of the drug excreted unchanged, as in 16.6% following intravenous administration and less following oral administration.

Indications

Levorid D Tablets are indicated for the relief of the symptoms of allergic rhinitis such as sneezing, rhinorrhoea, nasal congestion, itching and lacrimation. It should be administered when both the antihistamine properties of levocetirizine and the nasal decongestant activity of phenylephrine are desired.

Dosage and Administration

Adults and Adolescents (12 years and above)

One tablet twice daily.

The recommended dosage should not be exceeded.

Contraindications

Levocetirizine Hydrochloride

Hypersensitivity to levocetirizine, cetirizine or its parent compound hydroxyzine.

Patients with severe renal impairment (<10 ml/min creatinine clearance) and patients undergoing hemodialysis should not be administered Levorid D Tablets. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Phenylephrine Hydrochloride

The product is contraindicated in patients who have previously shown hypersensitivity to any of the ingredients or intolerance to phenyleprine. Due to its phenylephrine component, LEVORID D Tablets are contraindicated in patients receiving concurrent administration of monoamine oxidase inhibitors or within 14 days of ceasing such treatment. Avoid in patients on tricyclic antidepressants. LEVORID D Tablets are also contraindicated in patients with cardiovascular diseases, hypertension, aortic aneurysm, severe or unstable ischaemic heart disease, such as angina and recent myocardial infarction, hyperthyroidism, diabetes mellitus, closed angle glaucoma, prostatic enlargement and phaeochromocytoma. Because phenylephrine has actions that promote smooth muscle contractility, including in the uterus, and may induce umbilical vasospasm, it should be avoided in pregnancy.

Warnings and Precautions

Levocetirizine Hydrochloride

The use of the film-coated tablet formulation is not recommended in children aged less than 6 years since this formulation does not allow for appropriate dose adaptation. It is recommended to use a paediatric formulation of levocetirine. The use of the film-coated tablet formulation is not recommended in children aged less than 6 years since this formulation does not allow for appropriate dose adaptation. It is recommended to use a paediatric formulation of levocetirine. The administration of levocetirizine to infants and toddlers aged less than 2 years is not recommended.

Comparative clinical trials have revealed no evidence that levocetirizine at the recommended dose impairs mental alertness, reactivity or the ability to drive. In clinical trials the occurrence of somnolence, fatigue and asthenia has been reported in some patients under therapy with levocetirizine. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination, such as operating machinery or driving a motor vehicle, after ingestion of levocetirizine. Concurrent use of levocetirizine with alcohol or other central nervous system (CNS) depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur.

Urinary retention has been reported post-marketing with levocetirizine. Levocetirizine should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention. Discontinue, if urinary retention occurs.

Phenylephrine Hydrochloride

Agonists at alpha1-adrenoceptors may produce coronary vasospasm; so, care should be exercised in the use of phenylephrine in patients with ischaemic heart disease. In patients with chronic pulmonary hypertension and right ventricular failure, using phenylephrine to increase right ventricular coronary perfusion pressure by raising the aortic blood pressure leads to detrimental effects on the right ventricular function and is not recommended. Phenylephrine should be used with caution in patients with occlusive vascular disease including Raynaud’s Phenomenon. In cirrhosis, there is a reduction in vascular alpha-adrenergic responsiveness and larger doses of phenylephrine may be required for any desired effect. Concurrent administration of monoamine oxidase inhibitors is an absolute contraindication. Severe or unpredictable increases in blood pressure may occur if the patient is receiving concurrent treatment with a monoamine oxidase inhibitor drug as a result of increased receptor sensitivity. Because phenylephrine has actions that promote smooth muscle contractility, including in the uterus, and may induce umbilical vasospasm, it should be avoided in pregnancy. Phenylpehrine should not be administered concomitantly with tricyclic antidepressants and in patients with hypertension, unstable angina and recent myocardial infarction, and hyperthyroidism.

Drug Interactions

Levocetirizine Hydrochloride

In vitro data indicate that levocetirizine is unlikely to produce pharmacokinetic interactions through the inhibition or induction of liver drug-metabolizing enzymes. No in vivo drug–drug interaction studies have been performed with levocetirizine. Drug interaction studies have been performed with racemic cetirizine.

Pharmacokinetic interaction studies performed with racemic cetirizine demonstrated that cetirizine did not interact with antipyrine, pseudoephedrine, erythromycin, glipizide and diazepam, azithromycin, ketoconazole and cimetidine. There was a small decrease (~16%) in the clearance of cetirizine caused by a 400 mg dose of theophylline. It is possible that higher theophylline doses could have a greater effect.

The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased.

Ritonavir increased the plasma AUC of cetirizine by about 42%, along with an increase in the half-life (53%) and a decrease in the clearance (29%) of cetirizine. The disposition of ritonavir was not altered by concomitant cetirizine administration.

In sensitive patients, the simultaneous administration of cetirizine or levocetirizine and alcohol or other CNS depressants may have effects on the CNS, although it has been shown that the racemate cetirizine does not potentiate the effect of alcohol.

Comparative clinical trials have revealed no evidence that levocetirizine at the recommended dose impairs mental alertness, reactivity or the ability to drive. Nevertheless, some patients could experience somnolence, fatigue and asthenia under therapy with levocetirizine. Therefore, patients intending to drive, engage in potentially hazardous activities or operate machinery should take their response to the medicinal product into account.

Phenylephrine Hydrochloride

Hypertension may occur when phenylephrine is given concurrently with antidepressants of both monoamine oxidase and tricyclic types, ganglion-blocking agents, adrenergic-blocking drugs, rauwolfia alkaloids and methyldopa. May increase the possibility of arrhythmias in digitalised patients. May enhance the cardiovascular effects of other sympathomimetic amines (e.g. decongestants). It should not be taken together with vasodilators, beta-blockers or enzyme inducers such as alcohol.

Hepatic and Renal Impairment

In cirrhosis, there is a reduction in vascular alpha-adrenergic responsiveness and larger doses of phenylephrine may be required for any desired effect. Levocetirizine is known to be substantially excreted by the kidneys and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. 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 renal function.

Pregnancy

Because of the potential promotion of uterine contractility and peripheral vasoconstriction, with the possibility of foetal hypoxia, phenylephrine and, hence, this combination is best avoided during pregnancy. In addition, since phenylephrine may reduce placental perfusion, the product should not be used in patients with a history of pre-eclampsia.

Lactation

Excretion of phenylephrine in breast milk has not been reported. No peri- and post-natal animal studies have been conducted with levocetirizine. Cetirizine has been reported to be excreted in human breast milk. Because levocetirizine is also expected to be excreted in human milk, use of this combination in nursing mothers is not recommended.

Paediatric Use

The combination is not recommended for children below 12 years of age.

Geriatric Use

Clinical studies of levocetirizine for each approved indication did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. The positive inotropic effect of phenylephrine is reduced in the elderly because of loss of alpha-adrenergic receptors. This combination should be used cautiously as co-morbidities such as ischaemic heart disease, hypertension and unstable angina are prevalent in this age group.

Undesirable Effects

Levocetirizine Hydrochloride

Use of levocetirizine has been associated with somnolence,headache, fatigue, nasopharyngitis, dry mouth and pharyngitis in subjects, 12 years of age and older, and pyrexia, somnolence, cough and epistaxis in children, 6 to 12 years of age in clinical trials. Further uncommon incidences of adverse reactions like asthenia or abdominal pain and urinary retention were observed. . Additional adverse reactions of medical significance observed at a higher incidence than in placebo in adults and adolescents aged 12 years and older exposed to levocetirizine are syncope (0.2%) and weight increased (0.5%).

Adverse reactions reported in subjects 1 to 5 years of age and in 6 months to 11 months of age were pyrexia, diarrhoea, vomiting, otitis media, constipation, salivary hypersecretion, thirst, hunger, fatigue, anorexia, somnolence, psychomotor hyperactivity, sleep disorder, middle insomnia, epistaxis, pruritius, headache. In paediatric patients (1 to 5 years of age) exposed to levocetirizine, pyrexia, diarrhoea, vomiting and otitis media were common adverse effects. In paediatric patients (6 months to 11 months of age) exposed to levocetirizine, diarrhoea and constipation were the common adverse effects.

Elevations of blood bilirubin and transaminases were reported in <1% of patients in the clinical trials. The elevations were transient and did not lead to discontinuation in any patient.

In addition to the adverse reactions reported during clinical studies and listed above, very rare cases of the following adverse drug reactions have been reported in post-marketing experience

Immune System Disorders: Hypersensitivity, including anaphylaxis.

Metabolism and Nutrition Disorders: Increased appetite

Psychiatric Disorders: Aggression, agitation, hallucinations, depression, insomnia, suicidal ideation.

Nervous System Disorders: Convulsion, paraesthesia, dizziness. syncope, tremor, dysguesia.

Ear and Labyrinth disorder: Vertigo

Eyes Disorders: Visual disturbances, blurred vision  

Cardiac Disorders: Palpitations tachycardia

Respiratory, Thoracic and Mediastinal Disorders: Dyspnoea.

Gastrointestinal Disorders: Nausea, vomiting, diarrhoea

Hepatobiliary Disorders: Hepatitis.

Skin and Subcutaneous Tissue Disorders: Angioneurotic oedema, fixed-drug eruption, pruritus, rash, urticaria.

Musculoskeletal, Connective Tissues and Bone Disorders: Myalgia, Arthralgia.

Investigations: Weight increased, abnormal liver function tests.

Renal and Urinary Disorders: dysuria, urinary retention

General Disorders and Administration Site Conditions: oedema

Besides these events reported under treatment with levocetirizine, other potentially severe adverse events have been reported from the postmarketing experience with cetirizine. Since levocetirizine is the principal pharmacologically active component of cetirizine, one should take into account the fact that the following adverse events could also potentially occur under treatment with levocetirizine: hallucinations, suicidal ideation, orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis and stillbirth.

Phenylephrine Hydrochloride

Persistent and/or severe hypertension is a potentially lethal hazard of the response to phenylephrine. Severe hypertension complicated by headache, nausea, vomiting and profound reflex bradycardia has been reported, and infants and young children appear to be especially at risk. Although reported, such systemic effects are rare with topical application. Rarely, palpitations, allergic reactions and occasionally urinary retention in males.

The vasoconstrictor and pressor effects of phenylephrine may be hazardous to patients who are also suffering from hypertension, aortic aneurysm, severe or unstable ischaemic heart disease or hyperthyroidism.

Severe or unpredictable increases in blood pressure may occur if the patient is receiving concurrent treatment with a monoamine oxidase inhibitor drug, as a result of increased receptor sensitivity.

Severe tissue necrosis may occur if potent vasopressors such as phenylephrine are injected other than intravenously. Local application to the conjunctiva may cause stinging.

Administration of phenylephrine, like other alpha1-adrenergic agents, interferes with potassium movement into the cells during acute potassium administration, although normally there is no effect on serum potassium.

Overdosage

Levocetirizine Hydrochloride

Symptoms of overdose may include drowsiness in adults; in children, there is initially agitation and restlessness, followed by drowsiness. There is no known specific antidote to levocetirizine. Should overdose occur, consider standard measures to remove any unabsorbed drug. Gastric lavage should be considered following short-term ingestion. Levocetirizine is not effectively removed by haemodialysis.

Phenylephrine Hydrochloride

Cases of deliberate overdose have been reported, but there are no recorded fatalities.

Features of severe overdosage of phenylephrine include haemodynamic changes and cardiovascular collapse with respiratory depression. Treatment includes early gastric lavage and symptomatic and supportive measures. Hypertensive effects may be treated with an i.v. alpha-receptor-blocking agent.

Phenylephrine overdose is likely to result in: irritability, restlessness, nervousness, headache, difficulty in micturition, dizziness,thirst, convulsions, insomnia, increased blood pressure, nausea, vomiting, Mydriasis, acute angle closure glaucoma (most likely to occur in those with closed angle glaucoma), tachycardia, palpitations, allergic reactions (e.g. rash, urticaria, allergic dermatitis), dysuria, urinary retention (most likely to occur in those with bladder outlet obstruction, such as prostatic hypertrophy). In severe overdosage, gastric lavage and aspiration should be performed.

Additional symptoms may include hypertension, and possibly reflex bradycardia. In severe cases confusion, hallucinations, seizures and arrhythmias may occur.

In most cases, a severe hypertensive response can be countered by means of an alpha1-antagonist, such as intravenous phentolamine.

Packaging Information

LEVORID-D Tablets...................... Pack of 10 tablets

Last Updated: Mar 2016
Last Reviewed: Mar 2016