Elriz XL Tablets

Levocetirizine hydrochloride & Ambroxol Hydrochloride modified release (5 mg +75mg)

Each modified release uncoated bilayered tablet contains:

Levocetirizine Hydrochloride IP 5 mg

(As immediate release)

Ambroxol Hydrochloride IP 75 mg

(As prolonged release)

Excipients q.s.

Colour: Sunset Yellow

Modified release uncoated bilayered tablet

5mg + 75mg

4.1 Therapeutic Indication

For symptomatic relief of productive cough associated with allergic rhinitis, when both antihistamine and mucolytic agents are desired.

4.2 Posology and method of administration

Adults and adolescents 12 years and above:1 tablet once a day

Elderly

Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment.

Renal impairment

The dosing intervals must be individualised according to renal function (eGFR – estimated Glomerular Filtration Rate). Refer to the following table and adjust the dose as indicated.

Dosing adjustments for patients with impaired renal function (as per Levocetirizine dose):

In paediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient and his body weight. There are no specific data for children with renal impairment.

Hepatic impairment

No dose adjustment is needed in patients with solely hepatic impairment. In patients with hepatic impairment and renal impairment, adjustment of the dose is recommended (see Renal impairment above).

Method of administration - Oral

Tablet should be swallowed whole & not to be broken, crushed or chewed. It may be taken with or without food. It is recommended to take the daily dose in one single intake.

4.3 Contraindications

• Patients with history of hypersensitivity to any component of the product
• Hypersensitivity to the active substance, to cetirizine, to hydroxyzine, to any other piperazine derivatives or to any of the other excipients.
• Patients with end stage renal disease with eGFR below 10 ml/min (requiring dialysis treatment).
• Patients undergoing haemodialysis
• Children < 12 years of age

4.4 Special warnings and precautions for use

• Precaution is recommended with concurrent intake of alcohol.
• Caution should be taken in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention.
• Caution should be taken in patients with epilepsy and patients at risk of convulsion as levocetirizine may cause seizure aggravation.
• Response to allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
• Pruritus may occur when levocetirizine is stopped even if those symptoms were not present before treatment initiation. The symptoms may resolve spontaneously. In some cases, the symptoms may be intense and may require treatment to be restarted. The symptoms should resolve when the treatment is restarted.
• In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with Elriz XL.
• 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 Elriz XL.
• Concurrent use of Elriz-XL with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.
• The use of Elriz XL (Ambroxol) should be carefully considered in patients predisposed to peptic ulcers.
• Ciliary dyskinesia: In patients with ciliary dyskinesia the benefit of liquefaction of secretions should be carefully weighed against the risk of congestion of secretions.

Pediatric population

The use of ELRIZ®XL tablet is not recommended in children aged less than 12 years.

4.5 Drugs interactions

• No interaction studies have been performed with levocetirizine (including no studies with CYP3A4 inducers); studies with the racemate compound cetirizine demonstrated that there were no clinically relevant adverse interactions (with anti-pyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole and pseudoephedrine). A small decrease in the clearance of cetirizine (16%) was observed in a multiple dose study with theophylline (400 mg once a day); while the disposition of theophylline was not altered by concomitant cetirizine administration.
• In vitro data indicate that levocetirizine is unlikely to produce pharmacokinetic interactions through inhibition or induction of liver drug-metabolizing enzymes.
• In a multiple dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) further to concomitant cetirizine administration.
• The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased.
• In sensitive patients, the concurrent administration of cetirizine or levocetirizine and alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.
• After administration of ambroxol concentrations of antibiotics (amoxicillin, cefuroxime, erythromycin) in broncho-pulmonary secretions and sputum is increased.
• Anti-tussives: Concomitant administration of anti-tussives may impair the expectoration of liquefied bronchial mucus due to inhibition of the cough reflex and cause congestion of secretions.

4.6 Use in special populations

Pregnancy

Caution is advised when Elriz-XL is used during pregnancy. Use during the first trimester of pregnancy is not recommended.

Breast-feeding

Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human. Therefore, the excretion of levocetirizine in human milk is likely. Adverse reactions associated with levocetirizine may be observed in breastfed infants. Therefore, caution should be exercised when prescribing levocetirizine to lactating women.

Fertility

For levocetirizine no clinical data are available.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Levocetirizine

• Common adverse reactions with (≥1/100 to <1/10): Headache (3.2%), Somnolence (1.4%), dry Mouth (1.6%), and Fatigue (1.2%).
• The incidence of sedating adverse drug reactions such as somnolence, fatigue, and asthenia was altogether more common (8.1%) under compared to placebo (3.1%)
• Uncommon (≥1/1,000 to <1/100): asthenia or abdominal pain

Ambroxol

• Mild upper gastro-intestinal side effects primarily Taste disturbances, heartburn, dyspepsia, and occasionally nausea and vomiting have been reported.
• Allergic reactions have occurred rarely, primarily skin rashes.
• There have been extremely rare case reports of severe acute anaphylactic-type reactions but their relationship to Ambroxol is uncertain. Some of these patients have also shown allergic reactions to other substances.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: http://www.zuventus.co.in/safety.aspx

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Symptoms

Levocetirizine

• Symptoms of overdose may include drowsiness in adults. In children, agitation and restlessness may initially occur, followed by drowsiness.

Ambroxol

• There are no severe intoxications known following an overdose of Ambroxol. Manifestations that have been reported include short-term restlessness and diarrhoea. Consistent with the findings of preclinical studies, increased saliva production, nausea, vomiting, and a drop in blood pressure can be observed following extreme overdosing.

Therapeutic Measures: There is no known specific antidote. Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage may be considered shortly after ingestion of the drug. Levocetirizine is not effectively removed by haemodialysis.

5.1 Mechanism of Action

Levocetirizine, the active enantiomer of cetirizine, is a second- generation anti-histamine and a potent and selective antagonist of peripheral H1-receptors.

Ambroxol is frequently used as mucolytic and it also induces the synthesis of surfactant in lung alveolar type II cells. By this mechanism, it decreases the work and effort of breathing and can improve respiratory symptoms. It has also been proved to have antioxidant and anti-inflammatory activities

5.2 Pharmacodynamic properties

At half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose. Levocetirizine shows receptor occupancy of 90% at 4 hours and 57% at 24 hours. The onset of action of levocetirizine 5 mg has been observed at 1-hour post drug intake.

Ambroxol is shown to exert several activities: i) secretolytic activity (i.e., promotes mucus clearance, facilitates expectoration, and eases productive cough); ii) anti-inflammatory and antioxidant activity; and iii) a local anesthetic effect through sodium channel blocking at the level of the cell membrane.

5.3 Pharmacokinetic properties

Levocetirizine exhibited linear pharmacokinetics over the therapeutic dose range in adult healthy subjects.

Pharmacokinetics in special Populations

• Elderly Levocetirizine dose should be adjusted in accordance with renal function in elderly patients
• Hepatic Insufficiency No dose adjustment is needed in patients with solely hepatic impairment.
• Renal Insufficiency Dosage and frequency of administration of ELRIZ®XL should be reduced
• Dosage and frequency of administration of Levocetirizine should be reduced in patients with mild, moderate or severe renal impairment
• In patients with moderate to severe renal / hepatic impairment, a slower elimination rate may lead to the accumulation of ambroxol and/or ambroxol-metabolites formed in the liver.

6.1 Animal Toxicology or Pharmacology

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

ELRIZ®XL is a fixed dose combination of a Levocetirizine Hydrochloride (5mg) and Ambroxol Hydrochloride (75mg).

Levocetirizine hydrochloride is an orally active H1-receptor antagonist.

Molecular Formula: C₂₁H₂₅ClN₂O₃•HCl

Chemical name: (R)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy] acetic acid hydrochloride.

Molecular weight: 461.82

Molecular Structure:

Ambroxol is a metabolite of bromhexine and is widely used as a mucolytic.

Molecular Formula: C₁₃H₁₈Br₂N₂O.HCl

Chemical name: trans-4-((2-amino-3,5-dibromobenzyl) amino) cyclohexanol hydrochloride

Molecular Weight: 414.56 g/mol

Molecular Structure:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on the pack

8.3 Packaging information

10 blister strips of 10 tablets each

8.4 Storage and handing instructions

• Store in cool, dry and dark place.
• Keep out of reach of children.

• ELRIZ®XL Tablet should be swallowed whole & not to be broken, crushed or chewed.
• Somnolence Caution patients 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 dihydrochloride.
• Concomitant Use of Alcohol and other Central Nervous System Depressants Instruct patients to avoid concurrent use of levocetirizine hydrochloride with alcohol or other central nervous system depressants because additional reduction in mental alertness may occur.
• Dosing of Tablets Do not exceed the recommended daily dose in adults and adolescents 12 years of age. Advise patients to not ingest more than the recommended dose of levocetirizine hydrochloride because of the increased risk of somnolence at higher doses.
• Do not take this medicine, if you are allergic to Levocetirizine and/or Ambroxol Signs of an allergic reaction include a rash, itching or shortness of breath.
• Advice patients to talk to your doctor or pharmacist, if you get any side effects. This includes any possible side effects not listed in this leaflet.
• Advice patients If they have any further questions, ask doctor or pharmacist.