L-Ornithine L-Aspartate tablet

Each film coated tablet contains:

L-Ornithine L-Aspartate 150mg/ 500 mg

Excipients q.s

Tablet 150 mg/ 500 mg

4.1 Therapeutic indication

Treatment of associated conditions and sequelae of diseases with impaired hepatic detoxification (e.g. cirrhosis of the liver), when there are symptoms and signs of minimal or overt hepatic encephalopathy.

4.2 Posology and method of administration

2-3 tablets 3-4 times per day can be administered in mild to moderate liver disorders.

4.3 Contraindications

• Hypersensitivity to LOLA or any other excipients of this product.
• Severe renal insufficiency (serum creatinine value > 3 mg/100 ml).

4.4 Special warnings and precautions for use

• Monitoring of serum and urinary urea levels at regular intervals should be done.
• Should be used during pregnancy only if the potential benefits out-weigh the potential risk to the fetus.

4.5 Drugs interactions

No known drug-drug interaction.

4.6 Use in special populations

Pregnancy & Lactation

The administration in pregnancy and lactation should be avoided. If treatment is nevertheless

thought to be necessary, the benefits and risks should be carefully assessed.

4.7 Effects on ability to drive and use machines

No studies on the effect on the ability to drive and use machines have been performed

4.8 Undesirable effects

Very rarely side effects like nausea and vomiting occur. These side effects are usually transient and do not necessitate the withdrawal of the drug.

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: https://www.zuventus.com/drug-safety-reporting

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

4.9 Overdose

There is no data available for LOLA tablet overdosage. If any patient consumes excess of drug, it should be managed symptomatically.

5.1 Mechanism of Action

L-Ornithine-L-Aspartate is a stable salt of the amino acids ornithine and aspartic acid and provides substrates for urea genesis and glutamine synthesis, which are important mechanisms in ammonia detoxification.

5.2 Pharmacodynamic properties

It is well known that both ornithine and aspartic acid play a key role in liver metabolism. Ornithine is the starting point of ammonia detoxification. It brings ammonia into the urea cycle, in which ammonia is converted into a non-toxic substance urea. It activates ornithine transcarbamoylase and carbamoyl phosphate synthetase and acts as a substrate for urea genesis. Hence, LOLA can activate the periportal urea cycle in the liver. The other component of the drug, aspartic acid, not only represents an important stage in the reaction sequence involved in the urea cycle, but also features in the tricarboxylic acid cycle as oxaloacetate formed by transamination, thereby improving the energy balance of diseased liver. Furthermore, aspartic acid promotes natural regeneration of liver cells by taking part in pyrimidine biosynthesis.

After conversion to α-ketoglutarate, aspartate and ornithine, act as carbon sources for perivenous glutamine synthesis. LOLA up-regulates glutamine synthesis in the skeletal muscle by substrate provision for glutamine synthetase. Ammonia is consumed during urea formation and glutamine synthesis, and thereby LOLA decreases blood ammonia levels.

5.3 Pharmacokinetic properties

• L-Ornithine-L-Aspartate is rapidly absorbed and cleaved into L-Ornithine and L-Aspartate.
• Elimination half-life of each amino acid is short, approximately 40 min and bioavailability is 82.2 28% after oral administration.
• Some L-Aspartate appears unchanged in the urine.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on pack

• You will be regularly monitored for blood creatinine and blood/urine urea levels.
• Inform your doctor if you are pregnant, planning a pregnancy, or breastfeeding.
• Do not take this medicine if you are allergic to any of its ingredients.

23.09.2024

Pancreatin

ENZELO 10000

Each hard gelatin capsule contains:

Pancreatin IP 170 mg

(As enteric coated pellets)

Declared enzyme activity

Amylase (Ph.Eur.U)/U 8000

Lipase (Ph.Eur.U)/U 10000

Protease (Ph.Eur.U)/U 600

Approved Colours used in capsule shell

ENZELO 25000

Each hard gelatin capsule contains: Pancreatin IP 350 mg

(As enteric coated pellets)

Declared enzyme activity

Amylase (Ph.Eur.U)/U 18000

Lipase (Ph.Eur.U)/U 25000

Protease (Ph.Eur.U)/U 1000

Approved Colours used in capsule shell

Capsule

Pancreatin 170 mg / 350 mg

4.1 Therapeutic Indication

For the treatment of pancreatic exocrine insufficiency

4.2 Posology and method of administration

Adults (including the elderly) and children:

Initially one or two capsules during each meal. Dose increases, if required, should be added slowly, with careful monitoring of response and symptomatology.

It is important to ensure adequate hydration of patients at all times whilst dosing Enzelo 25000.

Fibrosing colonopathy has been reported in patients with cystic fibrosis taking in excess of 10,000 units of lipase/kg/day

Method of administration

Oral use.

Capsule should be swallowed whole & not to be opened, chewed or crushed.

4.3 Contraindications

Hypersensitivity to Pancreatin of porcine origin or to any of the excipients

4.4 Special warnings and precautions for use

Strictures of the ileo-caecum and large bowel (fibrosing colonopathy) have been reported in patients with cystic fibrosis taking high doses of pancreatin preparations. As a precaution, unusual abdominal symptoms or changes in abdominal symptoms should be medically assessed to exclude the possibility of fibrosing colonopathy, especially if the patient is taking in excess of 10,000 units of lipase/kg/day.

4.5 Drugs interactions

No interaction studies have been performed.

4.6 Use in special populations

Pregnancy

For pancreatic enzymes no clinical data on exposed pregnancies are available.

Animal studies show no evidence for any absorption of porcine pancreatic enzymes. Therefore, no reproductive or developmental toxicity is to be expected.

Caution should be exercised when prescribing to pregnant women.

Nursing Mothers

No effects on the suckling child are anticipated since animal studies suggest no systemic exposure of the breast-feeding woman to pancreatic enzymes. Pancreatic enzymes can be used during breast-feeding.

If required during pregnancy or lactation Enzelo should be used in doses sufficient to provide adequate nutritional status.

4.7 Effects on ability to drive and use machines

Enzelo has no or negligible influence on the ability to drive or use machines.

4.8 Undesirable effects

*Gastrointestinal disorders are mainly associated with the underlying disease. Similar or lower incidences compared to placebo were reported for abdominal pain and diarrhoea.

Strictures of the ileo-caecum and large bowel (fibrosing colonopathy) have been reported in patients with cystic fibrosis taking high doses of pancreatin preparations, see section 4.4 Special warnings and precautions for use.

Allergic reactions mainly but not exclusively limited to the skin have been observed and identified as adverse reactions during post-approval use. Because these reactions were reported spontaneously from a population of uncertain size, it is not possible to reliably estimate their frequency.

Paediatric population

No specific adverse reactions were identified in the paediatric population. Frequency, type and severity of adverse reactions were similar in children with cystic fibrosis as compared to adults.

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

4.9 Overdose

Extremely high doses of pancreatin have been reported to be associated with hyperuricosuria and hyperuricaemia.

Supportive measures including stopping enzyme therapy and ensuring adequate rehydration are recommended.

5.1 Mechanism of Action

The capsules dissolve rapidly in the stomach releasing plenty of minimicrospheres, a multidose principle which is designed to achieve good mixing with the chyme, emptying from the stomach together with the chyme and after release, good distribution of enzymes within the chyme.

When the minimicrospheres reach the small intestine the coating rapidly disintegrates (at pH > 5.5) to release enzymes with lipolytic, amylolytic and proteolytic activity to ensure the digestion of fats, starches and proteins. The products of pancreatic digestion are then either absorbed directly, or following further hydrolysis by intestinal enzymes.

5.2 Pharmacodynamic properties

Treatment with enzelo markedly improves the symptoms of pancreatic exocrine insufficiency including stool consistency, abdominal pain, flatulence and stool frequency, independent of the underlying disease.

5.3 Pharmacokinetic properties

Pharmacokinetic data are not available as the enzymes act locally in the gastro-intestinal tract. After exerting their action, the enzymes are digested themselves in the intestine.

6.1 Animal Toxicology or Pharmacology

Not applicable.

Pancreatin is a pancreatic enzyme supplement, containing Lipase, Amylase, Protease

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on Pack

8.3 Packaging information

10 Blister strips of 10 capsules each

8.4 Storage and handing instructions

Store below 25°C.

Protect from light & moisture.

Keep out of reach of children.

• Capsule should be swallowed whole & not to be opened, chewed or crushed.
• Capsule should be taken with the first bite of a meal
• Should be taken with sufficient fluid, adequate hydration should be ensured
• Dosage should not be changed or increased without the physician direction
• Sporadic doses (not taken with food) should be avoided
• Do not take this medicine, if you are allergic to porcine pancreatin.
• Signs of an allergic reaction include a rash, itching or shortness of breath.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
• If you have any further questions, ask your doctor or pharmacist.

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.

Levocetirizine Tablets IP 5 mg

Each film coated tablet contains

Levocetirizine Hydrochloride IP 5 mg

Excipients q.s.

Colour: Titanium Dioxide IP

Film-coated tablet. 5 mg

Therapeutic Indication

For allergic rhinitis and chronic urticaria.

Posology and method of administration

• Adults and adolescents 12 years and above:

The daily recommended dose is 5 mg (1 tablet).

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:

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).

Paediatric population

Children aged 6 to 12 years:

The daily recommended dose is 5 mg (1 film-coated tablet).

For children aged 2 to 6 years no adjusted dosage is possible with the film-coated tablet formulation. It is recommended to use a paediatric formulation of Elriz.

Method of administration

The film-coated tablet must be taken orally, swallowed whole with liquid and may be taken with or without food. It is recommended to take the daily dose in one single intake.

Duration of use:

Intermittent allergic rhinitis (symptoms experienced for less than four days a week or for less than four weeks a year) has to be treated according to the disease and its history; it can be stopped once the symptoms have disappeared and can be restarted again when symptoms reappear. In case of persistent allergic rhinitis (symptoms experienced for more than four days a week or for more than four weeks a year), continuous therapy can be proposed to the patient during the period of exposure to allergens.

There is clinical experience with the use of levocetirizine for treatment periods of at least 6 months. In chronic urticaria and chronic allergic rhinitis, there is clinical experience of use of cetirizine (racemate) for up to one year.

Contraindications

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 estimated Glomerular Filtration Rate (eGFR) below 15 ml/min (requiring dialysis treatment).

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.

Paediatric population

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 Elriz.

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 antipyrine, 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 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.

Use in special populations

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of levocetirizine in pregnant women. However, for cetirizine, the racemate of levocetirizine, a large amount of data (more than 1000 pregnancy outcomes) on pregnant women indicate no malformative or feto/ neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/fetal development, parturition or postnatal development

The use of levocetirizine may be considered during pregnancy, if necessary.

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.

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.

Undesirable effects

Clinical studies

Adults and adolescents above 12 years of age

In therapeutic studies in women and men aged 12 to 71 years, 15.1% of the patients in the levocetirizine 5 mg group had at least one adverse drug reaction compared to 11.3% in the placebo group. 91.6 % of these adverse drug reactions were mild to moderate.

In therapeutic trials, the dropout rate due to adverse events was 1.0% (9/935) with levocetirizine 5 mg and 1.8% (14/771) with placebo.

Clinical therapeutic trials with levocetirizine included 935 subjects exposed to the medicinal product at the recommended dose of 5 mg daily. From this pooling, following incidence of adverse drug reactions were reported at rates of 1% or greater (common: ≥1/100 to <1/10) under levocetirizine 5 mg or placebo:

Further uncommon incidences of adverse reactions (uncommon ≥1/1,000 to <1/100) like asthenia or abdominal pain were observed.

The incidence of sedating adverse drug reactions such as somnolence, fatigue, and asthenia was altogether more common (8.1%) under levocetirizine 5 mg than under placebo (3.1%).

Paediatric population

In two placebo-controlled studies in paediatric patients aged 6-11 months and aged 1 year to less than 6 years, 159 subjects were exposed to levocetirizine at the dose of 1.25 mg daily for 2 weeks and 1.25 mg twice daily respectively. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo.

In children aged 6-12 years double blind placebo controlled studies were performed where 243 children were exposed to 5 mg levocetirizine daily for variable periods ranging from less than 1 week to 13 weeks. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo.

Post-marketing experience

Adverse reactions from post-marketing experience are per System Organ Class and per frequency. The frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

• Immune system disorders: Not known: hypersensitivity including anaphylaxis
• Metabolism and nutrition disorders: Not known: increased appetite
• Psychiatric disorders: Not known: aggression, agitation, hallucination, depression, insomnia, suicidal ideation, nightmare
• Nervous system disorders: Not known: convulsion, paraesthesia, dizziness, syncope, tremor, dysgeusia
• Ear and labyrinth disorders:Not known: vertigo
• Eyes disorders: Not known: visual disturbances, blurred vision, oculogyration
• Cardiac disorders: Not known: palpitations, tachycardia
• Respiratory, thoracic and mediastinal disorders: Not known: dyspnoea
• Gastrointestinal disorders: Not known: nausea, vomiting, diarrhoea
• Hepatobiliary disorders: Not known: hepatitis
• Renal and urinary disorders: Not known: dysuria, urinary retention
• Skin and subcutaneous tissue disorders: Not known: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticarial
• Musculoskeletal, connective tissues, and bone disorders: Not known: myalgia, arthralgia
• General disorders and administration site conditions: Not known: oedema
• Investigations: Not known: weight increased, abnormal liver function tests
• Description of selected adverse reactions After levocetirizine discontinuation, pruritus has been reported.

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

Overdose

Symptoms

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

Management of overdoses

There is no known specific antidote to levocetirizine.

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.

Mechanism of Action

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

Pharmacodynamic properties

Pharmacotherapeutic group: antihistamine for systemic use, piperazine derivatives, ATC code: R06A E09.

Binding studies 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 min.

After single administration, levocetirizine shows a receptor occupancy of 90% at 4 hours and 57% at 24 hours.

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 pharmacodynamic activity of levocetirizine has been studied in randomised, controlled trials:

In a study comparing the effects of levocetirizine 5 mg, desloratadine 5 mg, and placebo on histamine-induced wheal and flare, levocetirizine treatment resulted in significantly decreased wheal and flare formation which was highest in the first 12 hours and lasted for 24 hours, (p<0.001) compared with placebo and desloratadine.

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.

Clinical efficacy and safety

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.

Chronic idiopathic urticaria was studied as a model for urticarial conditions. Since histamine release is a causal factor in urticarial diseases, levocetirizine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria.

ECGs did not show relevant effects of levocetirizine on QT interval.

Pharmacokinetic properties

The pharmacokinetics of levocetirizine are 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. In adults, peak plasma concentrations are achieved 0.9 h after dosing. Steady state is achieved after two 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.

Distribution

No tissue distribution data are available in humans, neither concerning the passage of levocetirizine through the blood-brain-barrier. In rats and dogs, the highest tissue levels are found in liver and kidneys, the lowest in the CNS compartment.

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 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 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 half-life is shorter in small children.

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

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.

Levocetirizine dihydrochloride, the active component of Elriz tablets and oral solution, is an orally active H1‑receptor antagonist. The chemical name is (R)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy] acetic acid dihydrochloride. Levocetirizine dihydrochloride is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. The empirical formula of levocetirizine dihydrochloride is C21H25ClN2O3•2HCl. The molecular weight is 461.82

Chemical structure is shown below:

Incompatibilities

Not applicable.

Shelf-life

Refer on the pack

Packaging information

2 Composite blister strips of 5 x 10 tablets each

Storage and handing instructions

• Store protected from light & moisture at a temperature not exceeding 30°C.
• Keep out of reach of children.

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 Levocetirizine hydrochloride Tablets

Do not exceed the recommended daily dose in adults and adolescents 12 years of age and older of 5 mg once daily in the evening. In children 6 to 11 years of age the recommended dose is 2.5 mg once daily in the evening. 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

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.