Coral Calcium & Vitamin D 3 Suspension

Each 5ml suspension contains:

Coral calcium equivalent to Elemental calcium 200 mg

Vitamin D 3 (as stabilized granules) 125 IU

Suspension (100 ml)

Coral Calcium 200mg & Vitamin-D 3 125 IU per 5ml

4.1 Therapeutic Indication

For the treatment of calcium and Vitamin D deficiency states

4.2 Posology and method of administration

Posology

Age Group: Children above 2 years.

Recommended usage level: 1 - 2 teaspoon twice daily, for children above the age of 2 years under medical advice by recognised medical doctor or dietician or nutritionist.

Not to exceed the recommended daily dosage.

4.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients present in this product.
• Diseases and/or conditions resulting in hypercalcemia and/or hypercalciuria (e.g. myeloma, bone metastases or other malignant bone disease, sarcoidosis; primary hyperparathyroidism).
• Nephrolithiasis/nephrocalcinosis
• Severe renal impairment and renal failure
• Hypervitaminosis D

4.4 Special warnings and precautions for use

Patients who are already taking thiazide diuretics and/or cardiac glycosides should be referred to their doctor prior to concomitant use. Concomitant use should be prescribed with caution due to the increased risk of hypercalcemia.

During long-term treatment, serum calcium levels should be followed and renal function should be monitored through measurements of serum creatinine. Monitoring is especially important in elderly patients on concomitant treatment with cardiac glycosides or diuretics and in patients with a high tendency to calculus formation. In case of hypercalcemia or signs of impaired renal function, the dose should be reduced or the treatment discontinued. It is advisable to reduce or interrupt treatment temporarily if urinary calcium exceeds 7.5 mmol/24 h (300 mg/24 h).

Vitamin D should be used with caution in patients with impairment of renal function and the effect on calcium and phosphate levels should be monitored. The risk of soft tissue calcification should be taken into account. In patients with severe renal insufficiency, vitamin D in the form of cholecalciferol is not metabolized normally and other forms of vitamin D should be used.

Coralium-D3 Suspension should be prescribed with caution to patients suffering from sarcoidosis, due to the risk of increased metabolism of Vitamin-D into its active form. These patients should be monitored with regard to the calcium content in serum and urine.

Coralium-D3 Suspension should be used with caution in immobilized patients with osteoporosis due to the increased risk of hypercalcemia.

The content of vitamin D (125 IU) in Coralium-D3 Suspension should be considered when prescribing other medicinal products containing vitamin D. Additional doses of calcium or vitamin D should be taken under close medical supervision. In such cases, it is necessary to monitor serum calcium levels and urinary calcium excretion frequently.

Milk-alkali syndrome (Burnett's syndrome), i.e. hypercalcemia, alkalosis, and renal impairment can develop when large amounts of calcium are ingested with absorbable alkali (food, enriched foods, or other medicinal products).

Allowances should be made for calcium and vitamin D supplements from other sources.

4.5 Drugs interactions

• Thiazide diuretics reduce the urinary excretion of calcium. Due to the increased risk of hypercalcemia, serum calcium should be regularly monitored during the concomitant use of thiazide diuretics.
• Systemic corticosteroids reduce calcium absorption. During concomitant use, it may be necessary to increase the dose of Coralium-D3 Suspension.
• Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D.
• Calcium carbonate may interfere with the absorption of concomitantly administered tetracycline preparations. For this reason, tetracycline preparations should be administered at least two hours before or four to six hours after oral intake of calcium.
• Hypercalcaemia may increase the toxicity of cardiac glycosides during treatment with calcium and vitamin D. Patients should be monitored with regard to electrocardiogram (ECG) and serum calcium levels.
• If a bisphosphonate or sodium fluoride is used concomitantly with Coralium D3 suspension, these medicinal products should be administered at least three hours before the intake of Coralium-D3 suspension since gastrointestinal absorption may be reduced.
• Rifampicin, phenytoin, or barbiturates may reduce the activity of vitamin D3, since they increase the rate of its metabolism.
• The absorption of quinolone antibiotics may be impaired if administered concomitantly with calcium. Quinolone antibiotics should be taken two hours before or six hours after intake of calcium.
• Calcium salts may decrease the absorption of iron, zinc or strontium. Consequently, the iron, zinc or strontium preparation should be taken at a distance of two hours from the calcium preparation.
• Calcium salts may reduce the absorption of the estramustin or thyroid hormones. It is recommended that taking CoraliumD3 suspension be spaced at least 2 hours from these medicines.
• Oxalic acid (found in spinach, sorrel and rhubarb), phosphate, and phytic acid (found in whole cereals) may inhibit calcium absorption through the formation of insoluble compounds with calcium ions. The patient should not take calcium products within two hours of eating foods high in oxalic acid and phytic acid.

4.6 Use in special populations

• Pregnancy

Coralium-D3 Suspension may be given during pregnancy in cases of calcium and vitamin D3 deficiency.

During pregnancy the daily dose should not exceed 1500 mg of calcium and 600 IU of vitamin D. Animal studies have shown toxic effects on reproduction at high doses of vitamin D. In pregnant women, all calcium or vitamin D overdose must be avoided as prolonged hypercalcemia in pregnancy may lead to retardation of physical and mental development, supravalvular aortic stenosis and retinopathy in the child. There are no indications that Vitamin D3 at therapeutic doses is teratogenic in humans.

• Breast-feeding

Coralium-D3 Suspension can be used during breast-feeding. Calcium and vitamin D pass into breast milk. This should be considered when giving additional vitamin D to the child.

• Fertility

There is no known harmful effect of endogenous levels of calcium and vitamin D in the normal range on fertility. There are no data available on the effect of Coralium D3 suspension on fertility.

4.7 Effects on the ability to drive and use machines

There are no data on the effect of this product on driving capacity and use of machines. An effect is, however, unlikely.

4.8 Undesirable effects

Adverse reactions are listed below, by system organ class and frequency. Frequencies are defined as: 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 reactions including pruritus, wheezing, urticaria, and oropharyngeal swelling have been reported in the post-marketing environment.

Metabolism and nutrition disorders

Uncommon: Hypercalcaemia and hypercalciuria. Very rare: Seen usually only in overdose, see 4.9: Milk-alkali syndrome

Gastrointestinal disorders

Rare: Constipation, flatulence, nausea, abdominal pain, and diarrhea. Very rare: Dyspepsia

Skin and subcutaneous disorders

Rare: Pruritus, rash and urticaria.

Other special population

Patients with renal impairment: potential risk of hyperphosphatemia, nephrolithiasis, and nephrocalcinosis.

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: www.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

Overdose can lead to hypervitaminosis and hypercalcemia. Symptoms of hypercalcemia may include anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, mental disturbances, polydipsia, polyuria, bone pain, nephrocalcinosis, renal calculi, and in severe cases, cardiac arrhythmias. Extreme hypercalcemia may result in coma and death.

Persistently high calcium levels may lead to irreversible renal damage and soft tissue calcification.

Milk-alkali syndrome may occur in patients who ingest large amounts of calcium and absorbable alkali. Symptoms are frequent urge to urinate, continuing headache, continuing loss of appetite, nausea or vomiting, unusual tiredness or weakness, hypercalcemia, alkalosis, and renal impairment.

Treatment of hypercalcemia: The treatment with calcium and vitamin D must be discontinued. Treatment with thiazide diuretics, lithium, vitamin A, vitamin D, and cardiac glycosides must also be discontinued. Emptying of the stomach in patients with impaired consciousness. Rehydration, and, according to severity, isolated or combined treatment with loop diuretics, bisphosphonates, calcitonin, and corticosteroids. Serum electrolytes, renal function, and diuresis must be monitored. In severe cases, ECG and CVP should be followed.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Calcium, combination with vitamin D and/or other drugs

Vitamin D increases the intestinal absorption of calcium. Administration of calcium and vitamin D3 (cholecalciferol) counteracts the increase of parathyroid hormone (PTH), which is caused by calcium deficiency and causes increased bone resorption.

A clinical study of institutionalized patients suffering from vitamin D deficiency indicated that a daily intake of of calcium 1000 mg/Vitamin D 800 IU for six months normalized the value of the 25-hydroxylated metabolite of Vitamin D3 and reduced secondary hyperparathyroidism and alkaline phosphatases.

An 18-month double-blind, placebo-controlled study including 3270 institutionalized women aged 84±6 years who received supplementation of vitamin D (800 IU/day) and calcium phosphate (corresponding to 1200 mg/day of elemental calcium), showed a significant decrease of PTH secretion. After 18 months, an “intent-to-treat” analysis showed 80 hip fractures in the calcium-vitamin D group and 110 hip fractures in the placebo group (p=0.004). A follow-up study after 36 months showed 137 women with at least one hip fracture in the calcium-vitamin D group (n=1176) and 178 in the placebo group (n=1127, p<0.02).

5.2 Pharmacokinetic properties

• Calcium

Absorption:

The bioavailability of coral calcium is approximately 70% as per study in animals by Japanese Dietetic Society. This is higher as compared to other calcium salts.

Unlike lime and fossilized calcium which are inert, live coral produces calcium in its ionized form. This calcium is able to bypass the digestive process. Hence, calcium and other trace minerals from coral are immediately available to the systems in the human body.

Distribution and metabolism:

99% of the calcium in the body is concentrated in the hard structure of bones and teeth. The remaining 1% is present in the intra- and extracellular fluids. About 50% of the total blood- calcium content is in the physiologically active ionized form with approximately 10% being complexed to citrate, phosphate, or other anions, the remaining 40% being bound to proteins, principally albumin.

Elimination:

Calcium is eliminated through feces, urine, and sweat. Renal excretion depends on glomerular filtration and calcium tubular reabsorption.

• Vitamin D

Absorption:

Vitamin D3 is absorbed in the small intestine.

Distribution and metabolism:

Cholecalciferol and its metabolites circulate in the blood bound to a specific globulin. Cholecalciferol is converted in the liver by hydroxylation to the active form 25-hydroxy cholecalciferol. It is then further converted in the kidneys to 1,25hydroxycolecalciferol. 1,25 hydroxy cholecalciferol is the metabolite responsible for increasing calcium absorption. Vitamin D which is not metabolized is stored in adipose and muscle tissues.

Elimination:

6.1 Animal Toxicology or Pharmacology

At doses far higher than the human therapeutic range teratogenicity has been observed in animal studies.

Coral Calcium is the calcium supplement obtained from the marine coral from Okinawa, Japan. A small sea animal creates coral by ingesting the ionic ocean minerals and secreting them into a coral formation. This natural balance of 72 organic coral minerals are harvested from above sea coral deposits crushed into an ultra-fine powder and sterilized with ozone. Coral Calcium contains up to 40% elemental calcium.

Coral minerals are organic in the sense that they have been previously digested by an animal. It is very difficult for the human body to digest inorganic minerals (similar to eating little rocks). Having been previously digested by the coral polyp, coral minerals are readily absorbable by the human body.

The bioavailability of coral calcium is approximately 70% as per study in animals by Japanese Dietetic Society.

Cholecalciferol is a Vitamin D. Cholecalciferol is a steroid hormone produced in the skin when exposed to ultraviolet light or obtained from dietary sources. The active form of cholecalciferol, 1,25-dihydroxycholecalciferol (calcitriol) plays an important role in maintaining blood calcium and phosphorus levels and mineralization of bone. The activated form of cholecalciferol binds to vitamin D receptors and modulates gene expression. This leads to an increase in serum calcium concentrations by increasing intestinal absorption of phosphorus and calcium, promoting distal renal tubular reabsorption of calcium and increasing osteoclastic resorption.

Molecular Formula: C₂₇H₄₄O

Molecular Weight: 384.6 g/mol

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

100 ml bottle

8.4 Storage and handling instructions

Store below 30°C. Protect from light & moisture.

Product is required to be stored out of reach of children

• This product is not intended to diagnose, treat, cure or prevent any disease.
• This product is not to be used as a substitute for varied diet.
• In case of accidental overdose, contact health care professional.
• Shake Well Before Use.
• This product is allergen free.

Montelukast Sodium & Levocetirizine Hydrochloride Dispersible Tablets [4 mg + 2.5 mg]

Each uncoated dispersible tablet contains:

Montelukast Sodium IP

equivalent to Montelukast 4 mg

Levocetirizine Hydrochloride IP 2.5 mg

Excipients q.s.

Colour: Lake of Quinoline Yellow

Dispersible tablet [4 mg + 2.5 mg]

4.1 Therapeutic indications

For relief of symptoms of allergic rhinitis (seasonal and perennial).

4.2 Posology and method of administration

Children (2-5 years): 1 tablet once daily Nukast ® 4DT Tablet can be taken with or without food.

Hepatic Impairment No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency.

Directions for use:

Disperse the tablet in one teaspoonful of previously boiled & cooled water before administration.

4.3 Contraindications

• Known hypersensitivity to montelukast, levocetirizine or cetirizine, or to any of the excipients.
• End stage renal disease at less than 10 ml/min creatinine clearance.
• Patients undergoing haemodialysis.
• Children with impaired renal function.

4.4 Special warnings and precautions for use

Montelukast

Acute Asthma: Montelukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled β2-agonist. Concomitant Corticosteroid Use: While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, montelukast should not be abruptly substituted for inhaled or oral corticosteroids.

Aspirin Sensitivity: Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast.

Eosinophilic Conditions: Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

Neuropsychiatric Events: Prescribers should carefully evaluate the risks and benefits of continuing treatment with montelukast if such events occur.

Phenylketonuria: Phenylketonuric patients should be informed about the presence of phenylalanine (a component of aspartame) in this product.

Levocetirizine

Somnolence: Concurrent use of levocetirizine 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.

Urinary Retention: 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.

4.5 Drug Interactions

Montelukast

Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin and warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative hypnotics, non-steroidal antiinflammatory agents, benzodiazepines, decongestants, and CYP 450 enzyme inducers. The area under the plasma concentration curve (AUC) for montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital. Since montelukast is metabolised by CYP 3A4, caution should be exercised, particularly in children, when montelukast is co-administered with inducers of CYP 3A4, such as phenytoin, phenobarbital and rifampicin.

Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants.

Based on in vitro data, clinically important drug interactions with less potent inhibitors of CYP 2C8 (e.g., trimethoprim) are not anticipated. Co-administration of montelukast with itraconazole, a strong inhibitor of CYP 3A4, resulted in no significant increase in the systemic exposure of montelukast.

Levocetirizine

In vitro data on metabolite interaction indicate that levocetirizine is unlikely to produce, or be subject to metabolic interactions. Levocetirizine at concentrations well above Cmax level achieved within the therapeutic dose ranges is not an inhibitor of CYP isoenzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, and 3A4, and is not an inducer of UGT1A or CYP isoenzymes 1A2, 2C9 and 3A4. No in vivo drug-drug interaction studies have been performed with levocetirizine. Drug interaction studies have been performed with racemic cetirizine.

Antipyrine, Azithromycin, Cimetidine, Erythromycin, Ketoconazole, Theophylline, and Pseudoephedrine

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

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

4.6 Use in special populations

Paediatric

The safety and efficacy of levocetrizine in paediatric patients under 2 years of age have not been established.

Pregnancy

No clinical studies available in human pregnancy. Therefore, Nukast ® 4DT Tablet should not be used in pregnancy.

Lactation

It is not known if montelukast is excreted in human milk. Cetirizine has been reported to be excreted in human breast milk. Because levocetirizine is also expected to be excreted in human milk this combination is not recommended during lactation.

Hepatic insufficiency

As levocetirizine is mainly excreted unchanged by the kidneys, it is unlikely that the clearance of levocetirizine is significantly decreased in patients with solely hepatic impairment. But montelukast is mainly excreted through bile; caution is to be exercised while prescribing this combination in patients with impaired hepatic function. The pharmacokinetics of montelukast in patients with more severe hepatic impairment or with hepatitis has not been evaluated.

Renal impairment

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. Dosage adjustment may be required in patients with impaired renal function. Hence this combination is not recommended in patients with impaired renal function. Driving and using machines

4.7 Effects on ability to drive and use machines

Nukat has no or negligible influence on the ability to drive and use machines. However, individuals have reported drowsiness or dizziness. 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

Montelukast

The most common adverse reactions (incidence ≥ 5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.

Pediatric Patients 2 to 5 Years of Age (≥ 2%)

Asthma: Fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis, thirst.

Pediatric Patients 2 to 14 Years of Age (≥ 2%)

Seasonal Allergic Rhinitis: Headache, otitis media, pharyngitis, and upper respiratory infection.

Pediatric Patients 6 to 23 Months of Age with Asthma (≥ 2%)

upper respiratory infection, wheezing; otitis media; pharyngitis, tonsillitis, cough; and rhinitis.

Levocetirizine

Use of levocetirizine has been associated with somnolence, fatigue, asthenia, and urinary retention.

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: www.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

No specific information is available on the treatment of overdosage with Nukast ® 4DT Tablet. Symptoms of overdose may include drowsiness, abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. Gastric lavage should be considered following short-term ingestion of Nukast ® 4DT Tablet.

5.1 Pharmacodynamic properties

Montelukast

The cysteinyl leukotrienes (LTC 4 , LTD 4 , LTE 4 ) are products of arachidonic acid metabolism and are released from various cells including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT 1 ) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis.

In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT 1 receptor. Montelukast inhibits physiologic actions of LTD 4 at the CysLT 1 receptor without any agonist activity.

Levocetirizine

Levocetirizine is the R-enantiomer and the active form of cetirizine. It is an orally active, potent, selective and long acting H 1 -histamine receptor antagonist with no anticholinergic activity. It blocks the binding of histamine to H 1 receptors thus preventing its systemic effects, such as vasodilation, edema, mucous secretion, and smooth muscle contraction. This results in providing relief from the symptoms of allergic rhinitis and asthma including sneezing, itching, rhinorrhea, dyspnea, bronchial hypersensitivity and mucus accumulation.

It has been demonstrated by recent studies that the treatment of Allergic rhinitis and asthma with concomitant administration of an anti-leukotriene (montelukast) and an antihistamine (levocetirizine), shows significantly better symptom relief and additional improvement in quality of life when compared with each agent given alone.

5.2 Pharmacokinetic Properties

Absorption: For the 4 mg chewable tablet, the mean C max is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state. The safety of montelukast in patients with asthma was also demonstrated in clinical trials in which the 4 mg chewable tablets were administered in the evening without regard to the time of food ingestion.

Levocetirizine is rapidly and extensively absorbed following oral administration. Peak plasma concentrations are achieved 0.9 g hour after dosing. Steady state is achieved after two days. Peak concentrations are typically 270ng/ml and 308ng/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 T max was delayed by about 1.25 hours and Cmax was decreased by about 36% after administration with a high fat meal; therefore, levocetirizine can be administered with or without food.

Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.

The mean plasma protein binding of levocetirizine in vitro ranged from 91 to 92%, independent of concentration in the range of 90-5000 ng/mL, which includes the therapeutic plasma levels observed. Following oral dosing, the average apparent volume of distribution is approximately 0.4 L/kg, representative of distribution in total body water.

Metabolism: Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients.

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.

Elimination: The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.

The plasma half-life in healthy adult subjects was about 8 to 9 hours after administration of oral tablets and oral solution. The mean apparent total body clearance is 0.63 ml/ kg/ min. 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. Renal clearance of levocetirizine correlates with that of creatinine clearance.

6.1 Animal Toxicology or Pharmacology

Montelukast sodium was found not to be genotoxic. Montelukast sodium was negative in microbial and mammalian cell mutagenesis assays, with and without metabolic activation. There was no evidence of clastogenic activity in the in vitro chromosomal aberration assay in Chinese Hamster Ovary cells, with or without a microsomal enzyme activation system, or of DNA damage in the in vitro alkaline elution assay in rat hepatocytes. Similarly, there was no induction of chromosomal aberrations in bone marrow cells of male or female mice.

Montelukast sodium was not carcinogenic when administered at oral doses of up to 200 mg/kg/day in 104-week study in rats, nor at oral doses up to 100 mg/kg/day in a 91-week study in mice. Systemic exposure in these studies, in terms of the plasma AUC for parent drug, was at least 30 times higher than that in humans at recommended dose levels.

Levocetrizine

Levocetirizine is the R-enantiomer of the marketed cetirizine. The long term oral toxicity, fertility and early developmental and prenatal postnatal developmental toxicity studies with cetirizine represent the toxicity profile of levocetirizine with supplemental bridging toxicity, developmental and genotoxicity studies conducted with levocetirizine. In genotoxicity studies, cetirizine was negative in the Ames, Human Peripheral

Lymphocytes

Chromosomal Aberration, Mouse Lymphoma and Mouse Micronucleus assays. Levocetirizine, In the carcinogenicity studies in rodents, the dietary doses were 1, 4 and 16 mg/kg for the mouse and 3, 8 and 20 mg/kg for the rat. The rats showed liver toxicity (hypertrophy, vacuolation and fat deposit). No tumors were seen in rats that were clinically significant, while male mice showed benign liver tumors which were due to enzyme induction.

Levocetirizine hydrochloride, is an orally active H1-receptor antagonist. The chemical name is 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]acetic acid;hydrochloride.

Levocetirizine dihydrochloride is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. The empirical formula of levocetirizine dihydrochloride is C₂₁H₂₆Cl₂N₂O₃ . The molecular weight is 425.3 g/mol and the chemical structure is shown below:

Montelukast sodium is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT 1 receptor. Montelukast sodium USP is described

chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1- methylethyl)phenyl]propyl]thio]methyl]   cyclopropaneacetic acid, monosodium salt. The empirical formula is C 35 H 35 CINNaO 3 S, and its molecular weight is 608.17. The structural formula is:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

30 Months

Packaging information

100 ml bottle

8.4 Storage and handling instructions

Store in a dry place below 30°C, away from light and moisture.

Keep out of reach of children.

Nature and contents of container

Blister ALU-ALU 1x10T

• Somnolence Caution patients against engaging in activities requiring complete mental alertness, and motor coordination after ingestion of levocetirizine dihydrochloride oral solution.
• Concomitant Use of Alcohol and other Central Nervous System Depressants Instruct patients to avoid concurrent use of levocetirizine dihydrochloride oral solution with alcohol or other central nervous system depressants because additional reduction in mental alertness may occur.
• Advise patients to not ingest more than the recommended dose of levocetirizine dihydrochloride oral solution because of the increased risk of somnolence at higher doses.
• Advise patients about the potential risk for serious neuropsychiatric symptoms and behavioral changes with montelukast sodium use.
• Discuss the benefits and risks of montelukast sodium with patients when prescribing or continuing treatment with montelukast sodium.
• Advise patients to monitor for changes in behavior or neuropsychiatric symptoms in patients taking montelukast sodium.
• Instruct patients to discontinue montelukast sodium and contact a healthcare provider immediately if changes in behavior or thinking that are not typical for the patient occur, or if the patient develops suicidal ideation or suicidal behavior.
• Advise patients to take montelukast sodium daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, and to contact their physicians if their asthma is not well controlled.
• Advise Patients that oral montelukast sodium is not for the treatment of acute asthma attacks. They should have appropriate short-acting inhaled β-agonist medication available to treat asthma exacerbations. Patients who have exacerbations of asthma after exercise should be instructed to have available for rescue a short-acting inhaled β-agonist. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes.
• Advise patients to seek medical attention if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed.
• Instruct patients to continue other anti-asthma medications as prescribed unless instructed by a physician.
• Instruct patients with known aspirin sensitivity to continue avoidance of aspirin or non- steroidal anti-inflammatory agents while taking montelukast sodium.