Nukast 10 mg Tablet

Montelukast Sodium & Levocetirizine Dihydrochloride Tablets [10 mg + 5 mg]

Each uncoated bilayered tablet contains :

Montelukast Sodium

Equivalent to Montelukast 10 mg

Levocetirizine Dihydrochloride USP 5 mg

Excipients q.s.

Tablet, Montelukast Sodium & Levocetirizine Dihydrochloride Tablets [10 mg + 5 mg]

4.1 Therapeutic indication

For the treatment of allergic rhinitis in adults only.

4.2 Posology and method of administration

4.3 Contraindications

• Patients who are hypersensitive to any of the component of the product.
• Patients with severe renal impairment at less than 10 ml/min creatinine clearance.
• Patients undergoing haemodialysis.

4.4 Warning and precautions

Montelukast

Acute Asthma

Montelukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. Therapy with Montelukast can be continued during acute exacerbations of asthma. While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, Montelukast should not be abruptly substituted for inhaled or oral corticosteroids. There are no data demonstrating that oral corticosteroids can be reduced when Montelukast is given concomitantly. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled beta2- 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 nonsteroidal anti-inflammatory agents while taking Montelukast. Although Montelukast is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other nonsteroidal anti-inflammatory drugs in Aspirin-sensitive asthmatic patients.

Eosinophilic conditions

Patients on therapy with Montelukast may present with systemic eosinophilia sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition, which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between, Montelukast and these underlying conditions has not been established.

Neuropsychiatric events

Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking Montelukast. Post-marketing reports with Montelukast use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, obsessive-compulsive symptoms, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving Montelukast appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Montelukastif such events occur

Phenylketonuria

Phenylketonuric patients should be informed about the presence of Phenylalanine (a component of Aspartame) in this product.

Levocetirizine

Somnolence

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 depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.

Urinary retention

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 Levocetirizine 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 CYP450 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 CYP3A4, 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.

In vitro studies have shown that Montelukast is a potent inhibitor of CYP 2C8. However, data from a clinical drug-drug interaction study involving Montelukast and rosiglitazone (a probe substrate representative of medicinal products primarily metabolised by CYP 2C8) demonstrated that Montelukast does not inhibit CYP 2C8 in vivo. Therefore, Montelukast is not anticipated to markedly alter the metabolism of medicinal products metabolised by this enzyme (e.g., Paclitaxel, Rosiglitazone and Repaglinide.)

In vitro studies have shown that Montelukast is a substrate of CYP 2C8, and to a less significant extent, of 2C9, and 3A4. In a clinical drug-drug interaction study involving Montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) gemfibrozil increased the systemic exposure of Montelukast by 4.4-fold. No routine dosage adjustment of Montelukast is required upon co-administration with Gemfibrozil or other potent inhibitors of CYP2C8, but the Physician should be aware of the potential for an increase in adverse reactions. 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. In sensitive patients the simultaneous administration of Cetirizine or Levocetirizine and alcohol or other CNS depressants may have effects on the central nervous system, although it has been shown that the racemate Cetirizine does not potentiate the effect of Alcohol.

4.6 Special populations

Pregnancy

There are no adequate and well controlled studies of either Montelukast or Levocetirizine in pregnant women.

Hence this combination should not be used during pregnancy

Lactation

Since Levocetirizine is excreted in breast-milk the combination is not recommended during lactation.

4.7 Effects on ability to drive and use machines

Patients should be cautioned against engaging in activities requiring complete mental alertness, and motor coordination such as operating machinery until their response to Nukast Tablets is known.

4.8 Undesirable effects

There is no data available on undesirable effects of this combination. However, side effects have been reported with individual molecules.

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, diarrhoea, otitis media, influenza, rhinorrhea, sinusitis, otitis.

Montelukast has been evaluated in 280 paediatric patients 2 to 14 years of age in a 2-week, multicentre, double-blind, placebo-controlled, parallel-group safety study. Montelukast administered once daily in the evening had a safety profile similar to that of placebo. In this study, the following events occurred with a frequency ≥ 2% and at an incidence greater than placebo : headache, otitis media, pharyngitis, and upper respiratory infection. The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis. The safety in patients 6 to 23 months of age is supported by data from pharmacokinetic and safety and efficacy studies in asthma in this pediatric population and from adult pharmacokinetic studies. The following adverse reactions have been reported in post-marketing use :

Blood and lymphatic system disorders : Increased bleeding tendency. Immune system disorders : Hypersensitivity reactions including Anaphylaxis, Hepatic eosinophilic infiltration.

Psychaitric disorders :

Agitation including aggressive behaviour or hostility, Anxiousness, Depression, Disorientation, Dream abnormalities, Hallucinations, Insomnia, Irritability, Restlessness, Somnambulism, Suicidal thinking and behaviour (including suicide), Tremor.

Nervous system disorder : Drowsiness, Paresthesia / hypoesthesia, Seizure. Respiratory, Thoracic and mediastinal disorder, Epistaxis.

Cardiac disorders : Palpitations.

Gastro-intestinal disorders : Diarrhoea, Dry mouth, Dyspepsia, Nausea, Vomiting.

Hepatobiliary disorders : Elevated levels of serum transminases (ALT, AST), Rare cases of cholestatic hepatitis, Hepatocellular liver injury and mixed-pattern liver injury have been reported in patients treated with Montelukast.

Most of these occurred in combination with other confounding factors, such as use of other medications, or when Montelukast was administered to patients who had underlying potential for liver disease, such as alcohol use or other forms of hepatitis

Skin and subcutaneous tissue disorders : Angioedema, Bruising, Urticaria, Pruritus, Rash, Erythema nodosum.

Musculoskeletal and connective tissue disorders : Arthralgia, Myalgia including muscle cramps.

General disorders and administration site conditions : Asthenia/fatigue, Malaise, Oedema. Patients with asthma on therapy with Montelukast may present with systemic eosinophilia. Sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients

Levocetirizine

Use of Levocetirizine has been associated with somnolence, fatigue, nasopharyngitis, dry mouth and pharyngitis in subjects 12 years of age and older. Further uncommon incidences of adverse reactions like asthenia, abdominal pain, syncope and weight- increase were observed. Adverse reactions reported in ≥ 2% of paediatric subjects aged 1 - 6 years exposed to Levocetirizine 1.25 mg twice daily in a 2-week placebo-controlled clinical trial were pyrexia, diarrhoea, vomiting and otitis media while in paediatric subjects 6 - 12 years of age exposed to Levocetirizine 5 mg once daily in placebo-controlled clinical trials 4 and 6 weeks in duration were pyrexia, cough, somnolence, epistaxis. In paediatric subjects 6 months to 11 months receiving 1.25 mg Levocetirizine once daily in a 2-week placebo controlled double blind safety trial the common side effects (≥ 3% subjects) were diarrhoea and constipation. 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.

Psychiatric disorders : Aggression, Agitation, Hallucination, Depression.

Nervous System disorders : Convulsion.

Eyes disorders : Visual disturbances.

Cardiac disorders : Palpitations, tachycardia.

Respiratory,

Thoracic, and mediastinal disorders : Dyspnoea.

Gastrointestinal disorders : Nausea, Vomiting.

Hepatobiliary disorders : Hepatitis.

Skin and subcutaneous tissue disorders : Angioneurotic edema, Fixed drug eruption, Pruritus, Rash urticaria.

Musculoskeletal, connective tissues, and bone disorders : Myalgia.

Investigations : Weight Increased, Abnormal liver functions tests.

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

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

4.9 Overdose

There is no data reported on the overdosage of this combination. In case of overdosage the stomach should be emptied by aspiration and gastric lavage if the patient reports immediately.

Treatment should be symptomatic and supportive.

5.1 Mechanism of action / pharmacodynamic properties

Montelukast The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) 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 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. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor. Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity. Levocetirizine 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. Pharmacokinetic / pharmacodynamic relationship 5 mg Levocetirizine provide 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. ECGs did not show relevant effects of Levocetirizine on QT interval.

5.2 Pharmacokinetic properties

Montelukast

Absorption

Montelukast is rapidly absorbed following oral administration. For the 5 mg tablet, the Cmax is achieved in 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.

Distribution

Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of Montelukast averages 8 - 11 liters.

Metabolism

Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of Montelukast are undetectable at steady state in adults and children. In vitro studies using human liver microsomes indicate that cytochrome P450 3A4, 2A6 and 2C9 are involved in the metabolism of Montelukast. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of Montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.

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 faecal 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.

Levocetirizine

The pharmacokinetics of Levocetirizine are linear, dose- and time-independent with low inter-subject variability.

Absorption

Levocetirizine is rapidly and extensively absorbed following oral administration. 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

Levocetirizine is 90% bound to plasma proteins. The distribution of Levocetirizine is restrictive, as the volume of distribution is 0.4 l/kg.

Metabolism

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 mean apparent total body clearance 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 feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.

6.1 Animal toxicology or pharmacology

No known animal toxicology data.

Montelukast selectively antagonizes leukotriene D4 (LTD4) at the cysteinyl leukotriene receptor, CysLT1, in the human airway thereby preventing airway edema, bronchoconstriction, enhanced secretion of thick, viscous mucus and nasal congestion. It is a safe and effective treatment for patients with allergic rhinitis and allergic asthma. Levocetirizine is the R-enantiomer and the active form of cetirizine. It is an orally active, potent, selective and long acting H1-histamine receptor antagonist with no anticholinergic activity. It blocks the binding of histamine to H1 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.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

24 Months

8.3 Packaging information

1 x 10 Tablets

8.4 Storage and handing instructions

Store protected from light and moisture at a temperature not exceeding 30°C.

KEEP AWAY FROM THE REACH OF CHILDREN.

Do not take Nukast if you

• Are allergic to Montelukast, Levocetirizine or any of the other ingredients of this medicine.
• If you suffer from severe kidney failure (severe renal failure with creatinine clearance below 10 ml/min). Talk to your doctor or pharmacist before taking Nukast
• If your asthma or breathing gets worse, tell your doctor immediately.
• This oral medicine is not meant to treat acute asthma attacks. If an attack occurs, follow the instructions your doctor has given you. Always have your inhaled rescue medicine for asthma attacks with you.
• It is important that you or your child take all asthma medications prescribed by your doctor.
• This medicine should not be substituted for other asthma medications your doctor has prescribed for you.
• Any patient on anti-asthma medicines should be aware that if you develop a combination of symptoms such as a flu-like illness, pins and needles or numbness of arms or legs, worsening of pulmonary symptoms, and/or rash, you should consult your doctor.
• If you suffer from epilepsy or are at risk of convulsions, please ask your doctor for advice as use of may make seizures worse. If you are likely to be unable to be unable to empty your bladder (due to conditions such as a spinal cord injury or enlarged prostate), please ask your doctor for advice. If you are scheduled for allergy testing, ask your doctor if you should stop taking Nukast for several days before testing. This medicine may affect your allergy test results.

Patients should be aware that various neuropsychiatric events (for example behaviour and mood related changes) have been reported in adults, adolescents and children with Nukast. If you develop such symptoms while taking Nukast you should consult your doctor.

Tell your doctor if you are taking the following medicines before starting Nukast :

• Phenobarbital (used for treatment of epilepsy)
• Phenytoin (used for treatment of epilepsy)
• Rifampicin (used to treat tuberculosis and some other infections)
• Gemfibrozil (used for treatment of high lipid levels in plasma)

If you suffer from mild to moderate kidney failure, your doctor may prescribe a lower dose according to the severity of your kidney disease. Patients who only have impaired liver function should take the usual prescribed dose. Patients who have both impaired liver and kidney function may be given a lower dose depending on the severity of the kidney disease.