INSTRUCTION

for medical use of the medicinal product

 

ALLERGINOL PLUS®

 

 

Composition:

active substances: montelukast, levocetirizine dihydrochloride;

1 film-coated tablet contains montelukast sodium 10.5 mg, equivalent to montelukast 10 mg, and levocetirizine dihydrochloride 5 mg;

excipients: microcrystalline cellulose, mannitol (Е 421), croscarmellose sodium, hydroxypropylcellulose, magnesium stearate, opadry white (polyethylene glycol; titanium dioxide (Е 171), hypromellose).

 

Pharmaceutical form. Film-coated tablet.

Basic physical and chemical properties: white, biconvex, round, film-coated tablets smoothed on both sides.

 

Pharmacotherapeutic group.

Antiasthmatic drugs. Orally active selective leukotriene receptor antagonist. ATC code R03D C03.

Antihistamine for systemic use. Piperazine derivatives. ATC code R06A E09.

 

Pharmacological properties.

Pharmacodynamics.

Allerginol Plus® contains a fixed combination of two active substances, such as montelukast and levocetirizine. The following mechanisms of action of each component are inherent in the drug Allerginol Plus®.

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, which are 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 bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during hypersensitivity 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 sodium is an active compound which binds with high affinity and selectivity to the CysLT1 receptor. Montelukast inhibits the physiological action of LTD4 on CysLT1 receptors without showing affinity for receptors.

Levocetirizine dihydrochloride

Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors. Binding studies revealed that levocetirizine has high affinity for human H1-receptors (К_і=3.2 nmol/l). Levocetirizine has an affinity 2-fold higher than that of cetirizine (K_i=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. The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1 hour post drug intake in placebo controlled trials in the model of the allergen challenge chamber. In vitro studies (Boyden chambers and cell layers techniques) show that levocetirizine inhibits eotaxin-induced eosinophil transendothelial migration through both dermal and lung cells. A pharmacodynamic experimental study in vivo (skin chamber technique) showed three main inhibitory effects of levocetirizine 5 mg in the first 6 hours of pollen-induced reaction, compared with placebo in 14 adult patients: inhibition of VCAM-1 release (vascular endothelial adhesion molecules type I), modulation of vascular permeability and a decrease in eosinophil recruitment. Pharmacodynamic studies have shown that, at half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose. Pharmacokinetic/pharmacodynamic relationship of levocetirizine at a dose of 5 mg is similar to the scheme of inhibition of histamine-induced reaction by the type of "bloom" cetirizine at a dose of 10 mg. As with cetirizine, the action on histamine-induced skin reactions is out of phase with the plasma concentrations. ECG data have not shown a corresponding effect of levocetirizine on the QT interval.

Pharmacokinetics.

Montelukast

Absorption. At a dose of 10 mg, the mean peak plasma concentration (C_max) is achieved 3–4 hours (T_max) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The mean peak plasma concentrations achieved 2 hours are not influenced by a standard meal. Safety and efficacy of montelukast in patients with asthma were demonstrated in clinical trials where the 10 mg film-coated tablet was administered without regard to the timing of food ingestion. Safety and efficacy of montelukast in patients with asthma were also demonstrated in clinical trials where 4 mg chewable tablet was administered in the evening without regard to the timing of food ingestion. Safety and efficacy of montelukast in patients with seasonal allergic rhinitis were demonstrated in clinical trials where the 10 mg film-coated tablet was administered in the morning or in the evening without regard to the timing of food ingestion.

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

Biotransformation. Montelukast is extensively metabolised. 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. Clinical studies of the effects of known cytochrome P450 3A4 inhibitors (eg, ketoconazole, erythromycin) or 2C9 (eg, fluconazole) on the pharmacokinetics of montelukast have not been performed. 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. In vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8. However, data obtained from a clinical drug interaction study with montelukast and rosiglitazone (a marker drug substrate was first metabolized by cytochrome CYP2C8) have shown that montelukast does not inhibit CYP2C8 in vitro and therefore should not change the metabolism of drugs metabolized by this enzyme.

Elimination. The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabelled 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. The mean plasma half-life of montelukast in young healthy volunteers is 2.7 to 5.5 hours. The pharmacokinetics of montelukast remains linear at oral doses up to 50 mg. There is a small accumulation (14%) of the active substance in plasma when taking 10 mg of montelukast once a day.

Levocetirizine dihydrochloride

The pharmacokinetics of levocetirizine is linear with 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. No tissue distribution data are available in humans, neither concerning the passage of levocetirizine through the blood-brain-barrier. 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 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.

 

Clinical particulars.

Indications.

The drug is intended to reduce the symptoms associated with seasonal and perennial allergic rhinitis, and rhinitis in patients with asthma.

 

Contraindications.

Hypersensitivity to montelukast sodium, levocetirizine or cetirizine, hydroxyzine, and to other components of the drug. The drug is also contraindicated in severe renal impairment (creatinine clearance <10 ml/min). Children under 15 years of age.

 

Interaction with other medicinal products and other forms of interaction.

Montelukast

Theophylline, prednisone and prednisolone: no dose adjustment is required when montelukast is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin, warfarin, thyroid hormones, sedative decongestants and inducers of the cytochrome P450 (CYP) enzyme.

Oral contraceptives, terfenadine, digoxin and warfarin: no clinically significant effect of montelukast on the following drugs has been found in a drug interaction study used the recommended clinical dose of montelukast: oral contraceptives (norethidrone 1 mg/ethyl estradiol 35 mg), terfenadine, digoxin and warfarin.

Thyroid hormones, sedative hypnotics, nonsteroidal anti-inflammatory drugs, benzodiazepines and anti-oedema drugs: there are no forms of interaction.

Cytochrome enzyme inducers Р450 (CYP): during the treatment with phenobarbital, which stimulates hepatic metabolism, the area under the curve “concentration-time” (AUC) of montelukast after a single dose of montelukast 10 mg decreased by approximately 40%. However, montelukast dose adjustment is not recommended. Montelukast is a potent inhibitor of cytochrome CYP2C8 in vitro. However, in a clinical drug interaction study with montelukast and rosiglitazone involved 12 healthy volunteers (a marker substrate, a representative of drugs metabolised mainly by cytochrome CYP2C8), it was found that the pharmacokinetics of rosiglitazone remains unchanged when co-administered with montelukast. This indicates no inhibition of CYP2C8 by montelukast in vivo. Therefore, montelukast is not expected to alter the metabolism of drugs metabolised by this enzyme (e.g., paclitaxel, rosiglitazone, repaglinide) in any way.

Levocetirizine dihydrochloride

In vitro data suggest that levocetirizine should not be expected to cause pharmacokinetic interactions by inhibiting or inducing hepatic enzymes that metabolize drugs. No in vivo drug interaction studies have been performed with levocetirizine.

Antipyrine, azithromycin, cimetidine, erythromycin, ketoconazole, theophylline and pseudoephedrine: according to the results of pharmacokinetic interaction studies with racemic cetirizine, the substance did not interact with antipyrine, pseudoephedrine, erythromycin, azithromycin, ketoconazole and cimetidine. In the course of such studies, there was a small decrease (by 16%) in the clearance of cetirizine when using theophylline at a dose of 400 mg. It can be assumed that higher doses of theophylline will have a more powerful effect.

Ritonavir increased plasma cetirizine concentrations by approximately 42%, the half-life – by 53%, and decreased cetirizine clearance by 29%. The distribution of ritonavir co-administered with cetirizine was slightly different (−11%). There are no data on the potentiation of the effect of sedatives when used in therapeutic doses. But the use of sedatives while taking the drug should be avoided.

Food does not affect the extent of drug’s absorption, but the concomitant consumption of food and the drug reduces the rate of drug’s absorption.

The concomitant use of cetirizine or levocetirizine with alcohol or other central nervous system (CNS) depressants in sensitive patients may cause a decreased attention and a reduced ability to perform work.

 

Precautions for use.

Montelukast

Acute asthma attacks.

Montelukast is not indicated to treat bronchospasm in acute asthma attacks, including asthmatic status. Patients should be advised to use appropriate medications in the event of such attacks. Montelukast therapy can be continued during acute asthma attacks. Montelukast therapy should not be replaced by inhaled or oral corticosteroids; the dose of inhaled corticosteroids can be gradually reduced under medical supervision.

Montelukast should not be used as monotherapy to relieve exercise-induced bronchospasm. If acute asthma attacks occur after exercise, patients should continue to use inhaled β-agonists as a prophylactic as usual and carry short-acting inhaled β-agonists for emergency care.

Concomitant use with corticosteroids

While the dose of inhaled corticosteroids may be gradually reduced under medical supervision, montelukast should not be suddenly replaced by inhaled or oral corticosteroids.

Hypersensitivity to acetylsalicylic acid

Patients with known hypersensitivity to acetylsalicylic acid should refrain from using acetylsalicylic acid or non-steroidal anti-inflammatory drugs during montelukast therapy. Although montelukast is effective in improving airway function in patients with asthma with documented hypersensitivity to acetylsalicylic acid, it does not reduce the body's bronchoconstrictor response to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs in patients with bronchial asthma.

Neuropsychiatric disorders

Cases of neuropsychiatric events have been reported in adults, adolescents, and children treated with montelukast. The montelukast adverse events, such as agitation, aggressive behavior or hostility, anxiety, depression, disorientation, sleep disturbances, hallucinations, insomnia, irritability, tremor, somnambulism. suicidal behavior (including suicide) have been reported in the post-marketing study. The clinical details of some post-marketing reports of adverse events with montelukast are consistent with the effect induced by this drug. Both physicians, who prescribe this drug, and patients, should be aware of the possibility of neuropsychiatric disorders. Patients should be advised to inform their physician if they experience any symptoms. If a patient develops such events, the physician should carefully weigh the risks and benefits of continuing montelukast therapy.

Eosinophilia

In isolated cases, patients receiving montelukast have experienced systemic eosinophilia, sometimes with clinical vasculitis manifestations, so-called Churg-Strauss syndrome, which is treated with systemic corticosteroid therapy. These cases have usually been associated with a reduction in the dose of oral corticosteroids. The physician should closely monitor the patient's condition for timely detection of symptoms of eosinophilia, vasculitis, and worsening of pulmonary symptoms, heart complications and/or neuropathy as well.

Since montelukast is primarily excreted in bile, this combination drug should be cautiously prescribed to patients with hepatic impairment.

No differences in the safety and efficacy profile of this medicinal product were observed in elderly and younger patients. There is no evidence in clinical practice to indicate a difference in response to this drug in these two populations, but the presence of higher sensitivity to this drug in some elderly patients cannot be ruled out.

Levocetirizine dihydrochloride

Alcohol should be avoided during the use of the drug. No clinical trials of levocetirizine for each approved indication for use have been performed in a sufficient number of patients over 65 years of age to determine whether they have a different response to the drug compared to younger patients. Other clinical trials also have not shown any differences in response to young and elderly patients. In general, the elderly should be prescribed with caution and treatment should be initiated at the lowest doses, taking into account the higher incidence of hepatic, renal or cardiac impairments, and comorbidities or the use of other drugs as well.

Since levocetirizine is primarily excreted in the urine, patients with renal impairment and elderly patients who may have decreased glomerular filtration rate may require dose adjustment. This combination drug should be used with caution in such patients.

When prescribing the drug to patients with certain urinary retention factors (e.g., spinal cord injury, prostate hyperplasia), it should be considered that levocetirizine increases the risk of urinary retention.

Antihistamines suppress the response to a skin allergy test, the drug should be discontinued 3 days before the test (elimination period).

Pruritus may occur after stopping levocetirizine, even if these symptoms were not present before treatment. The symptoms may resolve spontaneously. In some cases, the symptoms may be intense and may require re-therapy after discontinuation.

In clinical trials, drowsiness, fatigue, and general weakness have been reported in some patients treated with levocetirizine. Patients should be warned that during treatment with the drug they should avoid activities requiring increased mental activity and precise coordination of movements, including work with mechanisms or driving. Alcohol and CNS depressants should be avoided during levocetirizine therapy, as this may cause decreased activity and increased CNS depression.

 

Pregnancy and lactation.

Pregnancy

Since relevant and well-controlled safety studies of montelukast or levocetirizine have not been performed during pregnancy, this combination is contraindicated in pregnant women.

Breast-feeding

Since levocetirizine is excreted in breast milk, this combination should not be used during breast-feeding.

Animal experiments have shown that montelukast is excreted in breast milk.

Fertility

There are no clinical data (including animal studies) on the effect of levocetirizine on fertility.

 

Effects on ability to drive and use machines.

No studies on the effect of a fixed combination of montelukast and levocetirizine on the ability to drive or use machines have been performed. Some patients may experience drowsiness, fatigue, and weakness in the course of levocetirizine therapy. Patients should refrain from driving or operating potentially hazardous machinery during the treatment.

 

Method of administration and dosage.

Adults and children over 15 years of age should take 1 tablet once a day in the evening, regardless of food intake. Swallow the tablets whole without chewing. The course of treatment is 14 days.

 

Children.

The drug should be used for children over 15 years of age.

 

Overdose.

No data is available on the treatment of overdose with this combined drug. However, cases of overdose with certain substances have been reported.

Montelukast

There have been reports of acute overdose in post-marketing experience and clinical studies with montelukast. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and paediatric patients. There were no adverse experiences in the majority of overdose reports. The most frequently occurring adverse experiences were consistent with the safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity. It is not known whether montelukast is dialysable by peritoneal- or haemo-dialysis.

Treatment is symptomatic.

Levocetirizine dihydrochloride

Symptoms of overdose may include drowsiness in adults. In children, agitation and restlessness may initially occur, followed by drowsiness. There is no known specific antidote to levocetirizine. In case of overdose, standard appropriate measures are recommended for the removal of unabsorbed drug. Gastric lavage may be considered shortly after ingestion of the drug. Levocetirizine is not effectively removed by haemodialysis.

Treatment is symptomatic.

 

Adverse reactions.

No data is available on the adverse reactions of this combination drug. However, the adverse reactions of some substances have been reported.

The adverse events have been classified according to frequency of occurrence: common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000) and very rare (<1/10,000).

Montelukast

The most common adverse reactions include dyspepsia, abdominal pain, rash, dizziness, headache, fatigue, fever, trauma, cough, nasal congestion and influenza.

The adverse reactions reported in the post-marketing period are as follows:

Blood system and lymphatic system disorders:

Rare: increased bleeding tendency.

Very rare: thrombocytopenia.

Immune system disorders:

Uncommon: hypersensitivity reaction, including anaphylaxis.

Very rare: eosinophilic liver infiltration.

Psychiatric disorders:

Uncommon: sleep disorders, including nightmares, hallucinations, insomnia, disorientation, insomnia, somnambulism, irritability, restlessness, anxiety, anger, impatience, agitation, including aggressive behaviour or hostility, depression.

Rare: psychomotor hyperactivity, tremor, tics.

Very rare: suicidal thinking and behaviour, disorientation, attention deficit, memory impairment

Nervous system disorders:

Uncommon: headache, lethargy and dizziness, paresthesia/hypoaesthesia, seizures, drowsiness, hyperkinesia.

Respiratory, thoracic and mediastinal disorders:

Uncommon: epistaxis, nosebleeds.

Very rare: Churg-Strauss syndrome, pulmonary eosinophilia.

Cardiovascular system disorders:

Rare: palpitation.

Gastrointestinal disorders:

Common: diarrhea, nausea, vomiting.

Uncommon: abdominal pain, dry mouth, dyspepsia,

Infections and invasions:

Very common: upper respiratory tract infections.

Hepatobiliary system disorders:

Common: the elevated levels of serum transaminases (ALT, AST) have been observed in patients taking montelukast.

Very rare: hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury). Most of these cases were accompanied by other aggravating factors, such as the use of other drugs or a predisposition to liver disease, namely alcohol abuse or hepatitis.

Skin and subcutaneous tissue disorders:

Common: rash.

Uncommon:  hematoma, urticaria, pruritus.

Rare: angioneurotic oedema.

Very rare: erythema nodosum, erythema multiforme, eczematous dermatitis.

Musculoskeletal, connective tissue and bone disorders:

Uncommon: arthralgia, myalgia including muscle cramps.

Renal and urinary disorders:

Uncommon: enuresis in children.

General disorders and administration site conditions:

Common: pyrexia.

Uncommon: asthenia/fatigue, discomfort, oedema, malaise, thirst.

In isolated cases, Churg-Strauss syndrome (CSS) has been reported during treatment with montelukast in patients with asthma. In isolated cases, patients with asthma receiving montelukast may experience systemic eosinophilia, sometimes accompanied by clinical manifestations of vasculitis, the so-called Churg-Strauss syndrome.

Levocetirizine dihydrochloride

The following adverse reactions have been reported in clinical trials:

common (> 1/100, < 1/10) – headache, drowsiness, dry mouth, fatigue;

uncommon (≥ 1/1000, <1/100) - general weakness, abdominal pain.

The use of levocetirizine for patients over 12 years of age was associated with the adverse reactions such as drowsiness, fatigue, nasopharyngitis, dry mouth and throat. Uncommon adverse reactions include asthenia and abdominal pain. Isolated cases of adverse reactions reported in the post-marketing are as follows:

Immune system disorders: hypersensitivity including anaphylaxis.

Psychiatric disorders: aggression, agitation sleep disorder, hallucinations, depression, insomnia, suicidal thinking, nightmares.

Nervous system disorders: drowsiness, headache, fatigue, weakness, asthenia, convulsions, paraesthesia, dizziness, syncope, tremor, vertigo, dysgueusia.

Eye disorders: visual disturbances, blurred vision, oculogyration.

Ear and labyrinth disorders: vertigo.

Cardiovascular system disorders: palpitation, tachycardia.

Respiratory, thoracic, and mediastinal disorders: dyspnoea.

Skin and subcutaneous tissue disorders: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticaria.

Musculoskeletal, connective tissues, and bone disorders: myalgia, arthralgia.

Investigations: weight increased, abnormal liver function tests.

Gastrointestinal disorders: nausea, diarrhea, vomiting, constipation, increased appetite, dry mouth, abdominal pain.

Hepatobiliary disorders: hepatitis.

Renal and urinary disorders: dysuria, urinary retention.

General disorders: oedema.

Description of selected adverse reactions

After levocetirizine discontinuation, pruritus has been reported.

Reporting of suspected adverse reactions

Reporting of 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 suspect adverse reactions.

 

Shelf life. 2 years.

 

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

 

Packaging.

Package No.10 (10x1): 10 tablets in a blister, 1 blister in a carton.

Package No.20 (10x2): 10 tablets in a blister, 2 blisters in a carton.

 

Terms of dispensing. On prescription.

 

Manufacturer. Bafna Pharmaceuticals Ltd., India.

 

Manufacturer’s registered address.

147, Madhavaram Red Hills Road Grantlyon Village Vadakarai Chennai Tamil Nadu IN 600052, India.

 

Applicant. SCAN BIOTECH LTD, India.

 

Applicant’s registered address.

E-4/300, Arera Colony Extension, 462016, Bhopal, (M.P.) India.

 

Date of last update. 13.05.2020