1. BAMBEC (30 tab/10 mg of Bambuterol hydrochloride in tablet) 

2. MONTELUKAST (50 tab/ 10 mg of montelukast sodium 10.4 mg in tab)

3. SALBUTAMOL (100 tab/4 mg of Salbutamol sulfate in tablet)

4. PHILLINE (10 ml/ 25 mg of Aminophylline Hydrate in ml)

 

BAMBEC (30 tab/10 mg of Bambuterol hydrochloride in tablet)

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 Therapeutic indications

Management of asthma, bronchospasm and/or reversible airways obstruction.

 Posology and method of administration

Posology

Bambec is formulated as a tablet and should be taken once daily, shortly before bedtime. The dose should be individualised.

Adults: The recommended starting doses are 10 mg–20 mg. The 10 mg dose may be increased to 20 mg if necessary after 1–2 weeks, depending on the clinical effect.

In patients who have previously tolerated β2-agonists well, the recommended starting dose, as well as maintenance dose, is 20 mg.

Older people: Dose adjustment is not required in older people.

Significant hepatic dysfunction: Not recommended because of unpredictable conversion to terbutaline.

Moderate to severely impaired renal function (GFR < 50 ml/min): It is recommended that the starting dose of Bambec should be halved in these patients.

Paediatric population: Until the clinical documentation has been completed, Bambec should not be used in children.

 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Bambec is presently not recommended for children due to limited clinical data in this age group.

 Special warnings and precautions for use

As terbutaline is excreted mainly via the kidneys, the dose of Bambec should be halved in patients with an impaired renal function (GFR ≤ 50 mL/min).

In patients with liver cirrhosis, and probably in patients with other causes of severely impaired liver function, the daily dose must be individualised, taking into account the possibility that the individual patient could have an impaired ability to metabolise bambuterol to terbutaline. Therefore, from a practical point of view, the direct use of the active metabolite, terbutaline (Bricanyl™), is preferable in these patients.

As for all β2-agonists, caution should be observed in patients with thyrotoxicosis.

Cardiovascular effects may be seen with sympathomimetic drugs, including Bambec. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with beta agonists. Patients with underlying severe heart disease (e.g. ischaemic heart disease, arrhythmia or severe heart failure) who are receiving Bambec should be warned to seek medical advice if they experience chest pain or other symptoms of worsening heart disease. Attention should be paid to assessment of symptoms such as dyspnoea and chest pain, as they may be of either respiratory or cardiac origin.

Although Bambec is not indicated for the treatment of premature labour it should be noted that bambuterol is metabolised to terbutaline and that terbutaline should not be used as a tocolytic agent in patients with pre-existing ischaemic heart disease or those patients with significant risk factors for ischaemic heart disease.

Due to the hyperglycaemic effects of β2-agonists, additional blood glucose controls are recommended initially in diabetic patients.

Due to the positive inotropic effects of β2-agonists these drugs should not be used in patients with hypertrophic cardiomyopathy.

β2-agonists may be arrhythmogenic and this must be considered in the treatment of the individual patient.

Unpredictable inter-individual variation in the metabolism of bambuterol to terbutaline has been shown in subjects with liver cirrhosis. The use of an alternative β2-agonist is recommended in patients with cirrhosis and other forms of severely impaired liver function.

Potentially serious hypokalaemia may result from β2-agonist therapy. Particular caution is recommended in acute severe asthma as the associated risk may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatments (see section 4.5). It is recommended that serum potassium levels are monitored in such situations.

Asthma patients who require treatment with Bambec must have optimum anti-inflammatory treatment with corticosteroids. The patients must be instructed to continue taking their anti-inflammatory medication after the start of treatment with Bambec, even if the asthma symptoms diminish. If a previously effective dosage regimen no longer gives the same symptomatic relief this suggests that the underlying disease has worsened. The patient should urgently seek further medical advice and a re-evaluation of the asthma treatment must be carried out. Consideration should be given to the requirements for additional therapy (including increased dosages of anti-inflammatory medication). Treatment with Bambec must not be begun or the dose increased during an acute exacerbation of the asthma. Severe exacerbations of asthma should be treated as an emergency in the usual manner.

Precaution should be applied when treating patients predisposed to angle closure glaucoma.

Bambec tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

 Interaction with other medicinal products and other forms of interaction

Bambuterol prolongs the muscle-relaxing effect of suxamethonium (succinylcholine). A prolongation of the muscle-relaxing effect of suxamethonium of up to 2-fold has been observed in some patients after taking Bambec 20 mg on the evening prior to surgery. The inhibition is dose-dependent and fully reversible after cessation of treatment with bambuterol. This is due to the fact that plasma cholinesterase, which inactivates suxamethonium, is partly inhibited by bambuterol. Studies on the effects on plasma cholinesterase showed that bambuterol inhibited activity, but that this was reversible. However in extreme situations, the interaction may result in a prolonged apnoea time which may be of clinical importance. This interaction should also be considered with other muscle relaxants, which are metabolised by plasma cholinesterase.

Beta-receptor blocking agents (including eye-drops), especially those which are non-selective, may partly or totally inhibit the effect of beta-stimulants. Therefore, Bambec tablets and non-selective β-blockers should not normally be administered concurrently.

Hypokalemia may result from β2-agonist therapy and may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics (see section 4.4).

Bambec should be used with caution in patients receiving other sympathomimetics.

Six cases have been reported where concomitant treatment with salbutamol and ipratropium, used in asthma (nebuliser), has caused narrow angle glaucoma. Terbutaline is likely to interact, similar to salbutamol, with ipratropium when administered in a nebuliser. The combination is discouraged in predisposed patients.

 Fertility, pregnancy and lactation

Pregnancy

Although no teratogenic effects have been observed in animals after administration of bambuterol, caution is recommended during the first trimester of pregnancy.

Beta-agonists should be used with caution at the end of pregnancy because of the tocolytic effect.

Transient hypoglycaemia has been reported in newborn preterm infants after maternal β2-agonist treatment.

Breast-feeding

It is unknown whether bambuterol or intermediary metabolites are excreted in human breast milk. Terbutaline, the active metabolite of bambuterol, is excreted in breast milk, but at therapeutic doses of terbutaline no effect on breastfed newborns/infants are anticipated. A decision must be made whether to discontinue breast-feeding or to discontinue Bambec therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

 Effects on ability to drive and use machines

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

 Undesirable effects

Most of the adverse reactions are characteristic of sympathomimetic amines. The intensity of the adverse reactions is dose-dependent. Tolerance to these effects has usually developed within 1-2 weeks.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to < 1/100), Rare (≥1/10,000 to < 1/1,000), Very rare (<1/10,000) and Not known (cannot be estimated from available data).

Overdose

Symptoms

Overdosing may result in high levels of terbutaline and therefore the same symptoms and signs as recorded after overdosage with Bricanyl: Headache, anxiety, tremor, nausea, tonic muscle cramps, palpitations, tachycardia and cardiac arrhythmias.

A fall in blood pressure sometimes occurs after terbutaline overdosage.

Laboratory findings: Hyperglycaemia and lactic acidosis sometimes occur. High doses of β2-agonists may cause hypokalemia as a result of redistribution of potassium.

Overdosage with Bambec is likely to cause a considerable inhibition of plasma cholinesterase, that may last for days .

Management

Usually no treatment is required. In particularly severe cases of overdosage, the following measures may be considered on a case-by-case basis: Gastric lavage and activated charcoal.

Determine acid-base balance, blood glucose and electrolytes. Monitor heart rate and rhythm and blood pressure. The preferred antidote for haemodynamically significant cardiac arrhythmias is a cardioselective beta-blocking agent, but beta-blocking drugs should be used with caution in patients with a history of bronchospasm. If the β2-mediated reduction in peripheral vascular resistance significantly contributes to the fall in blood pressure, a volume expander should be given.

 Pharmacodynamic properties

Pharmacotherapeutic group: selective β2-agonists, bambuterol, ATC code: R03C C12.

Mechanism of action

Bambuterol is an active precursor of the selective β2-adrenergic agonist terbutaline. Bambuterol is the bis-dimethylcarbamate of terbutaline, and is present in the formulation as a 1:1 racemate.

Pharmacodynamic effects

Pharmacodynamic studies have shown that after oral administration of bambuterol to guinea pigs, a sustained protective effect was achieved against histamine-induced bronchoconstriction. At equipotent doses, the duration of the relaxing activity was more prolonged than after plain terbutaline. Bambuterol, or the monocarbamate ester, did not exert any smooth muscle relaxing properties. The bronchoprotective effects seen after oral administration of bambuterol are related to the generation of terbutaline, as were the secondary effects (effects on other organs).

Pharmacodynamic studies have been conducted in asthmatics and healthy volunteers. The effects observed were bronchodilation, tremor and increases in heart rate. The metabolic effects included a small increase in blood glucose, while the effect on serum potassium was negligible. In short-term studies on lipoprotein metabolism, an increase in HDL cholesterol has been observed. In conclusion, all pharmacodynamic effects observed can be ascribed to the active metabolite terbutaline.

 Pharmacokinetic properties

Absorption

On average, 17.5% of an oral dose is absorbed. Approximately 70–90% of the absorption occurs in the first 24 hours.

Biotransformation

Bambuterol is metabolised in the liver and terbutaline is formed by both hydrolysis and oxidation. After absorption from the gut, about 2/3 of terbutaline is first-pass metabolised, bambuterol escapes this first-pass metabolism. Of the absorbed amount, about 65% reaches the circulation. Bambuterol therefore has a bioavailability of about 10%.

Distribution

Protein binding of bambuterol is low, 40–50% at therapeutic concentrations.

Elimination

The terminal half-life of bambuterol after an oral dose is 9–17 hours.

Hepatic Impairment

All categories of subjects studied were able to form terbutaline in a predictive way except for liver cirrhotics.

 Preclinical safety data

Bambuterol has not revealed any adverse effects which pose a risk to man at therapeutic dosages in the toxicity studies.

Bambuterol is given as a racemate: (-)-bambuterol is responsible for the pharmacodynamic effects via generation of (-)-terbutaline. (+)-bambuterol generates the pharmacodynamic inactive (+)-terbutaline. Both (+) and (-)-bambuterol are equally active as plasma cholinesterase inhibitors. This inhibition is reversible.

The toxicity studies showed that bambuterol has β2-stimulatory effects, expressed as cardiotoxicity in dogs, and at high doses, observed in the acute toxicity studies, cholinergic effects.

There is no evidence from the preclinical safety data to indicate that bambuterol cannot be used in man for the intended indications with sufficient safety.

 

  

 

MONTELUKAST (50 tab/ 10 mg of montelukast sodium 10.4 mg in tab)

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 Therapeutic indications

Montelukast 10 mg film-coated tablets is indicated in the treatment of asthma as add-on therapy in adults and adolescents from 15 years of age and older with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom “as-needed” short acting beta-agonists provide inadequate clinical control of asthma. In those asthmatic patients in whom Montelukast 10 mg film-coated tablets is indicated in asthma, Montelukast 10 mg film-coated tablets can also provide symptomatic relief of seasonal allergic rhinitis.

Montelukast 10 mg film-coated tablets is also indicated in the prophylaxis of asthma in which the predominant component is exercise-induced bronchoconstriction.

 Posology and method of administration

Method of administration:

For oral use.

Posology:

The dosage for adults and adolescents 15 years of age and older with asthma, or with asthma and concomitant seasonal allergic rhinitis, is one 10 mg tablet daily to be taken in the evening.

Montelukast sodium should not be used concomitantly with other products containing the same active ingredient, montelukast.

General recommendations:

The therapeutic effect of Montelukast 10 mg film-coated tablets on parameters of asthma control occurs within one day. Montelukast 10 mg film-coated tablets may be taken with or without food. Patients should be advised to continue taking Montelukast 10 mg film-coated tablets even if their asthma is under control, as well as during periods of worsening asthma. Montelukast 10 mg film-coated tablets should not be used concomitantly with other products containing the same active ingredient, montelukast.

No dosage adjustment is necessary for the elderly, or for patients with renal insufficiency, or mild to moderate hepatic impairment. There are no data on patients with severe hepatic impairment. The dosage is the same for both male and female patients.

Therapy with Montelukast 10 mg film-coated tablets in relation to other treatments for asthma.

Montelukast 10 mg film-coated tablets can be added to a patient's existing treatment regimen.

Inhaled corticosteroids:

Treatment with Montelukast 10 mg film-coated tablets can be used as add-on therapy in patients when inhaled corticosteroids plus "as needed" short acting beta-agonists provide inadequate clinical control. Montelukast 10 mg film-coated tablets should not be abruptly substituted for inhaled corticosteroids (see section 4.4).

10 mg film-coated tablets are available for adults and adolescents above 15 years old.

Other available strengths/pharmaceutical forms:

5 mg chewable tablets are available for paediatric and adolescents patients 6 to 14 years of age.

4 mg chewable tablets are available for paediatric patients 2 to 5 years of age.

 Contraindications

Hypersensitivity to the active substance(s)

 Special warnings and precautions for use

Patients should be advised never to use oral montelukast to treat acute asthma attacks and to keep their usual appropriate rescue medication for this purpose readily available. If an acute attack occurs, a short-acting inhaled beta-agonist should be used. Patients should seek their doctor's advice as soon as possible if they need more inhalations of short-acting beta-agonists than usual.

Montelukast should not be substituted abruptly for inhaled or oral corticosteroids.

There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.

In rare cases, patients on therapy with anti-asthma agents including 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 cases usually, but not always, have been associated with the reduction or withdrawal of oral corticosteroid therapy. The possibility that leukotriene receptor antagonists may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. Patients who develop these symptoms should be reassessed and their treatment regimens evaluated.

Treatment with montelukast does not alter the need for patients with aspirin-sensitive asthma to avoid taking aspirin and other non-steroidal anti-inflammatory drugs.

This medicinal product contains lactose monohydrate.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

 Interaction with other medicinal products and other forms of interaction

Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In drug-interactions studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following medicinal products: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/ norethindrone 35/1), terfenadine, digoxin and warfarin.

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, 2C8, and 2C9, caution should be exercised, particularly in children, when montelukast is co-administered with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital and rifampicin.

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 metabolized 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 CYP 2C8, 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.

 Fertility, pregnancy and lactation

Use during pregnancy

Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/foetal development.

Limited data from available pregnancy databases do not suggest a causal relationship between Montelukast 10 mg film-coated tablets and malformations (i.e. limb defects) that have been rarely reported in worldwide post marketing experience.

Montelukast 10 mg film-coated tablets may be used during pregnancy only if it is considered to be clearly essential.

Use during breastfeeding

It is unknown whether montelukast is excreted in human milk. Studies in rats have shown that montelukast is excreted in milk .

Montelukast 10 mg film-coated tablets may be used in breast-feeding only if it is considered to be clearly essential

 Effects on ability to drive and use machines

Montelukast is not expected to affect a patient's ability to drive a car or operate machinery. However, in very rare cases, individuals have reported drowsiness or dizziness.

 Undesirable effects

The frequency using the following convention: Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); 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).

Montelukast has been evaluated in clinical studies as follows:

• 10 mg film-coated tablets in approximately 4000 adult asthmatic patients 15 years of age and older.

• 10 mg film-coated tablets in approximately 400 adult asthmatic patients with seasonal allergic rhinitis 15 years of age and older.

• 5 mg chewable tablets in approximately 1750 paediatric asthmatic patients 6 to 14 years of age.

 Overdose

Symptoms

No specific information is available on the treatment of overdose with montelukast. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to patients for 22 weeks and in short term studies, up to 900 mg/day to patients for approximately one week without clinically important adverse experiences.

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 (approximately 61 mg/kg in a 42 month old child). 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.

Treatment

It is not known whether montelukast is dialysable by peritoneal- or haemo-dialysis.

 Pharmacodynamic properties

Pharmacotherapeutic group: Other systemic drugs for obstructive airway diseases, Leukotriene receptor antagonist

ATC code: R03D C03

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 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 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 which binds with high affinity and selectivity to the CysLT1 receptor. In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD4 at doses as low as 5 mg. Bronchodilation was observed within 2 hours of oral administration. The bronchodilation effect caused by a beta agonist was additive to that caused by montelukast. Treatment with montelukast inhibited both early- and late phase bronchoconstriction due to antigen challenge. Montelukast, compared with placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study, treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum) and in peripheral blood while improving clinical asthma control.

In studies in adults, montelukast, 10 mg once daily, compared with placebo, demonstrated significant improvements in morning FEV1 (10.4% vs 2.7% change from baseline), AM peak expiratory flow rate (PEFR) (24.5 L/min vs 3.3 L/min change from baseline), and significant decrease in total beta-agonist use ( -26.1% vs -4.6% change from baseline). Improvement in patient-reported daytime and nighttime asthma symptoms scores was significantly better than placebo.

Studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled corticosteroid (% change from baseline for inhaled beclometasone plus montelukast vs beclometasone, respectively for FEV1: 5.43% vs 1.04%; beta-agonist use: -8.70% vs 2.64%). Compared with inhaled beclometasone (200 µg twice daily with a spacer device), montelukast demonstrated a more rapid initial response, although over the 12-week study, beclometasone provided a greater average treatment effect (% change from baseline for montelukast vs beclometasone, respectively for FEV1: 7.49% vs 13.3%; beta agonist use: -28.28% vs -43.89%). However, compared with beclometasone, a high percentage of patients treated with montelukast achieved similar clinical responses (e.g., 50% of patients treated with beclometasone achieved an improvement in FEV1 of approximately 11% or more over baseline while approximately 42% of patients treated with montelukast achieved the same response).

A clinical study was conducted to evaluate montelukast for the symptomatic treatment of seasonal allergic rhinitis in adult asthmatic patients 15 years of age and older with concomitant seasonal allergic rhinitis. In this study, montelukast 10 mg tablets administered once daily demonstrated a statistically significant improvement in the Daily Rhinitis Symptoms score, compared with placebo. The Daily Rhinitis Symptoms score is the average of the Daytime Nasal Symptoms score (mean of nasal congestion, rhinorrhea, sneezing, nasal itching) and the Nighttime Symptoms score (mean of nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings scores). Global evaluations of allergic rhinitis by patients and physicians were significantly improved, compared with placebo. The evaluation of asthma efficacy was not a primary objective in this study.

In an 8-week study in paediatric patients 6 to 14 years of age, montelukast 5 mg once daily, compared with placebo, significantly improved respiratory function (FEV1 8.71% vs 4.16% change from baseline; AM PEFR 27.9 L/min vs 17.8 L/min change from baseline) and decreased "as-needed" beta-agonist use (-11.7% vs +8.2% change from baseline).

Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximal fall in FEV1 22.33% for montelukast vs 32.40% for placebo; time to recovery to within 5% of baseline FEV1 44.22 min vs 60.64 min). This effect was consistent throughout the 12-week study period. Reduction in EIB was also demonstrated in a short term study in paediatric patients (maximal fall in FEV1 18.27% vs 26.11%; time to recovery to within 5% of baseline FEV1 17.76 min vs 27.98 min). The effect in both studies was demonstrated at the end of the once-daily dosing interval.

In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment with montelukast, compared with placebo, resulted in significant improvement in asthma control (FEV1 8.55% vs -1.74% change from baseline and decrease in total beta-agonist use -27.78% vs 2.09% change from baseline).

 Pharmacokinetic properties

Absorption

Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10 mg film-coated tablet was administered without regard to the timing of food ingestion.

For the 5 mg chewable 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 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.

Cytochrome P450 2C8 is the major enzyme in the metabolism of montelukast. Additionally CYP 3A4 and 2C9 may have a minor contribution, although itraconazole, an inhibitor of CYP 3A4, was shown not to change pharmacokinetic variables of montelukast in healthy subjects that received 10 mg montelukast daily. Based on in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

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.

Characteristics in patients

No dosage adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impairment have not been undertaken. Because montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (Child-Pugh score>9).

With high doses of montelukast (20- and 60-fold the recommended adult dose), decrease in plasma theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.

 

 

  

 

SALBUTAMOL (100 tab/4 mg of Salbutamol sulfate in tablet)

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 What Salbutamol tablets are and what they are used for

Salbutamol tablets belong to a group of medicines called selective beta-2-androgenic agonists, which can be used to relax the muscles of the airways and womb. Salbutamol tablets may be used in:

asthma, to relieve the narrowing of the airways

chronic bronchitis

emphysema

 Before you take

Do not take Salbutamol tablets and tell your doctor if you:

are allergic (hypersensitive) to salbutamol or any other ingredients in Salbutamol tablets (see section 6)

have threatened abortion (potential miscarriage) during the first six months of pregnancy

are taking beta-blockers such as propranolol

Check with your doctor or pharmacist before taking Salbutamol tablets if you have:

an overactive thyroid gland (thyrotoxicosis).

diabetes.

a history of heart disease, irregular heart rhythm or angina.

Although it is not known exactly how often this happens, some people occasionally experience chest pain (due to heart problems such as angina). Tell your doctor/midwife if you develop these symptoms whilst receiving treatment with salbutamol, but do not stop using this medicine unless told to do so.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Especially:

diuretics, guanethidine, reserpine or methyldopa (to treat high blood pressure)

monoamine oxidase inhibitors e.g. tranylcypromine (for depression)

tricyclic antidepressants e.g. amitriptyline (for depression)

beta-blockers such as propranolol

corticosteroids

theophylline (for breathing problems).

inhaled anaesthetics (advise your doctor or dentist if you are undergoing any dentistry or surgery)

digoxin (for heart problems)

xanthines such as theophylline, aminophylline (for asthma)medicines for diabetes

Pregnancy and breast-feeding

If you are pregnant, planning to become pregnant or are breast-feeding tell your doctor or pharmacist before taking this medicine.

Sugar intolerance

If you have been told you have an intolerance to some sugars, contact your doctor before taking this medicine, as it contains a sugar called lactose.

Ingredients warning

Salbutamol tablets contain carmoisine (E122) which may cause allergic reactions.

Tests

If you have severe asthma, your doctor may monitor you more closely by carrying out certain tests.

 How to take

Always take Salbutamol tablets exactly as your doctor has told you. If you are not sure, check with your doctor or pharmacist.

Swallow the tablets with water

If you notice the tablets are not working as well as before, contact your doctor for advice.

Adults:

Usual dose is 4mg three or four times a day. Your doctor may increase this gradually up to a maximum of 8mg three or four times a day. Some patients may be treated successfully with 2mg three or four times a day.

Elderly or patients known to be sensitive to this product or other similar drugs:

Initially 2mg three or four times a day should be given.

Children 2-6 years:

1-2mg three or four times a day.

Children 6-12 years:

2mg three or four times a day.

Children over 12 years:

2-4mg three or four times a day.

Children under 2 years:

Not recommended.

If you take more than you should

If you (or someone else) swallow a lot of tablets at the same time, or you think a child may have swallowed any contact your nearest hospital casualty department or tell your doctor immediately. Symptoms of an overdose include low levels of potassium in the blood which may cause muscle twitching or weakness and an irregular heart beat.

If you forget to take the tablets

Do not take a double dose to make up for a forgotten dose. If you forget to take a dose take it as soon as you remember it and then take the next dose at the right time.

 Possible side effects

Like all medicines, Salbutamol tablets can cause side effects, although not everybody gets them.

Stop taking Salbutamol tablets and contact your doctor at once if you experience

an allergic reaction such as swelling of the face, lips, throat or tongue, pale or red irregular raised patches with severe itching (hives), difficulty breathing, low blood pressure, collapse

chest, jaw or shoulder pain (which may be accompanied with shortness of breath, feeling or being sick)

Tell your doctor if you notice any of the following effects or if you notice any not listed:

increased lactic acid in the body: rapid breathing, being sick, stomach pain.

low blood potassium: muscle twitching or weakness, an irregular heart beat.

other: headaches, increased blood sugar levels, slight shaking (usually of the hands), a tense feeling, widening of blood vessels which can cause an increase in heart function and heart rate, an irregular heart beat, muscle spasm, fluid on the lungs. An increase in the amount of acid in the body (ketoacidosis) may occur in diabetics.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

 How to store

Keep out of the reach and sight of children.

Store below 25°C in a dry place.

Do not use Salbutamol tablets after the expiry date stated on the label/carton/bottle. The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

 Further information

What Salbutamol tablets contain

The active substance (the ingredient that makes the tablets work) is salbutamol sulfate. Each tablet contains 4.8mg of the active ingredient equivalent to 4mg salbutamol.

The other ingredients are maize starch, lactose monohydrate, dispersed pink (erythrosine (E127), carmoisine (E122), titanium dioxide (E171), sodium starch glycollate, talc, magnesium stearate.

 

 

 

 

PHILLINE (10 ml/ 25 mg of Aminophylline Hydrate in ml)

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 Therapeutic indications

PHILLINE is a complex of theophylline and ethylenediamine and is given for its theophylline activity to relax smooth muscle and to relieve bronchial spasm.

PHILLINE Injection is indicated for relief of bronchospasm associated with asthma and in chronic obstructive pulmonary disease.

 Posology and method of administration

Posology:

PHILLINE Injection B.P. 250mg/10ml is for slow intravenous administration. The solution may be injected very slowly, or it may be infused in a small volume of either 5% dextrose or 0.9% sodium chloride injection.

Maintenance therapy can be administered via larger volume infusion solutions, rate-regulated to deliver the required amount of drug each hour.

Therapeutic plasma concentrations of theophylline are considered to be in the range of 5 to 20mcg/ml and levels above 20mcg/ml are more likely to be associated with toxic effects. There is marked interpatient variation in the dosage required to achieve plasma levels of theophylline that are within the desired therapeutic range.

During therapy, patients should be monitored carefully for signs of toxicity and, where possible, the serum theophylline levels should also be monitored.

 Contraindications

Hypersensitivity to the ethylenediamine or those allergic to the theophyllines, caffeine or theobromine or to any of the excipients listed in section 6.1

PHILLINE should not be administered concomitantly with other xanthine drugs. When therapeutic doses of Aminophylline and/or theophylline are administered simultaneously by more than one route or in more than one preparation, the hazard of serious toxicity is increased.

The use of PHILLINE IV in children under 6 months of age is not generally recommended.

The use of PHILLINE is contra-indicated in patients with acute porphyria.

 Special warnings and precautions for use

To reduce the undesirable stimulating effects of PHILLINE on the central nervous and cardiovascular systems, intravenous administration of the drug should be slow and should not exceed a rate of 25 mg/min.

PHILLINE has a narrow therapeutic index and serum levels should be monitored regularly, particularly during initiation of therapy.

PHILLINE injection should be administered cautiously to patients over 55 years of age.

Elderly patients or those with cardiac or hepatic disease should be monitored carefully for signs of theophylline toxicity.

Children are particularly susceptible to the effects of theophylline and care is required when administrating PHILLINE to children.

There have been reports of seizures in children with theophylline plasma levels within the accepted therapeutic range. Alternative treatment should be considered in patients with a history of seizure activity and, if Aminophylline Injection is used in such patients, they should be carefully observed for possible signs of central stimulation.

Because the mean half-life of theophylline is shorter in smokers than in non-smokers, the former group may require larger doses of aminophylline.

Care should be taken in patients undergoing influenza immunisation or who have active influenza infection or acute febrile illness.

PHILLINE should be given with caution to patients with cardiac failure, chronic obstructive pulmonary disease, renal or hepatic dysfunction and in chronic alcoholism since clearance of PHILLINE is decreased.

During regular therapy serum potassium levels must be monitored. This is essential during combination therapy with beta2-agonists, corticosteroids or diuretics, or in the presence of hypoxia.

PHILLINE should be used with caution in patients with peptic ulcer, hyperthyroidism, glaucoma, diabetes mellitus, severe hypoxaemia, hypertension and compromised cardiac or circulatory function, as these conditions may be exacerbated.

Methylxanthines may increase gastric acidity and care should be taken when they are used in patients with a history of peptic ulceration.

PHILLINE should not be administered concurrently with other xanthine medications.

 Interaction with other medicinal products and other forms of interaction

The following drugs may decrease PHILLINE clearance resulting in increased plasma theophylline concentrations and the potential for increased toxicity:

• Fluvoxamine

The concomitant use of theophylline and fluvoxamine should usually be avoided. Where this is not possible, patients should have their theophylline dose halved and plasma theophylline should be monitored closely.

• Cimetidine

• Macrolide antibiotics (e.g. erythromycin, clarithromycin)

• Quinolone antibiotics (e.g. ciprofloxacin, norfloxacin)

• Fluconazole

• Isoniazid

• Propranolol

• Allopurinol (high doses e.g. 600 mg daily)

• Oral contraceptives

• Mexiletine, propafenone

• Calcium channel blockers, diltiazem, verapamil

• St John's Wort (Hypericum perforatum)

• Disulfiram

• Interferon alfa, influenza vaccine

• Methotrexate

• Zafirlukast

• Tacrine

• Thiabendazole

• Thyroid hormones

The following drugs may decrease plasma theophylline concentrations:

• Rifampicin

• Antiepileptics (e.g. carbamazepine, phenytoin, primidone, phenobarbitone)

• Ritonavir

• Aminoglutethimide

• Sulphinpyrazone

Other interactions:

• Xanthines:

Concurrent use of other xanthine derivatives, including theophylline and pentoxifylline are contraindicated due to the risk of toxicity.

• Lithium:

Aminophylline increases the excretion of lithium and may decrease its therapeutic effectiveness.

• Benzodiazepines:

Theophylline may reduce the effects of benzodiazepines.

• Quinolones:

Increased risk of convulsions.

• General anaesthetics:

Increased risk of convulsions with ketamine; increased risk of arrhythmias with halothane.

• Pancuronium:

Resistance to neuromuscular block with pancuronium has been reported in patients receiving aminophylline.

• Sympathomimetics:

PHILLINE may exhibit synergistic toxicity with ephedrine and other sympathomimetics and concurrent use may dispose the patient to cardiac arrhythmias.

• Beta2-adrenergic agonists:

Increased risk of cardiac arrhythmias (see also hypokalaemia).

• Beta-blockers:

Antagonism of bronchodilator effects.

• Cardiac glycosides:

The direct stimulatory effect of PHILLINE on the myocardium may enhance the sensitivity and toxic potential of the cardiac glycosides.

• Adenosine:

The anti-arrhythmic effect of adenosine is antagonised by theophylline

• Leukotriene antagonists:

In clinical trials co-administration with theophylline resulted in decreased plasma levels of zafirlukast, by approximately 30%, but with no effect on plasma theophylline levels. However, during post-marketing surveillance, there have been rare cases of patients experiencing increased theophylline levels when co-administered zafirlukast (see above).

• Doxapram:

Increased CNS stimulation.

• Hypokalaemia:

The hypokalaemic effects of beta2-adrenergic agonists may be potentiated by concomitant treatment with PHILLINE. There is an increased risk of hypokalaemia when theophylline derivatives are given with corticosteroids or diuretics (see 4.4 Special warnings and precautions for use).

• Regadenoson:

PHILLINE may prolong a seizure or cause multiple seizures because of its proconvulsant effect. Therefore administration of aminophylline solely for the purpose of terminating a seizure induced by Regadenoson is not recommended.

 Fertility, pregnancy and lactation

Fertility:

Animal reproduction studies have not been performed with theophyllines.

Pregnancy:

It is not known whether theophyllines can cause foetal harm when administered to pregnant women. Although the safe use of theophylline during pregnancy has not been established relative to potential risk to the foetus, theophyllines have been used during pregnancy without teratogenicity or other adverse foetal effect. Because of the risk of uncontrolled asthma, their safety during pregnancy when clearly needed is generally not seriously questioned. As with other drugs, aminophylline should only be used during pregnancy if considered essential by the physician. Theophylline crosses the placenta.

Breast-feeding

Theophylline is distributed into breast milk and may occasionally induce irritability or other signs of toxicity in nursing infants, and therefore should not be used if the mother is breast-feeding her infant.

 Effects on ability to drive and use machines

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

 Undesirable effects

PHILLINE may cause gastrointestinal irritation, stimulation of the central nervous system and effects on the cardiovascular system. Hypotension, arrhythmias and convulsions may follow intravenous injection, particularly if the injection is too rapid, and sudden deaths have been reported. Severe toxicity may occur without preceding milder symptoms (see also 4.9 Overdose).

The following adverse reactions are classified by system organ class and ranked under heading of frequency using the following convention: 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 reactions (see also Skin and subcutaneous tissue disorders).

Metabolism and nutrition disorders:

Not Known: Metabolic disturbances such as hypokalaemia, hypophosphataemia, and hyponatraemia may occur.

Psychiatric disorders

Not Known: Anxiety, insomnia. Higher doses may lead to maniacal behaviour, and delirium.

Nervous system disorders:

Not Known: Headache, confusion, restlessness, hyperventilation, vertigo/dizziness, tremor. Higher doses may lead to convulsions.

Eye disorders:

Not Known: Visual disturbances.

Cardiac disorders:

Not Known: Palpitations, tachycardia, cardiac arrhythmias, hypotension.

Gastrointestinal disorders:

Not Known: Nausea, vomiting, abdominal pain, diarrhoea, gastro-oesophageal reflux, gastrointestinal bleeding.

Skin and subcutaneous tissue disorders:

Not Known: Rash, maculo-papular rash, erythema, pruritus, urticaria, exfoliative dermatitis.

General disorders and administration site conditions :

Not Known: Intramuscular injections are painful, the pain lasting several hours. Higher doses may result in hyperthermia and extreme thirst.

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

 

 

 Overdose

PHILLINE has a narrow therapeutic index. Theophylline toxicity is most likely to occur when serum concentrations exceed 20 micrograms/ml and becomes progressively more severe at higher serum concentrations.

Doses over 3 g could be serious in an adult (40 mg/kg in a child). The fatal dose may be as little as 4.5 g in an adult (60 mg/kg in a child), but is generally higher.

Fatalities in adults have occurred during IV PHILLINE administration in large doses in patients with renal, hepatic or cardiovascular complications or where the injection has been given rapidly.

Symptoms

Tachycardia, in the absence of hypoxia, fever or administration of sympathomimetic drugs, may be an indication of theophylline toxicity.

Warning: Serious features may develop as long as 12 hours after overdosage with sustained release formulations.

Gastro-intestinal symptoms: Anorexia, nausea, vomiting, diarrhoea, and haematemesis.

Neurological symptoms: Restlessness, insomnia, irritability, headache, agitation, hallucinations, extreme thirst, slight fever, dilated pupils, and tinnitus. Seizures may occur even without preceding symptoms of toxicity and often result in death. Coma may develop in very severe cases.

Cardiovascular symptoms: Palpitations, arrhythmias, hypotension, supraventricular and ventricular arrhythmias may occur.

Metabolic symptoms: Hypokalaemia can develop rapidly and may be severe. Hyperglycaemia, albuminuria, hyperthermia, hypomagnesaemia, hypophosphataemia, hypercalcaemia, respiratory alkalosis and metabolic acidosis may also occur. Rhabdomyolysis may also occur.

Management

Treatment of overdosage is supportive and symptomatic.

Serum theophylline and potassium levels should be monitored. Repeated oral administration of activated charcoal enhances the elimination of theophylline from the body even after intravenous administration. Aggressive antiemetic therapy may be required to allow administration and retention of activated charcoal.

Seizures may be treated with IV diazepam 0.1-0.3mg/kg up to 10mg. Restoration of fluid and electrolytes balance is necessary. Hypokalaemia should be corrected by intravenous infusion of potassium chloride. Sedation with diazepam may be required in agitated patients.

Propranolol may be administered intravenously to reverse extreme tachycardia, hypokalaemia and hyperglycaemia provided the patient does not suffer from asthma.

In general, theophylline is metabolised rapidly and haemodialysis is not warranted. In patients with congestive heart failure or liver disease, haemodialysis may increase theophylline clearance by as much as 2-fold.

Charcoal haemoperfusion should be considered if:

• Ileus/ intestinal obstruction prevents administration of multiple dose activated charcoal.

• Plasma theophylline concentration > 80mg/L (acute) or > 60mg/L (chronic). In the elderly, charcoal haemoperfusion should be considered at theophylline concentrations >40 mg/L. Clinical features rather than theophylline concentration are the best guide for treatment.

 Pharmacodynamic properties

Pharmacotherapeutic group: Xanthines, ATC code: R03DA05

Mechanism of Action:

PHILLINE is a complex of theophylline and ethylenediamine and is given for its theophylline activity to relax smooth muscle and to relieve bronchial spasm. Theophylline is a smooth muscle relaxant and it relaxes the smooth muscle of the bronchial airways.

Other actions of theophylline include cardiac stimulation, reduction in venous pressure in congestive heart failure, leading to a marked increase in cardiac output. It has stimulant effect on respiration, and also a diuretic action of short duration.

 Pharmacokinetic properties

Theophylline is approximately 60% bound to plasma proteins but binding is decreased to about 40% in neonates and in adults with hepatic disease. The drug is widely distributed and it crosses the placenta and passes into breast milk.

Theophylline is metabolised in the liver and the metabolites are excreted in the urine. In adults, about 10% of a dose of theophylline is excreted unchanged in the urine. There is considerable inter-individual variation in the rate of hepatic metabolism of theophylline, resulting in large variations in clearance, serum concentrations and half-lives. Cigarette smoking increases theophylline clearance and shortens its serum half-life.