His Block M

Uses

His Block M is used for relief of symptoms of allergic rhinitis [seasonal or perennial], as prophylaxis in seasonal allergic rhinitis and treatment of comorbid asthma and allergic rhinitis in patients 15 years of age and over.

Montelukast sodium is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene (CysLT1), receptor.

Levocetirizine is the R-enantiomer of cetirizine. Levocetirizine is an orally active, potent, selective and long acting H1 -histamine receptor antagonist with no anticholinergic activity.

Recent studies have demonstrated that Allergic Rhinitis [AR] when treated concomitantly with an antileukotriene (montelukast) and an antihistamine (levocetrizine), shows significantly better symptom relief compared with the modest improvement of rhinitis symptoms with each of the treatments alone.

His Block M is also used to associated treatment for these conditions: Allergic Rhinitis (AR), Chronic Idiopathic Urticaria, Common Cold, Nasal Congestion, Perennial Allergic Rhinitis (PAR), Seasonal Allergic RhinitisAsthma, Exercise-Induced Bronchospasm, Perennial Allergic Rhinitis (PAR), Seasonal Allergic Rhinitis

How His Block M works

Levocetirizine selectively inhibits histamine H₁ receptors. This action prevents histamine from activating this receptor and causing effects like smooth muscle contraction, increased permeability of vascular endothelium, histidine uptake in basophils, stimulation of cough receptors, and stimulation of flare responses in the nervous system.

Cysteinyl leukotrienes (CysLT) like LTC4, LTD4, and LTE4, among others, are eicosanoids released by a variety of cells like mast cells and eosinophils. When such CysLT bind to corresponding CysLT receptors like CysLT type-1 receptors located on respiratory airway smooth muscle cells, airway macrophages, and on various pro-inflammatory cells like eosinophils and some specific myeloid stem cells activities that facilitate the pathophysiology of asthma and allergic rhinitis are stimulated.

In particular, CysLT-mediated airway bronchoconstriction, occluding mucous secretion, vascular permeability, and eosinophil recruitment are all types of effects that facilitate asthma. Alternatively, in allergic rhinitis, CysLTs are released by the nasal mucosa when exposed to allergens during both early and late phase reactions and participate in eliciting symptoms of allergic rhinitis like a congested nose and airway.

Subsequently, montelukast is a leukotriene receptor antagonist that binds with high affinity and selectivity to the CysLT type 1 receptor, which consequently assists in inhibiting any physiological actions of CysLTs like LTC4, LTD4, and LTE4 at the receptor that may facilitate asthma or allergic rhinitis.

Dosage

His Block M dosage

Adults [>15years]: 1 His Block M Tablet once daily. Due to the lack of clinical data, the administration of this product to infants less than 2 years of age is not recommended.

MONTELUKAST
Absorption
After administration of a 10-mg tablet to fasted adults, the mean peak montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax). The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal in the morning.

Distribution
Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 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 pediatric patients.

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

In several studies, the mean plasma half- life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (~14%).

LEVOCETIRIZINE
The pharmacokinetics of levocetirizine are linear with dose and time-independent with low inter-subject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.

Absorption
Levocetirizine is rapidly and extensively absorbed following oral administration. Peak plasma concentrations are achieved 0.9h 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 doseindependent and is not altered by food, but the peak concentration is reduced and delayed.

Distribution
No tissue distribution data are available in humans. Levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is restrictive, as the volume of distribution is 0.4 l/kg.

Biotransformation
The extent of metabolism of levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O-dealkylation and taurine conjugation.

Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose.

Due to its low metabolism and absence of metabolic inhibition potential, the interaction of levocetirizine with other substances, or vice-versa, is unlikely. 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 faeces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular sec.

Side Effects

Montelukast: Common side effects include dyspepsia, abdominal pain, rash, dizziness, headache, fatigue, fever, trauma, cough, nasal congestion.

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 or abdominal pain were observed.

Toxicity

Patients experiencing an overdose may present with drowsiness. Children may become agitated and restless before drowsiness. Patients should be treated with supportive measures. Dialysis will not assist in removing the drug from the body.

The maximal nonlethal dose in mice and rats is 240mg/kg.

The adverse effects associated with overdosage of montelukast include abdominal pain, somnolence, thirst, headache, vomiting, psychomotor hyperactivity, and less frequently, convulsion.

The oral LD50 value determined for mice and rats is >5000 mg/kg.

Montelukast has not been studied in pregnant women. Consequently, it should be used during pregnancy only if clearly needed.

Additionally, as it is unknown whether montelukast is excreted into human breast milk, there is also caution regarding the use of the medication in nursing mothers.

The plasma half-life of montelukast is somewhat prolonged in elderly patients, although no dosage adjustment is generally necessary.

Precaution

MONTELUKAST: Eosinophilic Conditions In rare cases, 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.

LEVOCETIRIZINE Patients should avoid engaging in hazardous occupation requiring complete mental alertness such as driving or operating machinery when taking levocetirizine. Precaution is recommended with intake of alcohol and in those who are on CNS depressants

Interaction

Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: Theophylline, Prednisolone, oral contraceptives (Norethindrone 1 mg/Ethinyl Oestradiol 35 mg), Terfenadine, Digoxin, and Warfarin.

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

Phenobarbital, which induces hepatic metabolism, decreased the AUC of Montelukast approximately 40% following a single 10 mg dose of Montelukast. No dosage adjustment for Montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as Phenobarbital or Rifampin, are co-administered with Montelukast.

Volume of Distribution

The volume of distribution of levocetirizine is 0.33±0.02L/kg.

The steady-state volume of distribution recorded for montelukast is an average between 8 to 11 litres.

Elimination Route

Following a 5mg oral dose of levocetirizine, a C_max of 0.27±0.04µg/mL with a T_max of 0.75±0.50h. The AUC of levocetirizine is 2.31±0.50µg*h/mL. Taking levocetirizine with food does not affect the AUC but delays T_max by 1.25 hours and lowers C_max by 36%.

It has been observed that montelukast is quickly absorbed following administration by the oral route. The oral bioavailability documented for the drug is 64%. Furthermore, it seems that having a regular meal in the morning or even a high fat snack in the evening does not affect the absorption of montelukast.

Half Life

The average half life of levocetirizine is 7.05±1.54 hours.

Studies have demonstrated that the mean plasma half-life of montelukast varies from 2.7 to 5.5 hours when observed in healthy young adults.

Clearance

The average clearance of levocetirizine is 0.57±0.18mL/min/kg.

The plasma clearance documented for montelukast is an average of 45 mL/min when observed in healthy adults.

Elimination Route

168 hours post dose an average of 85.4% of a radiolabeled dose was recovered with an average of 80.8% in the urine and 9.5% in the feces. In the urine, 77% of the dose was recovered as unchanged drug, 0.5% as the M8 and M9 metabolites, 0.4% as the M10a metabolite, 0.4% as the M10b metabolite, 0.3% as the M3 metabolite, 0.3% as the M4 and M5 metabolite, 0.2% as the M2 metabolite, and 0.1% as the M1 metabolite. In the feces, 9.0% of the dose was recovered as unchanged drug, 1.0% as the M4 and M5 metabolite, and 0.1% as the M1 metabolite.

It has been reported that montelukast and its metabolites are almost exclusively excreted in the bile and into the feces.

Pregnancy & Breastfeeding use

There are no adequate and well-controlled studies of either His Block M 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

Contraindication

His Block M is contraindicated in patients with known hypersensitivity to montelukast sodium, levocetirizine or cetirizine or to any other component of this product. His Block M is also contraindicated in patients with severe renal impairment at less than 10ml/min creatinine clearance. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.

Special Warning

Renal Impairment: As levocetrizine is mainly excreted through urine, dosage adjustment may be required in patients with impaired renal function. Hence this combination should be used with caution in such patients.

Hepatic Impairment: As montelukast is mainly excreted through bile, caution is to be exercised while prescribing this combination in patients with impaired hepatic function.

Pediatric Use:

Montelukast: The safety of Montelukast 4-mg chewable tablets in pediatric patients aged 2 to 14 years with allergic rhinitis is supported by data from studies conducted in pediatric patients aged 2 to 14 years with asthma. A safety study in pediatric patients 2 to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile. The safety and effectiveness in pediatric patients below the age of 12 months with asthma and 6 months with allergic rhinitis have not been established.

Levocetirizine: The safety and effectiveness of Levocetirizine in pediatric patients under 2 years of age have not been established. The effectiveness of Levocetirizine 2.5 mg once daily for the treatment of the symptoms of seasonal and perennial allergic rhinitis in children 2 to 6 years of age is supported by the extrapolation of demonstrated efficacy of Levocetirizine 5 mg once daily in patients 12 years of age and older and by the pharmacokinetic comparison in adults and children. In children 2 to 6 years of age the recommended dose of 2.5 mg once daily should not be exceeded.

Geriatric Use Montelukast: No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Levocetirizine: Clinical studies of levocetirizine for each approved indication did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy

Acute Overdose

There is no data to prove the overdosage of this combination. However, overdosage has been reported with individual molecules.

MONTELUKAST There have been reports of acute over-dosage 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 pediatric patients. There were no 6 adverse experiences in the majority of over-dosage 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 removed by peritoneal dialysis or hemodialysis.

LEVOCETIRIZINE Symptoms of overdose may include drowsiness in adults and initially agitation and restlessness followed by drowsiness, in children. There is no known specific antidote to levocetrizine. Should overdose occur, symptomatic or supportive treatment is recommended. Levocetrizine is not effectively removed by dialysis and dialysis will be ineffective unless a dialyzable agent has been concomitantly ingested.

Interaction with other Medicine

MONTELUKAST 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.

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.

Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast.

LEVOCETIRIZINE In vitro data indicate that levocetrizine is unlikely to produce pharmacokinetic interactions through inhibition or induction of liver drug-metabolizing enzymes. No in vivo drug-drug interaction studies have been performed with levocetrizine. Drug interaction studies have been performed with racemic cetrizine.

Pharmacokinetic interaction studies performed with racemic cetrizine demonstrated that cetrizine did not interact with antipyrine, pseudoephedrine, erythromycin, azithromycin, ketoconazole and cimetidine. There was a small decrease (~16%) in the clearance of cetrizine caused by a 400 mg dose of theophylline. It is possible that higher theophylline doses could have a greater effect. Ritonavir increased the plasma AUC of cetrizine by about 42% accompanied by an increase in half-life (53%) and a decrease in clearance (29%) of cetrizine. The disposition of ritonavir was not altered by concomitant cetrizine administration.

Storage Condition

Store in a cool dry place.
Protect from moisture and light.

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