Montelukast/ Levocetirizine Dihydrochloride

Registered South African indications:

• Relief of symptoms associated with allergic rhinitis (seasonal and perennial) in adults

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Hypersensitivity to cetirizine, hydroxyzine, or any other piperazine derivatives
• End-stage renal failure (CrCl<10ml/min)

South African recommendations

Caution recommended in the following patient groups

• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment (CrCl 10-79ml/min)
• Severe hepatic impairment

Montelukast

Acute asthma attacks

• Montelukast/ levocetirizine is not indicated in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus, as the efficacy of montelukast/ levocetirizine has not been established for the treatment of acute asthma attacks
• Patients should be advised never to use oral montelukast to treat acute asthma attacks and to keep their usual appropriate rescue medicine for this purpose readily available. If an acute attack occurs, a short-acting inhaled β-agonist should be used
• Patients should seek their doctors’ advice as soon as possible if they need more inhalations of short-acting β-agonists than usual

Oral corticosteroids

• 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

Eosinophilic conditions

• In rare cases, patients on therapy with anti-asthma medicines, 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 have sometimes been associated with the reduction or withdrawal of oral corticosteroid therapy. Although a causal relationship with leukotriene receptor antagonism has not been established, medical practitioners 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

Aspirin sensitivity

• Treatment with montelukast does not alter the need for patients with aspirin-sensitive asthma to avoid taking aspirin and other nonsteroidal anti-inflammatory medicines

Levocetirizine Dihydrochloride

Alcohol consumption

• Precaution recommended with concurrent alcohol intake

Urinary retention

• Caution should be taken in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention

Epilepsy

• Caution should be taken in patients with epilepsy and patients at risk of convulsions as levocetirizine may cause seizure aggravation

Allergy skin tests

• Response to allergy skin tests is inhibited by antihistamines and a wash-out period (3 days) is required before performing them

Effects when treatment is stopped

• Pruritus may occur when levocetirizine is stopped even if those symptoms were not present before treatment initiation. The symptoms may resolve spontaneously. In some cases, the symptoms may be intense and may require treatment to be restarted. The symptoms should resolve when the treatment is restarted

Montelukast/ Levocetirizine Dihydrochloride

Lactose content

• Montelukast/ levocetirizine contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine

Effects on ability to drive and use machines

• Montelukast/ levocetirizine may cause side effects, such as dizziness and drowsiness and can affect the ability to drive a vehicle and use machines
• Caution is advised before driving a vehicle or operating machinery until the effects of montelukast/ levocetirizine are known

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Relief of symptoms associated with allergic rhinitis (seasonal and perennial)

Montelukast/ Levocetirizine
10/5 (mg)

• Oral (fct): 1 tab, in the evening

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Swallow the tablet with liquid. The tablet can be taken with or without food

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Duration of use:
Intermittent allergic rhinitis (symptoms experienced for less than four days a week or for less than four weeks a year) must be treated according to the disease and its history; it can be stopped once the symptoms have disappeared and can be restarted again when symptoms reappear. In case of persistent allergic rhinitis (symptoms experienced for more than four days a week or for more than four weeks a year), continuous therapy can be proposed to the patient during the period of exposure to allergens

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Caution; not recommended
• The safety of montelukast and levocetirizine in pregnant women has not been established
• Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/fetal development. Animal reproduction studies are not always predictive of human response
• Montelukast/ levocetirizine should not be used during pregnancy

Breastfeeding

South African recommendations

• Caution; not recommended
• The safety of montelukast and levocetirizine in breastfeeding women has not been established. It is not known if montelukast is excreted in human breast milk
• Cetirizine, the racemate of levocetirizine, has been reported to be excreted in human breast milk. Therefore, the excretion of levocetirizine in human breast milk is likely
• Montelukast/ levocetirizine should not be used during breastfeeding

Fertility

South African recommendations

• There are no fertility data available

South African recommendations

• Mild (CrCl>79ml/min): No dose adjustment recommended
• Moderate to severe (CrCl 10-79ml/min): Caution; no dose adjustment recommended
  Montelukast/ levocetirizine is to be used with caution and under strict medical supervision
• End-stage (CrCl<10ml/min): Contraindicated

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available
  There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (Child-Pugh score >9)

South African recommendations

• No dose adjustment recommended
  The levocetirizine dose should be adjusted in accordance with renal function in elderly patients

Montelukast

Infections and Infestations

Frequent

• Upper respiratory infection

Blood and Lymphatic System Disorders

Less frequent

• Increased bleeding tendency
• Thrombocytopenia
• Hepatic eosinophilic infiltration

Immune System Disorders

Less frequent

• Hypersensitivity reactions including anaphylaxis
• Angioedema

Metabolism and Nutrition Disorders

Less frequent

• Oedema

Psychiatric Disorders

Less frequent

• Dream abnormalities including nightmares
• Insomnia
• Somnambulism
• Anxiety
• Agitation including aggressive behaviour or hostility
• Depression
• Psychomotor hyperactivity including irritability, restlessness, tremor
• Disturbance in attention
• Memory impairment
• Tic
• Hallucinations
• Disorientation
• Suicidal thinking and behaviour (suicidality)

Nervous System Disorders

Less frequent

• Dizziness
• Drowsiness
• Paraesthesia/hypaesthesia
• Seizure

Cardiac Disorders

Less frequent

• Palpitations

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Epistaxis
• Churg-Strauss syndrome (CSS)
• Pulmonary eosinophilia

Gastrointestinal Disorders

Frequent

• Diarrhoea
• Nausea
• Vomiting

Less frequent

• Dry mouth
• Dyspepsia

Hepato-Biliary Disorders

Frequent

• Elevated serum transaminases (ALT, AST) levels

Less frequent

• Hepatitis (including cholestatic, hepatocellular and mixed-pattern liver injury)

Skin and Subcutaneous Tissue Disorders

Frequent

• Rash

Less frequent

• Bruising
• Urticaria
• Pruritus
• Erythema nodosum
• Erythema multiforme

Musculoskeletal and Connective Tissue Disorders

Less frequent

• Arthralgia
• Myalgia including muscle cramps

Renal and Urinary Disorders

Less frequent

• Enuresis in children

General Disorders and Administration Site Conditions

Frequent

• Pyrexia

Less frequent

• Asthenia/fatigue
• Malaise

Levocetirizine Dihydrochloride

Nervous System Disorders

Frequent

• Headache
• Somnolence

Gastrointestinal Disorders

Frequent

• Dry mouth

Less frequent

• Abdominal pain

General Disorders and Administration Site Conditions

Frequent

• Fatigue

Less frequent

• Asthenia

Post-marketing:

Immune System Disorders

Frequency unknown

• Hypersensitivity including anaphylaxis

Metabolism and Nutrition Disorders

Frequency unknown

• Increased appetite

Psychiatric Disorders

Frequency unknown

• Aggression
• Agitation
• Hallucinations
• Depression
• Insomnia
• Suicidal ideation

Nervous System Disorders

Frequency unknown

• Convulsions
• Paraesthesia
• Dizziness
• Syncope
• Tremor
• Dysgeusia

Eye Disorders

Frequency unknown

• Visual disturbances
• Blurred vision

Ear and Labyrinth Disorders

Frequency unknown

• Vertigo

Cardiac Disorders

Frequency unknown

• Palpitations
• Tachycardia

Respiratory, Thoracic and Mediastinal Disorders

Frequency unknown

• Dyspnoea

Gastrointestinal Disorders

Frequency unknown

• Nausea
• Vomiting
• Diarrhoea

Hepato-Biliary Disorders

Frequency unknown

• Hepatitis

Skin and Subcutaneous Tissue Disorders

Frequency unknown

• Angioneurotic oedema
• Fixed drug eruption
• Pruritus
• Rash
• Urticaria

Musculoskeletal and Connective Tissue

Frequency unknown

• Myalgia
• Arthralgia

Renal and Urinary Disorders

Frequency unknown

• Dysuria
• Urinary retention

General Disorders and Administration Site Conditions

Frequency unknown

• Oedema

Investigations

Frequency unknown

• Increased body mass
• Abnormal liver function tests

Montelukast

• Inducers of CYP3A4, 2C8 and 2C9
• Phenytoin
• Phenobarbital
• Rifampicin
• Gemfibrozil

Levocetirizine Dihydrochloride

• Ritonavir

Other intercations

• Alcohol or CNS depressants (when taken with cetirizine or levocetirizine)

None routine

Montelukast

The cysteinyl leukotrienes (LTC4 , LTD4 , LTE4 ) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1 ) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In 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 5mg. Bronchodilation was observed within 2 hours of oral administration. 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.

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 (Ki = 3.2nmol/L). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3nmol/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. Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.