FEXMONT-180

Indications

• Prophylaxis of asthma
• Management of seasonal allergic rhinitis
• Symptomatic relief of seasonal allergic rhinitis in patients with asthma

Dosage

Adults: 10 mg once daily, taken in the evening.

Mechanism of action

Montelukast binds with high affinity and selectivity to the cysteinyl leukotriene receptor type-1 (CysLT1). This action inhibits the physiological effects of cysteinyl leukotrienes (like LTC4, LTD4, and LTE4), which include bronchoconstriction, mucus secretion, and eosinophil recruitment. By blocking these receptors, montelukast effectively reduces the bronchoconstriction and other symptoms associated with asthma and allergic rhinitis.

Pharmacodynamics

Montelukast exhibits significant affinity for the CysLT1 receptor, preferentially blocking the effects of leukotriene LTD4 at doses as low as 5 mg. Clinical studies have shown that montelukast can inhibit both early and late phase bronchoconstriction due to antigen exposure by approximately 75% and 57%, respectively. The onset of bronchodilation can occur within 2 hours of oral administration, and its effects can be additive when used with beta agonists. However, doses above 10 mg daily do not provide additional clinical benefits in adults.

Pharmacokinetics

Montelukast is well absorbed following oral administration, with peak plasma concentrations occurring within 3 to 4 hours. It is extensively metabolized in the liver, primarily via cytochrome P450 enzymes. The half-life of montelukast is approximately 2.7 to 5.5 hours, allowing for once-daily dosing. It is eliminated via bile, with a small percentage excreted unchanged in urine. Special populations, such as those with hepatic impairment, may require caution, although specific dosage adjustments have not been established.

Adverse effects

• Headache
• Abdominal pain
• Dizziness
• Fatigue
• Nausea
• Rash
• Changes in mood or behavior
• Sleep disturbances

Interactions

• Opicapone: Severe (increases exposure)
• Selpercatinib: Severe (increases exposure)
• Deferasirox: Unknown (increases exposure)
• Leflunomide: Unknown (increases exposure)
• Mifepristone: Unknown (increases exposure)
• Mitotane: Unknown (decreases exposure)
• Teriflunomide: Unknown (increases exposure)
• Rifampicin: Unknown (decreases exposure)

Precautions

• Caution in patients with hepatic impairment
• Use with caution in patients with renal impairment
• Consider risk of mood changes and behavioral side effects

Pregnancy

Manufacturer advises to avoid use during pregnancy due to limited information available.

Breast-feeding

Manufacturer advises to avoid during breastfeeding, especially in the first few days after birth due to potential transfer of antibodies to the infant.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets: 10 mg (adults and children over 15 years)
• Chewable tablets: 5 mg (children 6–14 years)
• Granules: 4 mg (children 6 months–5 years)

Indications

• Symptomatic relief of seasonal allergic rhinitis
• Symptomatic relief of chronic idiopathic urticaria

Dosage

Children: For children aged 6 to 11 years, the recommended dose is 30 mg twice daily. For those aged 12 to 17 years, the dose is 120 mg once daily for allergic rhinitis and 180 mg once daily for chronic idiopathic urticaria.

Adults: For adults, the recommended dose is 120 mg once daily or 180 mg once daily for chronic idiopathic urticaria.

Mechanism of action

Fexofenadine works by selectively antagonizing peripheral H1 receptors, inhibiting the effects of histamine, a substance in the body that causes allergic symptoms. By blocking these receptors, fexofenadine prevents the typical allergic responses such as itching, sneezing, and runny nose.

Pharmacodynamics

Fexofenadine exhibits a high affinity for H1 receptors, but it does not penetrate the blood-brain barrier effectively, which minimizes its sedative effects compared to first-generation antihistamines. The drug's action begins within an hour of administration and can last for up to 24 hours, providing sustained relief from allergic symptoms.

Pharmacokinetics

Fexofenadine is absorbed rapidly from the gastrointestinal tract, with peak plasma concentrations occurring approximately 2 to 3 hours after oral administration. It has a bioavailability of around 33%, and food can affect its absorption. The drug is primarily excreted unchanged in the feces and urine, with a half-life ranging from 14 to 15 hours. In patients with renal impairment, dosing adjustments may be required, particularly in those with an estimated glomerular filtration rate (eGFR) less than 10 mL/min.

Contra-indications

• Acute porphyrias

Adverse effects

• Asthenia
• Constipation
• Drowsiness
• Dry mouth
• Abdominal pain
• Aggression
• Agitation
• Angioedema
• Increased appetite
• Arthralgia
• Depression
• Dizziness
• Dyspnoea
• Hallucinations
• Hepatitis
• Myalgia
• Nausea
• Oedema
• Palpitations
• Paraesthesia
• Seizures
• Skin reactions
• Sleep disorders
• Suicidal ideation
• Syncope
• Tachycardia
• Taste altered
• Tremor
• Urinary disorders
• Vertigo
• Vision disorders
• Vomiting
• Weight increased

Interactions

• Non-sedating antihistamines such as levocetirizine may enhance effects

Precautions

• Use with caution in patients with renal impairment
• Patients should be advised that drowsiness can occur and may affect the performance of skilled tasks such as cycling or driving

Pregnancy

Most manufacturers of antihistamines advise avoiding their use during pregnancy; however, there is no evidence of teratogenicity.

Breast-feeding

Most antihistamines are present in breast milk in varying amounts; although not known to be harmful, most manufacturers advise avoiding their use in mothers who are breastfeeding.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Oral suspension
• Oral solution
• Tablets (120 mg, 180 mg)

Indications

• Allergic rhinitis (hay fever)
• Chronic urticaria (hives)

Dosage

Children: For children aged 6-12 years, the usual dosage is 30 mg twice daily. For children aged 12 years and older, the adult dosage applies.

Adults: The typical adult dosage for fexofenadine is 120 mg once daily or 60 mg twice daily.

Mechanism of action

Fexofenadine functions as an inverse agonist at the H1 histamine receptor, stabilizing its inactive form and preventing activation. This inhibition reduces the release of pro-inflammatory cytokines from mast cells and basophils, thereby alleviating allergic symptoms such as itching, runny nose, and watery eyes. It does not cross the blood-brain barrier, minimizing central nervous system effects.

Pharmacodynamics

Fexofenadine effectively antagonizes the actions of histamine, leading to a decrease in the typical symptoms associated with allergic reactions. Its long duration of action (approximately 24 hours) permits once or twice daily dosing. The onset of action occurs within 1-3 hours after administration. Notably, fexofenadine's absorption can be impaired by fruit juice, which should be avoided during its use.

Pharmacokinetics

Fexofenadine is rapidly absorbed after oral administration, with peak plasma concentrations reached within 2-3 hours. It has a bioavailability of approximately 40% when taken with fruit juice, and its elimination half-life is about 14.4 hours. The drug is primarily excreted unchanged in the feces and urine, indicating minimal hepatic metabolism.

Interactions

• berotralstat+fexofenadine: Moderate (increases concentration)
• eliglustat+fexofenadine: Moderate (increases exposure)
• roxadustat+fexofenadine: Moderate (increases exposure)
• sotorasib+fexofenadine: Moderate (increases exposure)
• tucatinib+fexofenadine: Moderate (increases exposure)
• vemurafenib+fexofenadine: Moderate (increases exposure)
• apalutamide+fexofenadine: Unknown (decreases exposure)
• darolutamide+fexofenadine: Unknown (increases concentration)
• dronedarone+fexofenadine: Unknown (increases exposure)
• bulevirtide+fexofenadine: Unknown (increases exposure)

Pregnancy

Fexofenadine is classified as a pregnancy category C drug. Animal studies have shown an adverse effect, but there are no well-controlled studies in pregnant women. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Fexofenadine is excreted in breast milk in small amounts. Caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Mechanism of action

The H₁ histamine receptor is responsible for mediating hypersensitivity and allergic reactions. Exposure to an allergen results in degranulation of mast cells and basophils, which then release histamine and other inflammatory mediators. Histamine binds to, and activates, H₁ receptors, which results in the further release of pro-inflammatory cytokines, such as interleukins, from basophils and mast cells. These downstream effects of histamine binding are responsible for a wide variety of allergic symptoms, such as pruritus, rhinorrhea, and watery eyes. Fexofenadine is considered an “inverse agonist” of the H₁ receptor because it binds to and stabilizes the inactive form of the receptor, preventing its activation and subsequent downstream effects. It has a potent and selective affinity for H₁ receptors, and there is no evidence that it carries antidopaminergic, antiserotonergic, anticholinergic, sedative, or adrenergic blocking activity. Fexofenadine does not cross the blood-brain barrier and thus is unlikely to cause significant CNS effects. Fexofenadine is a specific, selective, histamine H1-receptor antagonist. ... Fexofenadine has been shown to inhibit histamine release from peritoneal mast cells in rats. Unlike terfenadine, fexofenadine does not block the potassium channel involved in repolarization of cardiac cells (i.e., blockade of the delayed rectifier potassium current IK). As a result, fexofenadine lacks the cardiotoxic potential of terfenadine. Fexofenadine also does not possess appreciable anticholinergic, antidopaminergic, or alpha- or beta-adrenergic blocking effects at usual antihistaminic doses in pharmacologic studies. It has been suggested that the increased safety profile of fexofenadine compared with the parent drug results from the lack of fexofenadine-induced cardiotoxicity in addition to only minimal metabolism of fexofenadine in the liver by the cytochrome P-450 microsomal enzyme system. Evidence from animal models using fexofenadine have suggested that the apparent lack of cardiotoxic effects of the drug may have resulted at least in part from lack of blockade of the potassium channel involved in repolarization of cardiac cells (ie, blockade of the delayed rectifier potassium current IK). Prolongations in the QTc interval were not reported in dogs receiving oral fexofenadine hydrochloride dosages of 10 mg/kg daily for 5 days or in rabbits receiving an IV fexofenadine hydrochloride dose of 10 mg/kg (resulting in plasma fexofenadine concentrations 28 or 63 times the therapeutic plasma concentrations in humans, respectively, based on a dosage of 60 mg of fexofenadine hydrochloride given twice daily). In addition, no effect was observed on calcium-channel current, delayed potassium-channel current, or action potential duration in guinea pig myocytes, sodium current in rat neonatal myocytes, or on the delayed rectifier potassium channel cloned from human heart at fexofenadine concentrations up to 1.0 X10-5 M (approximately equivalent to 32 times the therapeutic plasma concentrations in humans, based on a dosage of 60 mg of fexofenadine hydrochloride given twice daily). In vitro, terfenadine exhibits a similar affinity for histamine H1-receptors from brain and peripheral tissues; however, in vivo, unlike first generation antihistamines, terfenadine and fexofenadine do not readily cross the blood-brain barrier and therefore do not appear to interact appreciably with H1-receptors within the CNS at usual doses.

Pharmacodynamics

Fexofenadine relieves allergy symptoms by antagonizing the actions of histamine, an endogenous compound predominantly responsible for allergic symptomatology. The relatively long duration of action of fexofenadine (approximately 24 hours) allows for once or twice daily dosing, and its rapid absorption allows for an onset of action within 1-3 hours. Fexofenadine should not be taken with fruit juice, as this may impair its absorption.

Mechanism of action

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. Montelukast inhibits bronchoconstriction due to antigen challenge. Montelukast is a selective leukotriene receptor antagonist of the cysteinyl leukotriene CysLT1 receptor. The cysteinyl leukotrienes (LTC4 , LTD4, LTE4) are products of arachidonic acid metabolism that are released from various cells, including mast cells and eosinophils. They bind to cysteinyl leukotriene receptors (CysLT) found in the human airway. Binding of cysteinyl leukotrienes to leukotriene receptors has been correlated with the pathophysiology of asthma, including airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process, factors that contribute to the signs and symptoms of asthma. Montelukast binding to the CysLT1, receptor is high-affinity and selective, preferring the CysLT1 receptor to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or beta-adrenergic receptor. Montelukcast inhibits physiologic actions of LTD4 at the CysLT1 receptors, without any agonist activity. Because of the role of leukotrienes in the pathogenesis of asthma, modification of leukotriene activity may be used to reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control. Inhibition of leukotriene-mediated effects may be achieved by drugs that interrupt 5-lipoxygenase activity and prevent formation of leukotrienes (e.g., zileuton) or by antagonism of leukotriene activity at specific receptor sites in the airway (e.g., montelukast, zafirlukast). The antagonist activity of montelukast is selective, competitive, and reversible. Montelukast competitively inhibits the action of LTD4 at a subgroup of CysLT receptors (CysLT1) in airway smooth muscle. In vitro, montelukast possesses affinity for the CysLT1 receptor that is similar to that of LTD4. In in vitro studies, montelukast antagonized contraction of isolated animal smooth muscle produced by LTD4, but did not antagonize contraction produced by LTC4. In animal studies, montelukast antagonized contraction of airway smooth muscle produced by LTD4 or antigen.

Pharmacodynamics

Montelukast is a leukotriene receptor antagonist that demonstrates a marked affinity and selectivity to the cysteinyl leukotriene receptor type-1 in preference to many other crucial airway receptors like the prostanoid, cholinergic, or beta-adrenergic receptors. As a consequence, the agent can elicit substantial blockage of LTD4 leukotriene-mediated bronchoconstriction with doses as low as 5 mg. Moreover, a placebo-controlled, crossover study (n=12) demonstrated that montelukast is capable of inhibiting early and late phase bronchoconstriction caused by antigen challenge by 75% and 57% respectively. In particular, it has been documented that montelukast can cause bronchodilation as soon as within 2 hours of oral administration. This action can also be additive to the bronchodilation caused by the concomitant use of a beta agonist. Nevertheless, clinical investigations performed with adults 15 years of age and older revealed that no additional clinical benefit is obtained when doses of montelukast greater than 10 mg a day are used. Additionally, in clinical trials with adults and pediatric asthmatic patients aged 6 to 14 years, it was also determined that montelukast can reduce mean peripheral blood eosinophils by about 13% to 15% from baseline in comparison to placebo during double-blind treatment periods. At the same time, in patients aged 15 years and older who were experiencing seasonal allergic rhinitis, the use of montelukast caused a median reduction of 13% in peripheral blood eosinophil counts when compared to placebo as well.