POSATEX

Indications

• Management of asthma in adults and adolescents not adequately controlled with inhaled corticosteroids and short-acting beta-2 agonists
• Allergic rhinitis
• Nasal polyps

Dosage

Children: For children aged 12-17 years, initially 400 micrograms daily in 1-2 divided doses, single dose to be inhaled in the evening, reduced to 200 micrograms once daily if control is maintained.

Adults: 1 inhalation once daily; dosage may be increased to 400 micrograms twice daily if necessary.

Mechanism of action

Mometasone furoate works by binding to glucocorticoid receptors, leading to the modulation of gene expression. This results in the inhibition of pro-inflammatory cytokines and chemokines, thereby reducing inflammation in the airways and nasal passages. It also inhibits the activation of inflammatory cells such as eosinophils and mast cells, contributing to its therapeutic effects.

Pharmacodynamics

As a corticosteroid, mometasone furoate exhibits significant anti-inflammatory effects, which are crucial in the management of asthma and allergic conditions. The drug reduces airway hyper-responsiveness and decreases mucus production, leading to improved airflow and decreased symptoms such as wheezing and shortness of breath. Its rapid onset of action is beneficial for acute symptom relief.

Pharmacokinetics

Mometasone furoate is well-absorbed when administered by inhalation or nasal spray. It undergoes extensive first-pass metabolism in the liver, resulting in low systemic bioavailability. The drug is primarily excreted via the feces, with a small percentage eliminated through the urine. The half-life of mometasone furoate is approximately 5.8 hours, allowing for once-daily dosing in many cases.

Adverse effects

• Candida infection
• Nasal ulceration
• Throat irritation
• Headache
• Cough

Interactions

• Corticosteroids
• Beta2 agonists

Precautions

• Use with caution in patients with active or quiescent tuberculosis infections
• Monitor for signs of infection
• Use in hepatic impairment requires caution

Pregnancy

Use only if potential benefit outweighs risk-limited information available.

Breast-feeding

Avoid-present in milk in animal studies.

Storage

Store below 30°C. Protect from light and moisture.

Formulations

• {'form': 'Inhalation powder', 'strength': '200 micrograms per dose', 'brand': 'Asmanex Twisthaler'}
• {'form': 'Aqueous nasal spray', 'strength': '50 micrograms per dose', 'brand': 'Flixonase'}

Indications

• Invasive aspergillosis
• Fusariosis
• Chromoblastomycosis and mycetoma
• Coccidioidomycosis

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing information.

Adults: Refer to BNF for specific dosing guidelines. Doses may vary based on the indication and patient condition.

Mechanism of action

Posaconazole exerts its antifungal activity by inhibiting the cytochrome P-450 dependent enzyme, sterol 14-alpha-demethylase, which is crucial for the synthesis of ergosterol, a vital component of the fungal cell membrane. By binding to the heme cofactor of this enzyme, posaconazole disrupts ergosterol synthesis, leading to an accumulation of toxic sterol precursors and resulting in impaired cell growth and eventual cell death.

Pharmacodynamics

Structurally related to itraconazole, posaconazole's modifications enhance its potency and spectrum of antifungal activity. It can exhibit fungicidal or fungistatic effects depending on the concentration and the fungal strain. Its effectiveness against a wide array of fungi makes it a valuable option in the management of invasive fungal infections.

Pharmacokinetics

Posaconazole is available in oral and intravenous formulations. Its bioavailability is significantly affected by food intake; therefore, it is recommended to avoid taking the oral solution with food. Posaconazole is highly lipophilic, leading to extensive tissue distribution. It is metabolized primarily in the liver via CYP3A4, and its elimination half-life is approximately 35 hours, allowing for once-daily dosing in many cases. Caution is advised in patients with hepatic impairment due to the risk of hepatotoxicity.

Contra-indications

• History of congestive heart failure
• Severe hepatic disorders

Adverse effects

• Headache
• Nausea
• Vomiting
• Diarrhoea
• Fatigue
• Anorexia
• Pulmonary oedema
• Skin reactions
• Altered taste
• Dysphonia
• Hearing loss
• Tremor
• Hypersensitivity reactions
• Angioedema
• Severe cutaneous adverse reactions (SCARs)
• Pancreatitis
• Photosensitivity
• Hypertriglyceridaemia
• Peripheral neuropathy
• Thrombocytopenia
• Leucopenia
• Erectile dysfunction
• Urinary incontinence
• Increased risk of infection

Interactions

• Primidone - decreases concentration of posaconazole
• Phenobarbital - decreases concentration of posaconazole
• Antiarrhythmics - increases exposure to posaconazole
• Disopyramide - increases exposure to posaconazole
• Dronedarone - increases exposure to posaconazole
• Second-generation antipsychotics - increases exposure to posaconazole
• Lurasidone - increases exposure to posaconazole
• Statins - increases exposure to posaconazole
• Atorvastatin - increases exposure to posaconazole
• Efavirenz - decreases exposure to posaconazole

Precautions

• Caution in patients with renal impairment
• Caution with intravenous use in mild hepatic impairment
• Monitor for signs of liver disorder

Pregnancy

Manufacturer advises caution during pregnancy; potential benefit must outweigh risk.

Breast-feeding

Small amounts present in milk; manufacturer advises to avoid breastfeeding during treatment.

Storage

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

Formulations

• Oral solution (50 mg/5 ml)
• Capsules (100 mg)

Indications

• Asthma
• Allergic rhinitis
• Skin conditions (e.g., eczema, dermatitis)

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing guidelines.

Adults: Refer to the specific BNF guidelines for adult dosing, which may vary based on the condition being treated.

Mechanism of action

Mometasone exerts its anti-inflammatory effects by crossing cell membranes and binding with high affinity to specific cytoplasmic glucocorticoid receptors. This interaction diminishes the release of leukocytic acid hydrolases, prevents macrophage accumulation at inflamed sites, interferes with leukocyte adhesion to capillary walls, reduces capillary membrane permeability, and inhibits the release of histamine and kinin. Additionally, mometasone inhibits the formation of scar tissue and acts through phospholipase A2 inhibitory proteins, known as lipocortins, which control the synthesis of potent inflammatory mediators like prostaglandins and leukotrienes.

Pharmacodynamics

Mometasone demonstrates medium potency as a corticosteroid, effectively reducing inflammation without significant systemic absorption due to extensive hepatic metabolism. Its local effects are favored over systemic effects, making it suitable for chronic conditions like asthma, where immediate symptom relief is not expected. The onset of action may take 1 to 2 weeks for maximum improvement in asthma symptoms following inhalation. Discontinuation of mometasone may allow for sustained asthma stability for several days.

Pharmacokinetics

Mometasone is extensively metabolized in the liver, resulting in a low systemic bioavailability. Its pharmacokinetic profile includes rapid absorption and distribution, with a half-life that supports once-daily dosing in many cases. The lack of active metabolites contributes to its safety profile, minimizing systemic effects while providing effective local action.

Interactions

• cobicistat+mometasone: Unknown (increases exposure)
• idelalisib+mometasone: Unknown (increases exposure)
• clarithromycin+mometasone: Unknown (increases exposure)

Pregnancy

Mometasone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Caution should be exercised when administering mometasone to nursing mothers, as it is not known whether it is excreted in human milk.

Storage

Store at room temperature, away from light and moisture. Do not freeze.

Formulations

• Mometasone furoate nasal spray
• Mometasone furoate inhalation aerosol
• Mometasone furoate cream
• Mometasone furoate ointment
• Mometasone furoate lotion

Indications

• Bacterial infections
• Skin and soft tissue infections
• Urinary tract infections
• Respiratory tract infections
• Gastrointestinal infections

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidance in the paediatric population.

Adults: Refer to the BNF for specific dosing recommendations based on the type and severity of infection.

Mechanism of action

Orbifloxacin functions by inhibiting bacterial DNA gyrase and topoisomerase IV. These enzymes are essential for the supercoiling and relaxation of DNA, which is necessary for DNA replication and transcription. By interfering with these processes, orbifloxacin prevents bacterial cell division and leads to cell death.

Pharmacodynamics

The pharmacodynamics of orbifloxacin involve its bactericidal action against a wide range of bacteria. The drug is concentration-dependent, meaning its efficacy is related to the peak concentration achieved in the body. Orbifloxacin demonstrates time-dependent killing, with prolonged exposure contributing to its antibacterial effect. Resistance can occur through mutations in the target enzymes or efflux pump mechanisms.

Pharmacokinetics

Orbifloxacin is well-absorbed following oral administration, with an extensive volume of distribution. It is metabolized primarily in the liver, and the elimination half-life is approximately 5 to 8 hours. The drug is excreted mainly in the urine, both as unchanged drug and metabolites. The pharmacokinetic properties may vary based on patient factors such as age, renal function, and concurrent medications.

Contra-indications

• Hypersensitivity to orbifloxacin or any of its components
• History of tendon disorders associated with fluoroquinolones
• Children and adolescents under 18 years of age

Adverse effects

• Nausea
• Diarrhea
• Headache
• Dizziness
• Rash
• Tendon rupture
• QT interval prolongation
• Photosensitivity reactions

Interactions

• Antacids containing aluminum, magnesium, or calcium may reduce the absorption of orbifloxacin
• Cation-containing products (such as iron and zinc supplements) may decrease the bioavailability of orbifloxacin
• CYP450 enzyme inhibitors or inducers may affect orbifloxacin metabolism

Precautions

• Use with caution in patients with a history of seizures or central nervous system disorders
• Monitor for signs of tendon pain or inflammation
• Consider alternative therapy in patients with renal impairment

Pregnancy

Orbifloxacin is not recommended during pregnancy due to potential risks to the fetus.

Breast-feeding

Orbifloxacin is excreted in breast milk; breastfeeding is not recommended during treatment.

Storage

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

Formulations

• Tablets
• Injectable solution

Mechanism of action

As a triazole antifungal agent, posaconazole exerts its antifungal activity through blockage of the cytochrome P-450 dependent enzyme, sterol 14α-demethylase, in fungi by binding to the heme cofactor located on the enzyme. This leads to the inhibition of the synthesis of ergosterol, a key component of the fungal cell membrane, and accumulation of methylated sterol precursors. This results in inhibition of fungal cell growth and ultimately, cell death. Posaconazole is a novel lipophilic antifungal triazole that inhibits cytochrome P450-dependent 14-alpha demethylase in the biosynthetic pathway of ergosterol. Inhibition of this enzyme leads to an accumulation of toxic 14-alpha methylsterols and a depletion of ergosterol, resulting in a perturbation of the function of the fungal cell membrane and blockage of cell growth and division. ... ... The primary mechanism of action of the drug was inhibition of the parasite's sterol C-14 alpha demethylase. The in vitro activity of the novel triazole antifungal agent posaconazole was assessed in 45 laboratories against approximately 19,000 clinically important strains of yeasts and molds. The activity of posaconazole was compared with those of itraconazole, fluconazole, voriconazole, and amphotericin B against subsets of the isolates. Strains were tested utilizing Clinical and Laboratory Standards Institute broth microdilution methods using RPMI 1640 medium (except for amphotericin B, which was frequently tested in antibiotic medium 3). MICs were determined at the recommended endpoints and time intervals. Against all fungi in the database (22,850 MICs), the MIC(50) and MIC(90) values for posaconazole were 0.063 microg/ml and 1 mug/ml, respectively. MIC(90) values against all yeasts (18,351 MICs) and molds (4,499 MICs) were both 1 mug/ml. In comparative studies against subsets of the isolates, posaconazole was more active than, or within 1 dilution of, the comparator drugs itraconazole, fluconazole, voriconazole, and amphotericin B against approximately 7,000 isolates of Candida and Cryptococcus spp. Against all molds (1,702 MICs, including 1,423 MICs for Aspergillus isolates), posaconazole was more active than or equal to the comparator drugs in almost every category. Posaconazole was active against isolates of Candida and Aspergillus spp. that exhibit resistance to fluconazole, voriconazole, and amphotericin B and was much more active than the other triazoles against zygomycetes. Posaconazole exhibited potent antifungal activity against a wide variety of clinically important fungal pathogens and was frequently more active than other azoles and amphotericin B.

Pharmacodynamics

Posaconazole is an antifungal agent structurally related to itraconazole. It is a drug derived from itraconzaole through the replacement of the chlorine substituents with flourine in the phenyl ring, as well as hydroxylation of the triazolone side chain. These modifications enhance the potency and spectrum of activity of the drug. Posaconazole can be either fungicial or fungistatic in action.

Mechanism of action

Unbound corticosteroids cross cell membranes and bind with high affinity to specific cytoplasmic receptors. Inflammation is decreased by diminishing the release of leukocytic acid hydrolases, prevention of macrophage accumulation at inflamed sites, interference with leukocyte adhesion to the capillary wall, reduction of capillary membrane permeability, reduction of complement components, inhibition of histamine and kinin release, and interference with the formation of scar tissue. The antiinflammatory actions of corticosteroids are thought to involve phospholipase A₂ inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes. Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone.

Pharmacodynamics

Mometasone is a medium-potency synthetic corticosteroid with antiinflammatory, antipruritic, and vasoconstrictive properties. Studies in asthmatic patients have demonstrated that mometasone provides a favorable ratio of topical to systemic activity due to its primary local effect along with the extensive hepatic metabolism and the lack of active metabolites. Though effective for the treatment of asthma, glucocorticoids do not affect asthma symptoms immediately. Maximum improvement in symptoms following inhaled administration of mometasone furoate may not be achieved for 1 to 2 weeks or longer after starting treatment. When glucocorticoids are discontinued, asthma stability may persist for several days or longer. Mometasone has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone. The clinical significance of these findings is unknown.