Mannitol Inhalation Powder: Uses, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Overview

Mannitol inhalation powder represents a breakthrough in the treatment landscape for cystic fibrosis (CF), a genetic disease causing thick lung mucus and digestive issues. It was approved by the US Food and Drug Administration (FDA) on October 5, 2010. This inhalable therapy offers a novel approach to managing the symptoms of CF by facilitating airway clearance and improving lung function. Its approval has ushered in a new treatment era, providing patients with an additional option to supplement existing therapies and enhance their overall quality of life.

Drug Group

Mannitol inhalation powder belongs to the group of medications known as osmotic agents or mucolytics. Osmotic agents draw water into the lungs, helping to thin and loosen mucus, which can be more easily cleared from the airways. This mechanism of action aids in improving airway clearance and facilitating better lung function, particularly in individuals with conditions like cystic fibrosis, where thick mucus buildup in the lungs is a significant concern.

Indications

Mannitol inhalation powder serves as an additional maintenance therapy for enhancing pulmonary function in individuals diagnosed with cystic fibrosis aged 18 years and older. It should be administered exclusively to adults who have completed the tolerance test.

Dosage Forms and Available Strengths

It is available in capsules containing 40 mg (milligrams) of Mannitol inhalation powder.

For Patients

What Is Cystic Fibrosis?

Cystic fibrosis (CF) is a genetic condition that impacts both the respiratory and digestive systems. It causes thick, sticky mucus buildup, leading to breathing difficulties, lung infections, and digestive problems.

What Does Add-on Maintenance Therapy in Cystic Fibrosis Mean?

Add-on maintenance therapy in cystic fibrosis encompasses supplemental treatments administered alongside standard care protocols. These therapies aim to optimize symptom management and improve overall health outcomes for individuals with cystic fibrosis. Examples include airway clearance techniques, inhaled medications, nutritional supplements, anti-inflammatory drugs, and CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapies. By combining these treatments, healthcare providers strive to alleviate symptoms, reduce disease progression, and enhance the quality of life for cystic fibrosis patients.

How Does the Mannitol Inhalation Powder Work?

Mannitol inhalation powder works by inducing bronchoconstriction, which narrows the airways. The exact mechanism is still unknown. Mannitol's osmotic properties also help hydrate the airway surface, facilitating mucus clearance in conditions such as cystic fibrosis.

What Are the Clinical Uses of Mannitol Inhalation Powder?

• Mannitol inhalation powder is primarily used in clinical settings to diagnose and treat bronchial hyperreactivity (heightened bronchial sensitivity causing airway constriction) in patients with conditions such as cystic fibrosis.

• It is utilized as part of a bronchial challenge test to assess airway responsiveness and to help diagnose conditions like asthma (chronic airway inflammation).

• Additionally, Mannitol inhalation powder may be prescribed to manage certain respiratory conditions characterized by excessive mucus production and airway obstruction.

What Is the Dose of the Mannitol Inhalation Powder?

To treat cystic fibrosis, the recommended dose of Mannitol inhalation powder is 400 mg (10 capsules) twice daily. Each capsule contains 40 mg of Mannitol. Administer orally in the morning and evening, with the evening dose taken two to three hours before bedtime.

How Is Mannitol Inhalation Powder Administered?

Prior Testing and Evaluation:

• Before initiating Mannitol inhalation powder therapy for cystic fibrosis, healthcare practitioners must conduct the Mannitol inhalation powder tolerance test under supervision.

• The tolerance test determines suitability for Mannitol inhalation powder maintenance therapy by evaluating patient response to the medication.

• During the tolerance test, patients are monitored for adverse events such as bronchospasm (airway muscle constriction causing breathing difficulty), decreased FEV1 (forced expiratory volume), or reduced oxygen saturation.

• Failure to pass the tolerance test contraindicates Mannitol inhalation powder use. Adequate rescue medication and resuscitation equipment must be available during testing, and the tolerance test should not be performed on clinically unstable patients.

Dosage Recommendations:

• The recommended dosage of Mannitol inhalation powder for patients passing the tolerance test is 400 mg twice daily via oral inhalation using the provided inhaler.

• Administer a short-acting bronchodilator five to 15 minutes before each Mannitol inhalation powder dose.

• The medication should be taken once in the morning and once in the evening, with the evening dose at least two to three hours before bedtime.

• Patients should be thoroughly educated on hygiene practices and inhaler use, including capsule loading and inhalation techniques.

• Replace the Mannitol inhalation powder inhaler every seven days, and if cleaning is required, ensure thorough air-drying before reuse.

What Are the Side Effects of Mannitol Inhalation Powder?

Side effects that warrant prompt reporting to the doctor or healthcare professional:

• Allergic reactions (skin rash, itching, hives, swelling of the face, lips, or tongue).

• Coughing up blood.

• Symptoms of infection comprise fever, chills, sore throat, cough, or chest pain.

• Difficulty breathing.

• Wheezing, which manifests as loud or whistling sounds while breathing.

Side effects that typically do not require immediate medical attention but should still be brought to the attention of the doctor or healthcare professional if they persist or become bothersome:

• Presence of bacteria in the sputum (mucus).

• Joint pain.

• Mild irritation or discomfort in the mouth or throat.

• Nausea and vomiting.

Keep in mind that this list may not cover all possible side effects. Contact the doctor for advice regarding any experienced side effects.

What Are the Things to Inform the Doctor Before Taking Mannitol Inhalation Powder?

Things to inform the doctor before taking Mannitol inhalation powder are:

• Medical history, including asthma, coughing up blood, lung, heart, or kidney conditions.

• Allergies to Mannitol or any medications.

• Current medications, including any supplements or herbal medication.

• Pregnancy, breastfeeding, or plans to become pregnant.

• Recent surgeries or medical procedures.

• Smoking and alcohol use.

• If one experiences exercise-induced bronchoconstriction or has concerns about tolerating the exercise, discuss this with the doctor and the history of bronchodilator use.

Dietary Considerations:

Patients must maintain a balanced diet unless the doctor specifies anything.

Missed Dose:

If a dose is missed, take it as soon as remembered unless it is almost time for the next scheduled dose. In that case, skip the missed dose and continue with the regular dosing schedule. Avoid doubling the doses to catch up with missed doses.

Overdose:

If individuals are susceptible, they may encounter bronchoconstriction due to an overdose. If there is excessive coughing and bronchoconstriction, promptly administer an inhaled short-acting bronchodilator and any other required medical interventions.

Storage and Handling:

• The storage temperature is 68 to 77 degrees Fahrenheit or °F (20 to 25 degrees Celsius or °C), with excursions permitted between 59 to 86 °F (15 to 30 °C). Do not refrigerate or freeze.

• Only use the provided inhaler, a white plastic device with a mouthpiece and blue piercing buttons. Throw the inhaler away after seven days of use and buy a new one.

Disposal:

Discard all unused blister packs and inhalers properly. Unused or expired medications should be safely discarded to avoid accidental exposure to others, including children or pets. Flushing them down the toilet is not recommended. Instead, contact the local waste management, recycling department, or pharmacist to utilize a take-back program. If a take-back program is unavailable, follow FDA guidelines for safe drug disposal, accessible through their website.

For Doctors

Chemical Taxonomy

Composition:

• Active Ingredient: D-Mannitol (referred to as Mannitol).

• Chemical Name: Hexane-1,2,3,4,5,6-hexyl.

• Chemical Structure: C6H14O6.

• Physical Properties: White or almost white crystalline powder or free-flowing granules

• Solubility: Freely soluble in water, very slightly soluble in alcohol.

• Polymorphism: Exhibits polymorphism.

Formulation:

Mannitol inhalation powder contains Mannitol powder spray-dried into particles of respirable size and filled into colorless and hard gelatin capsules. There are no inactive ingredients in Mannitol inhalation powder.

Device Description:

• The accompanying white plastic inhaler consists of a mouthpiece, blue piercing buttons, a capsule chamber, and a removable cap.

• Each blister pack contains ten capsules, each containing 40 mg of Mannitol.

• Capsules are clear and imprinted with “PXS” on the cap and “40 mg” on the body.

• It is available in packs of 10, 140, or 560 capsules, along with one, one, or four inhalers, respectively.

• The inhaler delivers 32.2 mg of Mannitol per inhalation under standardized conditions (flow rate of 60 L/min or liter per minute for two seconds). Actual lung delivery depends on patient-specific factors.

Administration:

• Upon piercing a capsule with the inhaler, the powder within becomes exposed for dispersion into the airstream generated by patient inhalation.

Note: The amount of drug delivered to the lungs may vary depending on patient factors such as inspiratory flow profile.

Patient Information:

• Tolerance Test: A healthcare practitioner must conduct a tolerance test before starting Mannitol treatment. This test requires monitoring oxygen saturation (SpO2), performing spirometry (FEV1), and managing acute bronchospasm.

• Use of Inhaled Short-Acting Bronchodilator: Patients should always use an inhaled short-acting bronchodilator, like Albuterol, five to 15 minutes before each Mannitol inhalation powder dose.

• Bronchospasm: Patients should be aware that bronchospasm may occur with Mannitol inhalation. If bronchospasm occurs, they should discontinue Mannitol inhalation powder and contact the healthcare provider immediately.

• Hemoptysis: Hemoptysis (coughing up blood) may occur with Mannitol inhalation. If this happens, patients should stop using Mannitol inhalation powder and contact their healthcare provider promptly.

Warnings and Precautions

• Tolerance Test: Mannitol inhalation powder can potentially induce bronchospasm, particularly in susceptible individuals. Before prescribing Mannitol inhalation powder for maintenance therapy, a healthcare professional capable of managing severe bronchospasm should conduct the tolerance test. In clinical trials, eight percent of adult patients with cystic fibrosis failed or did not complete the tolerance test. Mannitol inhalation powder should not be prescribed if the patient fails the tolerance test.

• Maintenance Therapy: Bronchospasm may still occur during Mannitol inhalation, even in patients who have passed the tolerance test. Therefore, during maintenance therapy, an inhaled short-acting bronchodilator must be administered five to 15 minutes before each Mannitol inhalation powder dose. In clinical studies, bronchospasm or bronchial hyperreactivity was reported in a small percentage of patients receiving Mannitol inhalation powder as maintenance therapy, necessitating immediate discontinuation of Mannitol inhalation powder and treatment with a short-acting bronchodilator or appropriate medical intervention.

• Hemoptysis: As reported in clinical studies, Mannitol inhalation powder may lead to hemoptysis. In adult patients, hemoptysis occurred in 10.4 percent of those receiving Mannitol inhalation powder and 9.5 percent of those receiving the control. Among pediatric patients aged six to 17 years, hemoptysis was reported in 7.8 percent of those receiving Mannitol inhalation powder and in 1.9 percent of those receiving the control. Mannitol inhalation powder should be discontinued if hemoptysis occurs. Additionally, Mannitol inhalation powder has yet to be studied in patients with a recent history of significant hemoptysis (volume greater than 60 mL or milliliter) within the previous three months. It is important to note that Mannitol inhalation powder is not indicated for use in children and adolescents.

What Are the Pharmacological Actions of Mannitol Inhalation Powder?

Pharmacodynamics: The pharmacodynamics of Mannitol are not known.

Mechanism of Action: The exact way Mannitol enhances lung function in cystic fibrosis patients remains unclear.

Pharmacokinetics

• Absorption: After inhaling 635 mg, Mannitol reaches peak concentration in plasma in 1.5 hours with a Cmax of 13.71 mcg/mL or micrograms per milliliter and AUC (area under the curve) of 73.15 mcg x hr/mL (hours per milliliter).

• Distribution: Given intravenously, Mannitol has a volume of distribution of 34.3 L or liter.

• Elimination: Mannitol is metabolized to fructose through a glycolytic pathway, with about 87 percent excreted unchanged in the urine. Its half-life is 4.7 hours.

• Excretion: Mannitol is mainly cleared by the kidneys. About 55 percent of inhaled Mannitol is excreted unchanged in the urine, similar to oral or intravenous administration.

• Specific Populations: No formal studies have been done on hepatic or renal impairment with Mannitol inhalation powder. Renal impairment may increase systemic exposure.

Non-Clinical Toxicity

• Carcinogenesis: In studies on animals (rats and mice), Mannitol at dietary concentrations up to five percent did not cause cancer. These doses were much higher than human doses.

• Mutagenesis: Mannitol showed no mutagenic effects in various tests, including bacterial gene mutation and chromosomal aberration assays.

• Impairment of Fertility: The impact of inhaled Mannitol on fertility has not been studied.

What Are the Contraindications of Mannitol Inhalation Powder?

Mannitol inhalation powder should not be used by individuals with the following conditions:

• Hypersensitivity to Mannitol or any of the capsule components

• Failure to pass the tolerance test.

What Are the Drug Interactions of Mannitol Inhalation Powder?

Formal studies on drug interactions involving Mannitol, the active ingredient in Mannitol inhalation powder, have not been conducted.

Clinical Studies

The safety of Mannitol inhalation powder was evaluated in three 26-week trials involving 761 adult cystic fibrosis (CF) patients. Notably, Mannitol inhalation powder is not indicated for use in patients aged six to 17. Among adult patients treated with Mannitol, 12.3 percent discontinued due to adverse reactions, and serious adverse reactions occurred in 18.8 percent.

The most common adverse reactions (occurring in more than three percent of patients and more frequently than in the control group) included cough, hemoptysis, oropharyngeal pain, vomiting, bacteria sputum identified, pyrexia (fever), and arthralgia (joint pain).

32 percent of adults receiving Mannitol inhalation powder reported CF exacerbations, with serious exacerbations occurring in 13 percent of patients. Subgroup analysis showed a higher incidence of serious CF exacerbations in the U.S. adult subgroup compared to the non-U.S. subgroup.

Use in Specific Populations

• Pregnancy: Limited data are available on Mannitol use during pregnancy. Animal studies showed no evidence of harm, but risks to pregnant women with cystic fibrosis exist. Cystic fibrosis may increase the risk of preterm delivery. Animal research indicated no fetal harm at doses up to 20 times the recommended human dosage.

• Lactation: It is unknown if Mannitol passes into breast milk. Consider the benefits of breastfeeding versus the potential risks to the child.

• Pediatric Use: Mannitol is not approved for use in children and adolescents. Limited data exists for patients aged six to 17 years.

• Geriatric Use: The safety and efficacy of Mannitol have not been established in patients aged 65 and older.

• Hepatic and Renal Impairment: There are no particular dosage guidelines for individuals with liver or kidney impairment. Increased exposure to Mannitol may occur in patients with renal impairment.