DailyMed Label: Bronchitol

DailyMed Label: Bronchitol

2024

DailyMed Prescription

Bronchitol

mannitol

Chiesi USA, Inc.

NDC: 10122-212

NDC: 10122-212

BRONCHITOL (mannitol) inhalation powder contains D-Mannitol (referred to throughout as mannitol) as the active ingredient. Mannitol is a hexahydric sugar alcohol, with the following chemical name hexane-1,2,3,4,5,6-hexol and chemical structure: Mannitol is a white or almost white crystalline powder or free-flowing granules with an empirical formula of C 6 H 14 O 6 and molecular weight of 182.2. Mannitol is freely soluble in water, and very slightly soluble in alcohol. Mannitol shows polymorphism. BRONCHITOL contains mannitol powder spray dried into particles of respirable size filled into clear, colorless hard gelatin capsules. There are no inactive ingredients in BRONCHITOL. The accompanying white plastic inhaler is comprised of a mouthpiece, blue piercing buttons, capsule chamber, and a removable cap. A blister pack consists of 10 capsules, each containing 40 mg mannitol. After a capsule is placed in the capsule chamber and pierced by firmly pressing and releasing the buttons on the side of the device, the powder within the capsule becomes exposed and ready for dispersion into the airstream generated by the patient upon inhalation through the mouthpiece. Under standardized in vitro test conditions, the inhaler delivers 32.2 mg of mannitol per inhalation when tested at a flow rate of 60 L/min for 2 seconds. The actual amount of drug delivered to the lungs will depend on patient factors, such as inspiratory flow profile. Bronchitol

BRONCHITOL is indicated as add-on maintenance therapy to improve pulmonary function in adult patients 18 years and older with Cystic Fibrosis.  Use BRONCHITOL only for adults who have passed the BRONCHITOL Tolerance Test [see Dosage and Administration ( 2.1 )]. BRONCHITOL is a sugar alcohol indicated as add-on maintenance therapy to improve pulmonary function in adult patients 18 years of age and older with cystic fibrosis. Use BRONCHITOL only in adults who have passed the BRONCHITOL Tolerance Test. ( 1 )

For Oral Inhalation Only. ( 2.1 ) The BRONCHITOL Tolerance Test is administered to identify patients who are appropriate for inhaled mannitol use. ( 2.1 ) Treatment of cystic fibrosis: 400 mg of BRONCHITOL (10 capsules) twice a day by oral inhalation, in the morning and evening, with the later dose taken 2-3 hours before bedtime. ( 2.2 ) Prior to prescribing BRONCHITOL for treatment of cystic fibrosis, the BRONCHITOL Tolerance Test (BTT) must be administered and performed under the supervision of a healthcare practitioner who is able to manage acute bronchospasm, to identify patients who are suitable candidates for BRONCHITOL maintenance therapy. Perform BTT to identify patients who experience bronchospasm, a decrease in FEV 1 , or a decrease in oxygen saturation with administration of BRONCHITOL. If a patient experiences any of these events during the BTT, the patient has failed the BTT. Do not prescribe BRONCHITOL. If a patient does not experience any of these events during BTT, the patient has passed the BTT and is a candidate for BRONCHITOL therapy. Ensure that rescue medication and resuscitation equipment are available for immediate use during the BTT. Do not perform the BTT if the patient is considered clinically unstable. See the BTT Healthcare Practitioner (HCP) Instructions for Use (IFU)  for complete instructions and to avoid medication errors associated with BTT dosing and procedures. Do not use BRONCHITOL add-on maintenance therapy in patients who fail the BTT [see Contraindications ( 4 )] . For patients who have passed the BTT, the recommended dosage of BRONCHITOL is 400 mg twice a day by oral inhalation (the contents of 10 capsules administered individually) via the inhaler  [see Dosage and Administration ( 2.1 )]. A short-acting bronchodilator should be administered by oral inhalation, 5-15 minutes before every dose of BRONCHITOL.  BRONCHITOL should be taken once in the morning and once in the evening, with the later dose taken at least 2-3 hours before bedtime. Instruct patients on safe hygiene practices (clean and dry hands thoroughly) and correct inhaler use, including loading of capsules and proper inhalation technique per the Patient Instructions for Use. The BRONCHITOL inhaler should be discarded and replaced after 7 days of use. If the inhaler does need to be washed, the patient should allow the inhaler to thoroughly air dry before next use.

Inhalation powder: 40 mg mannitol per capsule; clear, colorless hard gelatin capsule imprinted with “PXS 40 mg” Inhalation powder: 40 mg mannitol per capsule ( 3 )

BRONCHITOL is contraindicated in the following conditions: Hypersensitivity to mannitol or to any of the capsule components Failure to pass the BRONCHITOL Tolerance Test (BTT) Hypersensitivity to mannitol or to any of the capsule components. ( 4 ) Failure to pass the BRONCHITOL Tolerance Test. (4 )

BRONCHITOL can cause bronchospasm, which can be severe in susceptible patients. Because of the risk of bronchospasm, prior to prescribing BRONCHITOL, perform the BRONCHITOL tolerance test (BTT). The BTT must be administered under the supervision of a healthcare practitioner who can treat severe bronchospasm. Do not prescribe BRONCHITOL if the patient fails the BTT. Patients who pass the BTT may experience bronchospasm with maintenance use of BRONCHITOL. Advise patients to premedicate with an inhaled short-acting bronchodilator prior to each administration of BRONCHITOL. If bronchospasm occurs, immediately discontinue BRONCHITOL. Treat bronchospasm with an inhaled short-acting bronchodilator. ( 2.1 , 5.1 ) Hemoptysis can occur with BRONCHITOL use. Monitor patients with history of episodes of hemoptysis. If hemoptysis occurs, discontinue use of BRONCHITOL ( 5.2 ) BRONCHITOL Tolerance Test BRONCHITOL can cause bronchospasm, which can be severe in susceptible individuals. Because of the risk of bronchospasm, prior to prescribing BRONCHITOL, perform the BRONCHITOL Tolerance Test (BTT), to identify patients who are appropriate for maintenance treatment with BRONCHITOL. The BTT must be administered under the supervision of a healthcare practitioner who can treat severe bronchospasm. In clinical trials, 896 adult patients with cystic fibrosis underwent the BTT and 72 patients (8%) failed or did not complete the BTT. Do not prescribe BRONCHITOL if the patient fails the BTT.  Maintenance Therapy Bronchospasm may occur during inhalation of BRONCHITOL, even in patients who have passed the BTT. An inhaled short-acting bronchodilator must be administered 5-15 minutes before administration of each dose during maintenance therapy. In clinical studies, bronchospasm or bronchial hyperreactivity was reported in 4 of 414 adult patients (1.0%) receiving BRONCHITOL as maintenance therapy and in 2 of 347 adult patients (0.6%) receiving control (50 mg inhaled mannitol), even though these patients had passed the BTT. If bronchospasm occurs following dosing of BRONCHITOL, it should immediately be discontinued and treated with an inhaled short-acting bronchodilator or as medically appropriate. Hemoptysis may occur  with BRONCHITOL use. Hemoptysis was reported in 43 (10.4%) adult patients receiving BRONCHITOL and in 33 (9.5%) adult patients receiving control (50 mg inhaled mannitol) during clinical studies. In patients aged 6 years to 17 years, hemoptysis was reported in 12 of 154 (7.8%)  patients who received BRONCHITOL and in 2 of 105 (1.9%) patients who received control. BRONCHITOL has not been studied in patients with a history of episodes of significant hemoptysis (volume greater than 60 mL) in the previous 3 months. BRONCHITOL should be discontinued in the event of hemoptysis. BRONCHITOL is not indicated for use in children and adolescents.

The following clinically significant adverse reactions are described elsewhere in the labeling:

No formal drug interaction studies have been conducted with mannitol, the active ingredient in BRONCHITOL.

Risk Summary There are no adequate and well-controlled studies of BRONCHITOL in pregnant women. The available data on BRONCHITOL use in pregnant women are not sufficient to inform any drug-associated risks for major birth defects and miscarriage. Based on animal reproduction studies, no evidence of structural alterations was observed when mannitol was administered to pregnant rats and mice during organogenesis at doses up to approximately 20 and 10 times, respectively, the maximum recommended daily inhalation dose (MRDID) in humans [ see Data ]. There are risks to the mother associated with cystic fibrosis in pregnancy [see Clinial Considerations]. BRONCHITOL should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Cystic fibrosis may increase the risk for preterm delivery. Data Animal Data In animal reproduction studies, oral administration of mannitol to pregnant rats and mice during the period of organogenesis did not cause fetal structural alterations. The mannitol dose in rats and mice was approximately 20 and 10 times the maximum recommended human daily inhalation dose (MRDID) in humans, respectively, (on a mg/m 2 basis at maternal doses of 1600 mg/kg/day in both species). Risk Summary It is not known whether BRONCHITOL is excreted in human breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BRONCHITOL and any potential adverse effects on the breastfed child from BRONCHITOL or from the underlying maternal condition. BRONCHITOL is not indicated for use in children and adolescents. The safety and effectivenss of BRONCHITOL have not been established in pediatric patients for cystic fibrosis. Patients aged 6 years to 17 years were included in two 26-week, double-blind clinical trials (Trials 2 and 3). In these trials, 154 patients under 18 years of age received BRONCHITOL and 105 patients received control (50 mg inhaled mannitol). Hemoptysis was reported in 12 of 154 (7.8%)  patients who received BRONCHITOL and in 2 of 105 (1.9%) patients who received control. Clinical trials of BRONCHITOL did not include sufficient numbers of patients with cystic fibrosis who were 65 years of age and older to allow evaluation of safety and efficacy in this population. Clinical trials of BRONCHITOL did not include patients with hepatic or renal impairment. No specific dose recommendations for these patient populations are available. However, an increase in systemic exposure of mannitol can be expected in patients with renal impairment based on the kidney being its primary route of elimination.

BRONCHITOL (mannitol) inhalation powder:   40 mg of mannitol per capsule capsules are clear, colorless and imprinted in black with “PXS” on cap and “40 mg” on body supplied in cartons containing 10, 140 or 560 capsules in blister packs co-packaged with 1, 1, and 4 inhalers respectively in a carton BRONCHITOL is provided in 3 commercial presentations: Pack Quantities Inhalers Capsules NDC Number 4-week Treatment Pack (4 x 7-day treatment packs) 4 560 10122-212-56 7-day Treatment Pack 1 140 10122-212-14 Bronchitol Tolerance Test 1 10 10122-212-04 BRONCHITOL should be stored between 68°F-77°F (20°C-25°C) with excursions permitted between 59°F-86°F (15°C-30°C). [See USP Controlled Room Temperature]. Do not refrigerate. Do not freeze. The Training Kit (NDC 10122-216-01), containing empty gelatin capsules, should be stored between 68°F-77°F (20°C-25°C) with excursions permitted from 59°F-86°F (15°C-30°C). BRONCHITOL should only be used with the provided inhaler, which is a white plastic inhaler comprised of a mouthpiece, blue piercing buttons, capsule chamber, and a removable cap. All remaining unused (opened and unopened) blister packs and the inhalers should be properly discarded. Be sure to read the accompanying BRONCHITOL instructions completely before administration. If you have any questions, contact the supplier at 1-888-661-9260.

The precise mechanism of action of BRONCHITOL in improving pulmonary function in cystic fibrosis patients is unknown. The pharmacodynamics of mannitol are unknown. Absorption Following oral inhalation of 635 mg, the mean mannitol peak plasma concentration (Cmax) was 13.71 mcg/mL while the mean extent of systemic exposure (AUC) was 73.15 mcg•hr/mL. The mean time to peak plasma concentration (Tmax) after oral inhalation was 1.5 hour. Distribution Based on intravenous administration, the volume of distribution of mannitol was 34.3 L. Elimination Metabolism Mannitol is metabolized in a CYP-independent manner through the glycolytic pathway via dehydrogenation to fructose. The extent of metabolism of mannitol appears to be small. This is evident from a urinary excretion of about 87% of unchanged drug after an intravenous dose to healthy patients. Excretion Following oral inhalation, the elimination half-life of mannitol was 4.7 hours. The mean terminal elimination half-life for mannitol in plasma remained unchanged regardless of the route of administration (oral, inhalation, and intravenous). The urinary excretion rate versus time profile for mannitol was consistent for all routes of administration. The total clearance after intravenous administration was 5.1 L/hr while the renal clearance was 4.4 L/hr. Therefore, the clearance of mannitol was predominately via the kidney. Following inhalation of 635 mg of mannitol in 18 healthy patients, about 55% of the total dose was excreted in the urine as unchanged mannitol. Following oral or intravenous administration of a 500 mg dose, the corresponding values were 54% and 87% of the dose, respectively. Specific Populations Patients with Hepatic and Renal Impairment: Formal pharmacokinetic studies using BRONCHITOL have not been conducted in patients with hepatic or renal impairment. Since the drug is eliminated primarily via the  kidney, an increase in systemic exposure can be expected in renally impaired patients. Drug Interaction Studies No formal drug interaction studies have been conducted with BRONCHITOL.

Carcinogenesis In 2-year carcinogenicity studies in rats and mice mannitol did not show evidence of carcinogenicity at oral dietary concentrations up to 5% (or 7,500 mg/kg on a mg/kg basis). These doses were approximately 55 and 30 times the MRHDID, respectively, on a mg/m 2 basis. Mutagenesis Mannitol tested negative in the following assays: bacterial gene mutation assay, in vitro mouse lymphoma assay, in vitro chromosomal aberration assay in WI-38 human cells, in vivo chromosomal aberration assay in rat bone marrow, in vivo dominant lethal assay in rats, and in vivo mouse micronucleus assay. Impairment of Fertility The effect of inhaled mannitol on fertility has not been investigated.

The efficacy of BRONCHITOL for the treatment of cystic fibrosis (CF) was evaluated in 3 randomized, double-blind, controlled trials (Trials 1, 2, and 3). All three trials were 26-week, randomized, double-blind, controlled studies in patients with CF. Trial 1 (NCT02134353) evaluated patients 18 years of age or older with baseline FEV 1 >40% to <90% of predicted. Trial 2 (NCT00446680) evaluated patients 6 years of age or older with baseline FEV 1 > 30% to <90% of predicted. Trial 3 (NCT00630812) evaluated pateints 6 years of age or older with baseline FEV 1 > 40% to <90% of predicted. All three trials excluded CF patients with an episode of hemoptysis (>60 mL) in the 3 months prior to enrollment. The use of inhaled hypertonic saline was not permitted in any of the three trials, but continued use of their other standard of care CF therapies were allowed (e.g., bronchodilators, inhaled antibiotics, and dornase alfa). While CF patients aged 6 to 17 years were included in Trials 2 and 3, BRONCHITOL is not indicated for use in this age group [ see Indications (1), Warnings and Precautions (5), Adverse Reactions (6), Use in Specific Populations (8) ]. Patients were randomized to receive either BRONCHITOL 400 mg or control (50 mg inhaled mannitol) twice daily. Each dose of BRONCHITOL was preceded by use of an inhaled short-acting bronchodilator (albuterol or equivalent) taken 5 to 15 minutes prior to initiation of BRONCHITOL dosing. The primary efficacy endpoint in all three studies was improvement in lung function as determined by the mean change from baseline in pre-dose FEV 1 (mL) over 26 weeks of treatment and was analyzed using the pattern mixture model with multiple imputation. Trial 1 evaluated 423 adult patients with a mean age of 28 years and a mean FEV 1 63.9% predicted (range: 40.3% = minimum, 89.6% = maximum).  Treatment with BRONCHITOL resulted in a statistically significant improvement in FEV 1 . In Trial 1, the treatment difference between BRONCHITOL and control for the adjusted mean change in FEV 1 from baseline over 26 weeks was 51 mL (95% CI 6 to 97 mL) shown in Table 2.   Table 2: Change in FEV 1 (mL) from Baseline Over 26 weeks by Treatment Group (Trial 1, intention to treat population) Control (N=214) BRONCHITOL (N=209) Adjusted mean change from baseline 12 mL 63 mL Adjusted mean difference (95% CI), p-value 51 mL (6 to 97 mL), p=0.028 Trials 2 and 3 evaluated 295 and 305 patients, respectively. For the adjusted mean difference in the change from baseline in FEV 1 over 26 weeks in the intention-to-treat population in Trials 2 and 3, the treatment difference between BRONCHITOL and Control was 68 mL (95% CI: 24 to 113 mL) and 52 mL (95% CI: -3 to 107 mL), respectively.  Post-hoc descriptive analyses of the adult subgroups from Trials 2 and 3 were performed. The adult subgroup analyses in Trial 2 and 3 evaluated 209 and 157 adult patients, respectively. In Trial 2, there was an adjusted mean difference in the change from baseline in FEV 1 over 26 weeks in the intention-to-treat population of adults of 78 mL (95% CI: 21 to 135 mL). In Trial 3, there was an adjusted mean difference in the change from baseline in FEV 1 over 26 weeks in the intention-to-treat population of adults of 78 mL (95% CI: 2 to 153 mL).

Patient Information BRONCHITOL ® (BRONK-ih-tol) (mannitol) inhalation powder for oral inhalation use What is BRONCHITOL? BRONCHITOL is a prescription medicine that is used along with other therapies to improve lung function in people 18 years of age and older with cystic fibrosis (CF). BRONCHITOL is only for adults who have passed the BRONCHITOL Tolerance Test (BTT). Your first dose of BRONCHITOL is given during the BTT by your healthcare provider and tests if BRONCHITOL is right for you. Your healthcare provider will use equipment to monitor you and have medicine ready if you have bronchospasms during the test. If you have bronchospasms during your BTT, then you should not be prescribed BRONCHITOL. BRONCHITOL should not be used in children and adolescents. It is not known if BRONCHITOL is safe and effective in children under 18 years of age. Do not take BRONCHITOL if you: have had an allergic reaction to mannitol or any parts of the BRONCHITOL capsule. See the end of this Patient Information leaflet for a complete list of ingredients in BRONCHITOL. do not pass the BTT. Before you use BRONCHITOL, tell your healthcare provider about all your medical conditions, including if you: have ever coughed up blood or had blood in your mucus (sputum). are pregnant or planning on becoming pregnant. It is not known if BRONCHITOL will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while using BRONCHITOL. are breastfeeding or plan to breastfeed. It is not known if BRONCHITOL passes into your breast milk or if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby while using BRONCHITOL. Tell your healthcare provider about all medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of the medicines you take and show it to your healthcare provider and pharmacist when you get a new medicine. How should I use BRONCHITOL? See the step-by-step Patient Instructions for Use at the end of this Patient Information leaflet. BRONCHITOL is for oral inhalation only. Do not use BRONCHITOL until your healthcare provider has given you the BTT and approved you for treatment. Ask your healthcare provider or pharmacist if you have any questions. Use BRONCHITOL exactly as your healthcare provider tells you to use it. Do not swallow BRONCHITOL capsules. BRONCHITOL capsules should be used only with the provided inhaler device. An inhaled short-acting bronchodilator should be used 5 to15 minutes before every dose of BRONCHITOL. Use BRONCHITOL 2 times each day. Breathe in (inhale) through your mouth (oral inhalation) the capsule contents in 10 single BRONCHITOL capsules using the BRONCHITOL inhaler: 1 time in the morning 1 time at least 2 to 3 hours before bedtime If you use too much BRONCHITOL, call your healthcare provider or go to the nearest emergency room right away if you have any unusual symptoms, such as feelings that you cannot breathe, have wheezing, or cough a lot. Do not stop using BRONCHITOL or any other medicines unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider may change your medicines as needed. Call your healthcare provider or get emergency medical care right away if your breathing problems get worse while taking BRONCHITOL. What are the possible side effects of BRONCHITOL? BRONCHITOL may cause serious side effects, including: sudden breathing problems immediately after inhaling your medicine. Use your short-acting bronchodilator or rescue medicine if you have sudden breathing problems. Get emergency medical care right away if your bronchodilator or rescue medicine does not relieve the symptoms. coughing up of blood (hemoptysis). This is a serious but common side effect. Coughing up blood in your mucus can happen while you are using BRONCHITOL. Call your healthcare provider or get emergency medical care right away if you cough up a large amount of blood. The most common side effects of BRONCHITOL include: cough coughing up of blood pain or irritation in the back of your mouth and throat and discomfort when swallowing vomiting fever joint pain bacteria in your sputum Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of BRONCHITOL. You can ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Chiesi USA, Inc. at 1-888-661-9260. How should I store BRONCHITOL? Store BRONCHITOL at room temperature between 68°F to 77°F (20°C to 25°C). If your BRONCHITOL capsules are stored at temperatures more than 86°F (30°C), throw them away. Do not freeze BRONCHITOL. Do not refrigerate BRONCHITOL. Throw away the BRONCHITOL inhaler after 7 days and get a new one. Keep BRONCHITOL and all medicines out of the reach of children. General information about the safe and effective use of BRONCHITOL. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use BRONCHITOL for a condition for which it was not prescribed. Do not give BRONCHITOL to other people, even if they have the same symptoms that you have. It may harm them. This leaflet summarizes the most important information about BRONCHITOL. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about BRONCHITOL that is written for health professionals. What are the ingredients in BRONCHITOL? Active ingredient: mannitol Inactive ingredients: There are no inactive ingredients in BRONCHITOL. Capsules: gelatin and water. The imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide and black iron oxide E172. Manufactured by: Pharmaxis Ltd 20 Rodborough Road Frenchs Forest NSW 2086 AUSTRALIA Manufactured for: Chiesi USA, Inc. Cary, NC 27518 USA 1-888-661-9260 BRONCHITOL is registered in the US Patent and Trademark Office. All trademarks referenced herein are the property of their prospective owners. For more information about BRONCHITOL or how to use your inhaler, call 1-888-661-9260. This Patient Information has been approved by the U.S. Food and Drug Administration                                                                                      1/2024

Principal Display Panel - 40 mg 4 Week Carton Label Rx Only NDC 10122-212-56 Caution: Federal Law Prohibits Dispensing Without A Prescription Bronchitol ® (mannitol) inhalation powder 40 mg per capsule FOR ORAL INHALATION ONLY Do Not Swallow Bronchitol Capsules Complete entire package (56 Blister Packs) for 28 days treatment Contents: 56 Blister Cards: 560 capsules (40 mg each) 4 Bronchitol devices: For use with enclosed capsules only See package insert for complete dosage information For more information, call 1-888-661-9260. Principal Display Panel - 40 mg 4 Week Carton Label