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TOBI PODHALER (tobramycin) capsule 妥布霉素吸入干粉

2014-08-06 22:01:47 作者：新特药房来源：互联网浏览次数：361 文字大小：【大】【中】【小】

简介： TOBI PODHALER (tobramycin) capsule[Novartis Pharmaceuticals Corporation]美国食品药品管理局(FDA)和诺华公司宣布，TOBI Podhaler(妥布霉素吸入干粉)已获准用于发生肺部铜绿假单胞菌(Pa)感染的囊性纤 ...

关键字：妥布霉素吸入粉tobramycin inhalation powder药品商标名TOBI Podhaler 治疗囊性纤维化病人铜绿假单胞菌引起的慢性肺部感染

TOBI PODHALER (tobramycin) capsule
[Novartis Pharmaceuticals Corporation]
美国食品药品管理局(FDA)和诺华公司宣布，TOBI Podhaler(妥布霉素吸入干粉)已获准用于发生肺部铜绿假单胞菌(Pa)感染的囊性纤维化(CF)患者。TOBI Podhaler可通过袖珍干粉吸入器将抗生素妥布霉素送入肺内，因而比关联产品TOBI使用更便利，后者通过雾化器给药。
据诺华公司介绍，Pa感染是CF患者肺功能丧失的首要病因。尚不清楚对于年龄＜6岁的患者、肺功能超出特定范围的患者，以及肺部存在洋葱伯克霍尔德菌，TOBI Podhaler是否也安全、有效。
TOBI Podhaler在1个纳入674例年龄≥6岁、合并肺部Pa感染的CF患者的3期临床项目中得到了评估。其中425例患者接受了至少1剂TOBI Podhaler。2项试验对比评估了TOBI Podhaler与安慰剂的疗效，第3项试验则对比评估了TOBI Podhaler与安慰剂的安全性。各项研究均采用获准的剂量112 mg、2次/d(每剂包含4粒28 mg胶囊)，每个疗程包含28天治疗期和随后28 天停药期。疗效评估结果显示，TOBI Podhaler可比安慰剂更有效地改善肺功能。
在临床研究中接受TOBI Podhaler治疗的患者的常见不良反应包括咳嗽、咳血、肺紊乱(肺或CF急性加重)、气促、发热、咽痛、发声困难和头痛。
TOBI Podhaler不需要采用冰箱保存，而且与雾化Pa治疗不同的是，不需要动力源用于驱动给药装置。用于TOBI给药的雾化器必须每天用沸水消毒10分钟，而一次性Podhaler装置仅需在每次使用后用干布擦拭干净、并且每周更换即可。
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TOBI Podhaler safely and effectively. See full prescribing information for TOBI Podhaler.
TOBI® PODHALER™ (tobramycin inhalation powder), for oral inhalation use
Initial U.S. Approval: 1975
INDICATIONS AND USAGE
TOBI Podhaler is an antibacterial aminoglycoside indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa.
Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV1) <25% or >80%, or patients colonized with Burkholderia cepacia (1).
DOSAGE AND ADMINISTRATION
DO NOT swallow TOBI Podhaler capsules (2)
For use with the Podhaler device only (2)
For oral inhalation only (2)
The recommended dosage is the inhalation of four 28 mg capsules twice-daily for 28 days (2)
DOSAGE FORMS AND STRENGTHS
Inhalation powder: 28 mg in a capsule (3)
CONTRAINDICATIONS
Known hypersensitivity to any aminoglycoside (4)
WARNINGS AND PRECAUTIONS
Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction (5.1, 5.2, 5.3)
Ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported in clinical trials (5.1)
Aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function (5.3)
Bronchospasm can occur with inhalation of TOBI Podhaler (5.4)
Audiograms, serum concentrations, and renal function should be monitored as appropriate (5.5)
Fetal harm can occur when aminoglycosides are administered to a pregnant woman. Apprise women of the potential hazard to the fetus (5.6)
ADVERSE REACTIONS
The most common adverse reactions (≥10 % of TOBI Podhaler and TOBI patients in primary safety population) are cough, lung disorder, productive cough, dyspnea, pyrexia, oropharyngeal pain, dysphonia, hemoptysis, and headache (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Concurrent and/or sequential use of TOBI Podhaler with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided (7)
USE IN SPECIFIC POPULATIONS
Aminoglycosides can cause fetal harm when administered to a pregnant woman (8.1)
Nursing mother: discontinue drug or nursing, taking into consideration the importance of the drug to the mother (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 03/2013

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FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

TOBI Podhaler is indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa.

Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV1) <25% or >80% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

DO NOT SWALLOW TOBI PODHALER CAPSULES

FOR USE WITH THE PODHALER DEVICE ONLY

FOR ORAL INHALATION ONLY

TOBI Podhaler capsules must not be swallowed as the intended effects in the lungs will not be obtained. The contents of TOBI Podhaler capsules are only for oral inhalation and should only be used with the Podhaler device.

The recommended dosage of TOBI Podhaler for both adults and pediatric patients 6 years of age and older is the inhalation of the contents of four 28 mg TOBI Podhaler capsules twice-daily for 28 days using the Podhaler device.

Refer to the Instructions For Use (IFU) for full administration information.

Dosage is not adjusted by weight. Each dose of four capsules should be taken as close to 12 hours apart as possible; each dose should not be taken less than 6 hours apart.

TOBI Podhaler is administered twice-daily in alternating periods of 28 days. After 28 days of therapy, patients should stop TOBI Podhaler therapy for the next 28 days, and then resume therapy for the next 28 day on and 28 day off cycle.

TOBI Podhaler capsules should always be stored in the blister and each capsule should only be removed IMMEDIATELY BEFORE USE.

For patients taking several different inhaled medications and/or performing chest physiotherapy, the order of therapies should follow the physician’s recommendation. It is recommended that TOBI Podhaler is taken last.

3 DOSAGE FORMS AND STRENGTHS

Inhalation powder:

28 mg: clear, colorless hypromellose capsule with “NVR AVCI” in blue radial imprint on one part of the capsule and the Novartis logo “” in blue radial imprint on the other part of the capsule.

4 CONTRAINDICATIONS

TOBI Podhaler is contraindicated in patients with a known hypersensitivity to any aminoglycoside.

5 WARNINGS AND PRECAUTIONS

5.1 Ototoxicity

Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected auditory or vestibular dysfunction.

Ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported by patients in the TOBI Podhaler clinical studies [see Adverse Reactions (6.1)]. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution. Ototoxicity, manifested as both auditory (hearing loss) and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness.

5.2 Nephrotoxicity

Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected renal dysfunction.

Nephrotoxicity was not observed during TOBI Podhaler clinical studies but has been associated with aminoglycosides as a class.

5.3 Neuromuscular Disorders

Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected neuromuscular dysfunction.

TOBI Podhaler should be used cautiously in patients with neuromuscular disorders, such as myasthenia gravis or Parkinson’s disease, since aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function.

5.4 Bronchospasm

Bronchospasm can occur with inhalation of TOBI Podhaler [see Adverse Reactions (6.1)]. Bronchospasm should be treated as medically appropriate.

5.5 Laboratory Tests

Audiograms

Physicians should consider an audiogram at baseline, particularly for patients at increased risk of auditory dysfunction.

If a patient reports tinnitus or hearing loss during TOBI Podhaler therapy, the physician should refer that patient for audiological assessment.

Serum Concentrations

In patients treated with TOBI Podhaler, serum tobramycin concentrations are approximately 1 to 2 µg/mL one hour after dose administration and do not require routine monitoring. Serum concentrations of tobramycin in patients with known or suspected auditory or renal dysfunction or patients treated with a concomitant parenteral aminoglycoside (or other nephrotoxic or ototoxic medications) should be monitored at the discretion of the treating physician. If ototoxicity or nephrotoxicity occurs in a patient receiving TOBI Podhaler, tobramycin therapy should be discontinued until serum concentrations fall below 2 µg/mL.

The serum concentration of tobramycin should only be monitored through venipuncture and not finger prick blood sampling. Contamination of the skin of the fingers with tobramycin may lead to falsely increased measurements of serum levels of the drug. This contamination cannot be completely avoided by hand washing before testing.

Renal Function

Laboratory tests of urine and renal function should be conducted at the discretion of the treating physician.

5.6 Use in Pregnancy

Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta, and streptomycin has been associated with several reports of total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. Patients who use TOBI Podhaler during pregnancy, or become pregnant while taking TOBI Podhaler should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

TOBI Podhaler has been eva luated for safety in 425 cystic fibrosis patients exposed to at least one dose of TOBI Podhaler, including 273 patients who were exposed across three cycles (6 months) of treatment. Each cycle consisted of 28 days on-treatment (with 112 mg administered twice daily) and 28 days off-treatment. Patients with serum creatinine ≥ 2 mg/dL and blood urea nitrogen (BUN) ≥ 40 mg/dL were excluded from clinical studies. There were 218 males and 207 females in this population, and reflecting the cystic fibrosis population in the U.S., the vast majority of patients were Caucasian. There were 221 patients ≥ 20 years old, 121 patients ≥ 13 to < 20 years old, and 83 patients ≥ 6 to < 13 years old. There were 239 patients with screening FEV1 % predicted ≥ 50%, 156 patients with screening FEV1 % predicted < 50%, and 30 patients with missing FEV1 % predicted.

The primary safety population reflects patients from Study 1, an open-label study comparing TOBI Podhaler with TOBI (tobramycin inhalation solution, USP) over three cycles of 4 weeks on treatment followed by 4 weeks off treatment. Randomization, in a planned 3:2 ratio, resulted in 308 patients treated with TOBI Podhaler and 209 patients treated with TOBI. For both the TOBI Podhaler and TOBI groups, mean exposure to medication for each cycle was 28-29 days. The mean age for both arms was between 25 and 26 years old. The mean baseline FEV1 % predicted for both arms was 53%.

Table 1 displays adverse drug reactions reported by at least 2% of TOBI Podhaler patients in Study 1, inclusive of all cycles (on and off treatment). Adverse drug reactions are listed according to MedDRA system organ class and sorted within system organ class group in descending order of frequency.

Table 1: Adverse reactions reported in Study 1 (occurring in ≥2% of TOBI Podhaler patients)
Primary System Organ Class Preferred Term	TOBI Podhaler N=308 %	TOBI N=209 %
Respiratory, thoracic, and mediastinal disorders
Cough	48.4	31.1
Lung disorder1	33.8	30.1
Productive cough	18.2	19.6
Dyspnea	15.6	12.4
Oropharyngeal pain	14.0	10.5
Dysphonia	13.6	3.8
Hemoptysis	13.0	12.4
Nasal congestion	8.1	7.2
Rales	7.1	6.2
Wheezing	6.8	6.2
Chest discomfort	6.5	2.9
Throat irritation	4.5	1.9
Gastrointestinal disorders
Nausea	7.5	9.6
Vomiting	6.2	5.7
Diarrhea	4.2	1.9
Dysgeusia	3.9	0.5
Infections and infestations
Upper respiratory tract infection	6.8	8.6
Investigations
Pulmonary function test decreased	6.8	8.1
Forced expiratory volume decreased	3.9	1.0
Blood glucose increased	2.9	0.5
Vascular disorders
Epistaxis	2.6	1.9
Nervous system disorders
Headache	11.4	12.0
General disorders and administration site conditions
Pyrexia	15.6	12.4
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	4.5	4.8
Skin and subcutaneous tissue disorders
Rash	2.3	2.4

1This includes adverse events of pulmonary or cystic fibrosis exacerbations

Adverse drug reactions that occurred in <2% of patients treated with TOBI Podhaler in Study 1 were: bronchospasm (TOBI Podhaler 1.6%, TOBI 0.5%); deafness including deafness unilateral (reported as mild to moderate hearing loss or increased hearing loss) (TOBI Podhaler 1.0%, TOBI 0.5%); and tinnitus (TOBI Podhaler 1.9%, TOBI 2.4%).

Discontinuations in Study 1 were higher in the TOBI Podhaler arm compared to TOBI (27% TOBI Podhaler vs 18% TOBI). This was driven primarily by discontinuations due to adverse events (14% TOBI Podhaler vs 8% TOBI). Higher rates of discontinuation were seen in subjects ≥ 20 years old and those with baseline FEV1 % predicted < 50%.

Respiratory related hospitalizations occurred in 24% of the patients in the TOBI Podhaler arm and 22% of the patients in the TOBI arm. There was an increased new usage of antipseudomonal medication in the TOBI Podhaler arm (65% TOBI Podhaler vs 55% TOBI). This included oral antibiotics in 55% of TOBI Podhaler patients and 40% of TOBI patients and intravenous antibiotics in 35% of TOBI Podhaler patients and 33% of TOBI patients. Median time to first antipseudomonal usage was 89 days in the TOBI Podhaler arm and 112 days in the TOBI arm.

The supportive safety population reflects patients from two studies: Study 2, a double-blind, placebo-controlled design for the first treatment cycle, followed by all patients receiving TOBI Podhaler (replaced placebo) for two additional cycles, and Study 3, a double-blind, placebo-controlled trial for one treatment cycle only. Placebo in these studies was inhaled powder without the active ingredient, tobramycin. The patient population for these studies was much younger than in Study 1 (mean age 13 years old).

Adverse drug reactions reported more frequently by TOBI Podhaler patients in the placebo-controlled cycle (Cycle 1) of Study 2, which included 46 TOBI Podhaler and 49 placebo patients, were:

Respiratory, thoracic, and mediastinal disorders

Pharyngolaryngeal pain (TOBI Podhaler 10.9%, placebo 0%); dysphonia (TOBI Podhaler 4.3%, placebo 0%)

Gastrointestinal disorders

Dysgeusia (TOBI Podhaler 6.5%, placebo 2.0%)

Adverse drug reactions reported more frequently by TOBI Podhaler patients in Study 3, which included 30 TOBI Podhaler and 32 placebo patients, were:

Respiratory, thoracic, and mediastinal disorders

Cough (TOBI Podhaler 10%, placebo 0%)

Ear and labyrinth disorders

Hypoacusis (TOBI Podhaler 10%, placebo 6.3%)

Audiometric assessment

In Study 1, audiology testing was performed in a subset of approximately 25% of TOBI Podhaler (n=78) and TOBI (n=45) patients. Using the criteria for either ear of ≥ 10 dB loss at two consecutive frequencies, ≥ 20 dB loss at any frequency, or loss of response at three consecutive frequencies where responses were previously obtained, five TOBI Podhaler patients and three TOBI patients were judged to have ototoxicity, a ratio similar to the planned 3:2 randomization for this study.

Audiology testing was also performed in a subset of patients in both Study 2 (n=13 from the TOBI Podhaler group and n=9 from the placebo group) and Study 3 (n=14 from the TOBI Podhaler group and n=11 from the placebo group). In Study 2, no patients reported hearing complaints but two TOBI Podhaler patients met the criteria for ototoxicity. In Study 3, three TOBI Podhaler and two placebo patients had reports of ‘hypoacusis’. One TOBI Podhaler and two placebo patients met the criteria for ototoxicity. In some patients, ototoxicity was transient or may have been related to a conductive defect.

Cough

Cough is a common symptom in cystic fibrosis, reported in 42% of the patients in Study 1 at baseline. Cough was the most frequently reported adverse event in Study 1 and was more common in the TOBI Podhaler arm (48% TOBI Podhaler vs 31 % TOBI). There was a higher rate of cough adverse event reporting during the first week of active treatment with TOBI Podhaler (i.e., the first week of Cycle 1). The time to first cough event in the TOBI Podhaler and TOBI groups were similar thereafter. In some patients, cough resulted in discontinuation of TOBI Podhaler treatment. Sixteen patients (5%) receiving treatment with TOBI Podhaler discontinued study treatment due to cough events compared with 2 (1%) in the TOBI treatment group. Children and adolescents coughed more than adults when treated with TOBI Podhaler, yet the adults were more likely to discontinue: of the 16 patients on TOBI Podhaler in Study 1 who discontinued treatment due to cough events, 14 were ≥20 years of age, one patient was between the ages of 13 and <20, and one was between the ages of 6 and <13. The rates of bronchospasm (as measured by ≥20% decrease in FEV1 % predicted post-dose) were approximately 5% in both treatment groups, and none of these patients experienced concomitant cough.

In Study 2, cough was the most commonly reported adverse event during the first cycle of treatment (the double blind period of treatment) and occurred more frequently in placebo-treated patients (26.5%) than patients treated with TOBI Podhaler (13%). Similar percentages of patients in both treatment groups reported cough as a baseline symptom. In Study 3, cough events were reported by three patients in the TOBI Podhaler group (10%) and none in the placebo group (0%).

7 DRUG INTERACTIONS

No clinical drug interaction studies have been performed with TOBI Podhaler. In clinical studies, patients receiving TOBI Podhaler continued to take dornase alfa, bronchodilators, inhaled corticosteroids, and macrolides. No clinical signs of drug interactions with these medicines were identified.

Concurrent and/or sequential use of TOBI Podhaler with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided.

Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI Podhaler should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects – Pregnancy Category D [see Warnings and Precautions (5.6)]

No reproduction toxicology studies have been conducted with TOBI Podhaler. However, subcutaneous administration of tobramycin at doses of 100 or 20 mg/kg/day during organogenesis was not teratogenic in rats or rabbits, respectively. Doses of tobramycin ≥ 40 mg/kg/day were severely maternally toxic to rabbits and precluded the eva luation of teratogenicity. Ototoxicity was not eva luated in offspring during nonclinical reproduction toxicity studies with tobramycin.

Aminoglycosides can cause fetal harm (e.g., congenital deafness) when administered to a pregnant woman. No adequate and well-controlled studies of TOBI Podhaler in pregnant women have been conducted. If TOBI Podhaler is used during pregnancy, or if the patient becomes pregnant while taking TOBI Podhaler, the patient should be apprised of the potential hazard to the fetus.

8.3 Nursing Mothers

The amount of tobramycin excreted in human breast milk after administration by inhalation is not known. Because of the potential for ototoxicity and nephrotoxicity in infants, a decision should be made whether to terminate nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Patients 6 years and older were included in the Phase 3 studies with TOBI Podhaler; 206 patients below 20 years of age received TOBI Podhaler. No dosage adjustments are needed based on age. The overall pattern of adverse events in pediatric patients was similar to the adults. Dysgeusia (taste disturbance) was more commonly reported in younger patients six to 19 years of age than in patients 20 years and older, 7.4% vs 2.7%, respectively. Safety and effectiveness in pediatric patients below the age of 6 years have not been established.

8.5 Geriatric Use

Clinical studies of TOBI Podhaler did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Tobramycin is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function [see Warnings and Precautions (5.2, 5.5)].

8.6 Renal Impairment

Tobramycin is primarily excreted unchanged in the urine and renal function is expected to affect the exposure to tobramycin. The risk of adverse reactions to this drug may be greater in patients with impaired renal function. Patients with serum creatinine > 2 mg/dL and blood urea nitrogen (BUN) > 40 mg/dL have not been included in clinical studies and there are no data in this population to support a recommendation regarding dose adjustment with TOBI Podhaler [see Warnings and Precautions (5.2, 5.5)].

8.7 Hepatic Impairment

No studies have been performed in patients with hepatic impairment. As tobramycin is not metabolized, an effect of hepatic impairment on the exposure to tobramycin is not expected.

8.8 Organ Transplantation

Adequate data do not exist for the use of TOBI Podhaler in patients after organ transplantation.

10 OVERDOSAGE

The maximum tolerated daily dose of TOBI Podhaler has not been established.

In the event of accidental oral ingestion of TOBI Podhaler capsules, systemic toxicity is unlikely as tobramycin is poorly absorbed. Tobramycin serum concentrations may be helpful in monitoring overdosage.

Acute toxicity should be treated with immediate withdrawal of TOBI Podhaler, and baseline tests of renal function should be undertaken.

Hemodialysis may be helpful in removing tobramycin from the body.

In all cases of suspected overdosage, physicians should contact the Regional Poison Control Center for information about effective treatment. In the case of any overdosage, the possibility of drug interactions with alterations in drug disposition should be considered.

11 DESCRIPTION

TOBI Podhaler consists of a dry powder formulation of tobramycin for oral inhalation only with the Podhaler device. The inhalation powder is filled into clear, colorless hypromellose capsules.

Each clear, colorless hypromellose capsule contains a spray dried powder of 28 mg of tobramycin active ingredient with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), calcium chloride, and sulfuric acid (for pH adjustment).

The active component of TOBI Podhaler is tobramycin. Tobramycin is an aminoglycoside antibiotic. Its chemical name is O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxy-L-streptamine; its structural formula is:

Tobramycin has a molecular weight of 467.52, and its empirical formula is C18H37N5O9. Tobramycin is a white to almost white powder; visually free from any foreign contaminants. Tobramycin is freely soluble in water, very slightly soluble in ethanol, and practically insoluble in chloroform and ether.

The Podhaler device is a plastic device used to inhale the dry powder contained in the TOBI Podhaler capsule. Under standardized in vitro testing at a fixed flow rate of 60 L/min and volume of 2 L for 2 seconds, the Podhaler device has a target delivered dose of 102 mg of tobramycin from the mouthpiece (4 capsules per dose). Peak inspiratory flow rate and inhaled volumes were explored in 96 cystic fibrosis patients aged 6 years and older. Older patients with significant disease progression and associated decreases in forced expiratory volume (FEV1) and younger patients with inhaled volumes < 1 L were able to generate inspiratory flow rates and volumes required to receive their medication when following the instructions for use. However, no pediatric patients aged 6 to 10 years with FEV1 less than 40% predicted were eva luated.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tobramycin is an aminoglycoside antibiotic [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

Absorption

TOBI Podhaler contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes. TOBI Podhaler is specifically formulated for administration by oral inhalation. The systemic exposure to tobramycin after inhalation of TOBI Podhaler is expected to result from pulmonary absorption of the dose fraction delivered to the lungs as tobramycin and is not absorbed to any appreciable extent when administered via the oral route.

Serum concentrations

After inhalation of a 112 mg single dose (4 x 28 mg capsules) of TOBI Podhaler in cystic fibrosis patients, the maximum serum concentration (Cmax) of tobramycin was 1.02 ± 0.53 µg/mL (mean ± SD) and the median time to reach the peak concentration (Tmax) was 1 hour. In comparison, after inhalation of a single 300 mg dose of TOBI, Cmax was 1.04 ± 0.58 µg/mL and median Tmax was 1 hour. The extent of systemic exposure (AUC0-12) was also similar: 4.6 ± 2.0 µg∙h/mL following the 112 mg TOBI Podhaler dose and 4.8 ± 2.5 µg∙h/mL following the 300 mg TOBI dose. At the end of a 4-week dosing cycle of TOBI Podhaler (112 mg twice daily), the maximum serum concentration of tobramycin 1 hour after dosing ranged from 1.48 ± 0.69 µg/mL to 1.99 ± 0.59 µg/mL (mean ± SD).

Sputum concentrations

After inhalation of a 112 mg single dose (4 x 28 mg capsules) of TOBI Podhaler in cystic fibrosis patients, sputum Cmax of tobramycin was 1048 ± 1080 µg/g (mean ± SD). In comparison, after inhalation of a single 300 mg dose of TOBI, sputum Cmax was 737 ± 1028 µg/g. The variability in pharmacokinetic parameters was higher in sputum as compared to serum.

Distribution

A population pharmacokinetic analysis for TOBI Podhaler in cystic fibrosis patients estimated the apparent volume of distribution of tobramycin in the central compartment to be 85.1 L for a typical CF patient.

Binding of tobramycin to serum proteins is negligible.

Metabolism

Tobramycin is not metabolized and is primarily excreted unchanged in the urine.

Elimination

Tobramycin is eliminated from the systemic circulation primarily by glomerular filtration of the unchanged compound. Systemically absorbed tobramycin following TOBI Podhaler administration is also expected to be eliminated principally by glomerular filtration.

The apparent terminal half-life of tobramycin in serum after inhalation of a 112 mg single dose of TOBI Podhaler was approximately 3 hours in cystic fibrosis patients and consistent with the half-life of tobramycin after TOBI inhalation.

A population pharmacokinetic analysis for TOBI Podhaler in cystic fibrosis patients aged 6 to 58 years estimated the apparent serum clearance of tobramycin to be 14.5 L/h. No clinically relevant covariates that were predictive of tobramycin clearance were identified from this analysis.

12.4 Microbiology

Mechanism of Action

Tobramycin is an aminoglycoside antimicrobial produced by Streptomyces tenebrarius. It acts primarily by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death.

Tobramycin has in vitro activity against Gram-negative bacteria including P. aeruginosa. It is bactericidal in vitro at peak concentrations equal to or slightly greater than the minimum inhibitory concentration.

Susceptibility Testing

Interpretive criteria for inhaled antibacterial products are not defined. The in vitro antimicrobial susceptibility test methods used to determine the susceptibility for parenteral tobramycin therapy can be used to monitor the susceptibility of P. aeruginosa isolated from cystic fibrosis patients (1, 2, 3). The relationship between in vitro susceptibility test results and clinical outcome with TOBI Podhaler therapy is not clear. A single sputum sample from a cystic fibrosis patient may contain multiple morphotypes of P. aeruginosa and each morphotype may require a different concentration of tobramycin to inhibit its growth in vitro. Patients should be monitored for changes in tobramycin susceptibility.

Development of Resistance

In clinical studies, some increases from baseline to the end of the treatment period were observed in the tobramycin MIC for P. aeruginosa morphotypes. In general, a higher percentage of patients treated with TOBI Podhaler had increases in tobramycin MIC compared with placebo or patients treated with TOBI inhalation solution.

The clinical significance of changes in MICs for P. aeruginosa has not been clearly established in the treatment of cystic fibrosis patients.

Cross-Resistance

Some emerging resistance to aztreonam, ceftazidime, ciprofloxacin, imipenem, or meropenem were observed in the TOBI Podhaler clinical trials. As other anti-pseudomonal antibiotics were concomitantly utilized in many patients in the clinical trials, the association with TOBI Podhaler is not clear.

Other

No trends were observed in the isolation of treatment-emergent bacterial respiratory pathogens (Burkholderia cepacia, Stenotrophomonas maltophilia, Staphylococcus aureus and Achromobacter xylosoxidans).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were not conducted with TOBI Podhaler. A two-year rat inhalation toxicology study to assess carcinogenic potential of TOBI (tobramycin inhalation solution, USP) has been completed. Rats were exposed to TOBI for up to 1.5 hours per day for 95 weeks. Serum levels of tobramycin of up to 35 µg/mL were measured in rats, in contrast to the maximum 1.99 ± 0.59 µg/mL level observed in cystic fibrosis patients in TOBI Podhaler clinical trials. There was no drug-related increase in the incidence of any variety of tumor.

Additionally, tobramycin has been eva luated for genotoxicity in a battery of in vitro and in vivo tests. The Ames bacterial reversion test, conducted with 5 tester strains, failed to show a significant increase in revertants with or without metabolic activation in all strains. Tobramycin was negative in the mouse lymphoma forward mutation assay, did not induce chromosomal aberrations in Chinese hamster ovary cells, and was negative in the mouse micronucleus test.

Subcutaneous administration of up to 100 mg/kg of tobramycin did not affect mating behavior or cause impairment of fertility in male or female rats.

14 CLINICAL STUDIES

The Phase 3 clinical development program included two placebo-controlled studies (Studies 2 and 3) and one open-label study (Study 1), which randomized and dosed 157 and 517 patients, respectively, with a clinical diagnosis of cystic fibrosis, confirmed by quantitative pilocarpine iontophoresis sweat chloride test, well-characterized disease causing mutations in each CFTR gene, or abnormal nasal transepithelial potential difference characteristic of cystic fibrosis.

In the placebo-controlled studies, all patients were aged between 6 and 21 years old and had an FEV1 at screening within the range of 25% to 80% (inclusive) of predicted normal values for their age, sex, and height based upon Knudson criteria. In addition, all patients were infected with P. aeruginosa as demonstrated by a positive sputum or throat culture (or bronchoalveolar lavage) within 6 months prior to screening, and also in a sputum culture taken at the screening visit. Among the 76 patients treated with TOBI Podhaler, 37% were males and 63% were females. Thirty-six patients were between 6 and 12 years of age, and 40 patients were between 13 and 21 years of age. Patients had a mean baseline FEV1 of 56% of predicted normal value.

In both studies, >90% of patients received concomitant therapies for cystic fibrosis related indications. The most frequently used other antibacterial drugs (any route of administration) were azithromycin, ciprofloxacin, and ceftazidime. Consistent with the population of cystic fibrosis patients, the most frequently used concomitant medications included oral pancreatic enzyme preparations, mucolytics (especially dornase alfa), and selective β2-adrenoreceptor agonists.

Study 2

Study 2 was a randomized, three-cycle, two-arm trial. Each cycle comprised of 28 days on treatment followed by 28 days off treatment. The first cycle was double-blind, placebo-controlled with eligible patients randomized 1:1 to TOBI Podhaler (4 x 28 mg capsules twice daily) or placebo. Upon completion of the first cycle, patients who were randomized to the placebo treatment group received TOBI Podhaler for Cycles 2 and 3. The total treatment period was 24 weeks.

A total of 95 patients were randomized into Study 2 and received TOBI Podhaler (n=46) or placebo (n=49) in Cycle 1. All patients were less than 22 years of age (mean age 13.3 years) and had not received inhaled antipseudomonal antibiotics within four months prior to screening; 56% were female and 84% were Caucasian. This study was stopped early for demonstrated benefit and the primary analysis used the set of patients included in the interim analysis (n=79); 16 patients did not have data on the primary endpoint at that time. Of the 79 patients included in the interim analysis, 18 patients were excluded due to a failure to meet spirometry quality review criteria as determined by an external review panel. This resulted in a total of 61 patients, 29 in the TOBI Podhaler arm and 32 in the placebo arm, who were included in the primary analysis.

In the primary analysis, TOBI Podhaler significantly improved lung function compared with placebo as measured by the relative change in FEV1 % predicted from baseline to the end of Cycle 1 dosing. This analysis adjusted for the covariates of baseline FEV1 % predicted, age, and region, and imputed for missing data. Treatment with TOBI Podhaler and placebo resulted in relative increases in FEV1 % predicted of 12.54% and 0.09%, respectively (LS mean difference = 12.44%; 95% CI: 4.89, 20.00; p=0.002). Analysis of absolute changes in FEV1 % predicted showed LS means of 6.38% for TOBI Podhaler and -0.52% for placebo with a difference of 6.90% (95% CI: 2.40, 11.40). Improvements in lung function were achieved during the subsequent cycles of treatment with TOBI Podhaler, although the magnitude was reduced (Figure 1).

The percentage of patients using new antipseudomonal antibiotics in Cycle 1 was greater in the placebo treatment group (18.4%) compared with the TOBI Podhaler treatment group (13.1%). During the first cycle, 8.7% of TOBI Podhaler patients and 10.2% of placebo patients were treated with parenteral antipseudomonal antibiotics. In Cycle 1, two patients (4.4%) in the TOBI Podhaler treatment group required respiratory-related hospitalizations, compared with six patients (12.2%) in the placebo treatment group.

Figure 1 – Study 2: Mean relative change in FEV1 % predicted from baseline in Cycles 1-3 by treatment group

Error bars represent the mean relative change (95% CI)

Study 3

Study 3 was a randomized, double-blind, placebo-controlled trial, similar in design to Study 2. Eligible patients were randomized 1:1 to receive TOBI Podhaler (4 x 28 mg capsules twice daily) or placebo for one cycle (28 days on-treatment and 28 days off-treatment).

A total of 62 patients were randomized into Study 3 and allocated to TOBI Podhaler (n=32) or placebo (n=30). All patients were less than 22 years of age (mean age 12.9 years) and had not received inhaled antipseudomonal antibiotics within 4 months prior to screening; 64.5% were female and 98.4% were Caucasian.

In this study, the results were not statistically significant for the primary lung function endpoint when adjusting for the covariates of age (<13 years, ≥13 years) and FEV1 % predicted at screening (< 50%, ≥ 50%) and imputing for missing data. Improvement in lung function for TOBI Podhaler compared with placebo was eva luated using the relative change in FEV1 % predicted from baseline to the end of Cycle 1 dosing. Treatment with TOBI Podhaler (8.19%) compared to placebo (2.27%) failed to achieve statistical significance in relative change in FEV1 % predicted (LS mean difference = 5.91%; 95% CI: -2.54, 14.37; p=0.167). Analyses of absolute changes in FEV1 % predicted showed LS means of 4.86% for TOBI Podhaler and 0.48% for placebo with a difference of 4.38% (95% CI:-0.17, 8.94).

Study 1

Study 1 was a randomized, open-label, active-controlled parallel arm trial. Eligible patients were randomized 3:2 to TOBI Podhaler (4 x 28 mg capsules twice daily) or TOBI (300 mg/5 mL twice daily). Treatment was administered for 28 days, followed by 28 days off therapy (one cycle) for three cycles. The total treatment period was 24 weeks. The time to administer a dose of TOBI Podhaler (10th to 90th percentiles) ranged from 2-7 minutes at the end of the dosing period for Cycle 1, and 2-6 minutes at the end of the dosing period for Cycle 3.

A total of 517 patients were randomized in Study 1 and received TOBI Podhaler (n=308) or TOBI (n=209). Patients were predominantly 20 years of age or older (mean age 25.6 years) with no inhaled antipseudomonal antibiotic use within 28 days prior to study drug administration; 45% were female and 91% were Caucasian.

The primary purpose of Study 1 was to eva luate safety. Interpretation of efficacy results in Study 1 is limited by several factors including open-label design, testing of multiple secondary endpoints, and missing values for the outcome of FEV1 % predicted. The number (%) of patients with missing values for FEV1 % predicted at Weeks 5 and 25 in the TOBI Podhaler treated group were 40 (13.0%) and 86 (27.9%) compared to 15 (7.2%) and 40 (19.1%) in the TOBI treated group. Using imputation of the missing data, the mean differences (TOBI Podhaler minus TOBI) in the percent relative change from baseline in FEV1 % predicted at Weeks 5 and 25 were -0.87 (95% CI: -3.80, 2.07) and 1.62 (95% CI: -0.90, 4.14), respectively.

15 REFERENCES

Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – Ninth Edition; Approved Standard. CLSI Document M7-A9. CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, 2012.
CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – 11th ed. CLSI document M02-A11. CLSI, 2012.
CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational Supplement. CLSI document M100-S22. CLSI, 2012

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

TOBI Podhaler contains aluminum blister-packaged 28 mg TOBI Podhaler (tobramycin inhalation powder) clear, colorless hypromellose capsules with “NVR AVCI” in blue radial imprint on one part of the capsule and the Novartis logo “” in blue radial imprint on the other part of the capsule, and Podhaler devices.

Each Podhaler device consists of the inhaler body, mouthpiece, capsule chamber and blue push button. The Podhaler device is provided in a case that protects the device during shipment, storage and its one week in-use period.

Unit Dose (blister pack), Box of 224 capsules contains: NDC 0078-0630-35

4 weekly packs, each containing:

56 capsules (7 blister cards of 8 capsules)

1 Podhaler device

1 reserve Podhaler device

16.2 Information for Patients

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

Protect TOBI Podhaler from moisture.

TOBI Podhaler capsules should be used with the Podhaler device only. The Podhaler device should not be used with any other capsules.
Capsules should always be stored in the blister and each capsule should only be removed immediately before use.
Always use the new Podhaler device provided with each weekly pack.

Keep this and all drugs out of the reach of children.