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

2014-06-13 10:41:12 来源: 作者: 【大中小】浏览:293次评论:0条

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。
TOBI PODHALER (tobramycin) capsule
[Novartis Pharmaceuticals Corporation]
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
Back to Highlights and Tabs
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Ototoxicity
5.2 Nephrotoxicity
5.3 Neuromuscular Disorders
5.4 Bronchospasm
5.5 Laboratory Tests
5.6 Use in Pregnancy
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
8.8 Organ Transplantation
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Information for Patients
17 PATIENT COUNSELING INFORMATION
17.1 Ototoxicity
17.2 Bronchospasm
17.3 Risks Associated with Aminoglycosides
17.4 Laboratory Tests
17.5 Pregnancy
17.6 Cough
*
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

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