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Safety in Lactation: Non-beta lactam antibiotics and antibacterials

8 September 2021To be used in conjunction with individual drug entries for specific information and guidance. Aminoglycosides Only small or negligible amounts of aminoglycosides are found in…
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Lactation Safety Information

Gentamicin
Limited published evidence of safety
Small amounts in breast milk
Minimal absorption from the infant's GI tract
24 April 2018

New Medicines

ArikayceNontuberculous mycobacterial (NTM) lung infection caused by Mycobacterium Avium Complex (MAC), in adults who have persistent positive sputum cultures despite use of medically appropriate first-line therapy

Information

Arikayce
New formulation
Insmed
Insmed

Development and Regulatory status

Launched
Launched
Launched
December 2020
Yes
Yes
Dec 20Available in UK. 590mg liposomal nebuliser dispersion in vial, 28 plus Lamira nebuliser system=£9513 [31].
Oct 20Approved in EU [30]
Jul 20Recommended for EU approval by CHMP - the full indication is "for the treatment of non-tuberculous mycobacterial (NTM) lung infections caused by Mycobacterium avium Complex (MAC) in adults with limited treatment options who do not have cystic fibrosis (see sections 4.2, 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents" [29].
Aug 19Has been available in the US since Dec 18 [26].
Aug 19Filed in EU via centralised procedure [25].
Dec 18Results of PIII CONVERT study published. Enrolled pts (ALIS + guideline based therapy (GBT), n = 224; GBT-alone, n = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), COPD (14.3%), or both (11.9%). Culture conversion was achieved by 29% of pts with ALIS + GBT and 8.9% with GBT alone (OR: 4.22; 95% CI, 2.08-8.57; P < 0.001). Pts in the ALIS + GBT arm vs. GBT alone were more likely to achieve conversion (HR: 3.90; 95% CI, 2.00-7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of pts receiving ALIS + GBT and 50% receiving GBT alone; serious treatment-emergent adverse events occurred in 20% and 17.9% of pts, respectively.In the phase III CONVERT study, rates of serious treatment-emergent adverse events (TEAEs) were similar between amikacin liposomal inhaled (ALIS) and guideline-based therapy (GBT) treatment arms (20.2% for ALIS+GBT vs 17.9% for GBT alone). [27,28]
Sep 18Approved in the US where it will be priced it at $363 per vial, or $132,495 annually if taken daily as directed [23,24].
Mar 18Filed in US. [22]
Jan 17Insmed intends to resubmit its MAA when clinical data from its ongoing global phase 3 study are available [19].
Jun 16Marketing Authorization Application (MAA) application to European Medicines Agency (EMA) for ARIKAYCE™ for the treatment of nontuberculous mycobacteria (NTM) lung disease is withdrawn. The MAA filing was based on data from the company´s completed phase 2 study. During the May 2016 Committee for Medicinal Products for Human Use (CHMP) meeting, the CHMP indicated that the phase 2 study did not provide a sufficient amount of evidence to support approval [16].
Feb 16UK launch planned for Q4 16 [14].
Jul 15EU filing in Dec 14 was for both CF and NTM indications [13].
Mar 15Pivotal trials due to complete 2016.
Aug 14EU Marketing Authorization Application (MAA) anticipated by end of 2014. [9]
Jun 14FDA awards liposomal amikacin for inhalation breakthrough therapy status for treatment-refractory nontuberculous mycobacterial lung disease [8].
Feb 14EU positive opinion for orphan designation for Arikace for treatment of lung disease caused by nontuberculous mycobacteria (NTM) [7].
Jul 13The FDA has designated ARIKACE a Qualified Infectious Disease Product (QIDP) for the treatment of Non-Tuberculous Mycobacteria lung infections and granted Fast Track status [6].
Mar 11Insmed intends to file for orphan drug designation for NTM lung infections in the US and EU by the end of 2011 [1].

Category

Liposomal formulation of amikacin encapsulated inside nanoscale liposomal carriers designed for administration by oral inhalation via nebulisation. Designed to permit once-a-day dosing and to deliver amikacin directly to the target lung tissue.
In the United States and Canada, the estimated the annual prevalence of diagnosed NTM lung disease is 5.5–9.8 cases per 100,000 and increasing, with higher prevalence (20–47 cases per 100,000) in pts > 65 years. Prevalence rates vary but are increasing in Europe with the annual prevalence in the UK estimated at 6.5 per 100,000. MAC bacteria are the most common cause of NTM lung disease in most countries in North and South America, Europe, Asia, and Australia with the manufacturer estimating MAC being present in 22-43% of NTM isolates from the UK. [27,28]
Nontuberculous mycobacterial (NTM) lung infection caused by Mycobacterium Avium Complex (MAC), in adults who have persistent positive sputum cultures despite use of medically appropriate first-line therapy
Liposomal formulation
Inhalation

Further information

Yes

Trial or other data

Oct 18Inhaled antibacterial treatment for NTM lung infections as an addition to standard (oral or i.v.) treatment. As a further treatment option it will be additional to current costs. Will be used for treatment of adults with refractory NTM lung infection caused by MAC. Will be administered via Lamira (nebuliser handset and aerosol head) used with the PARI eBase Controller. It must not be administered by any other route or using any other nebulisation system [15]. There are currently no products indicated for treatment of NTM lung disease in the US or EU [17]. In the US, Arikayce is the first drug to be approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs [24]. Arikayce also was approved under the Accelerated Approval pathway and was granted Orphan Drug, Fast Track, Breakthrough Therapy, Priority Review, and Qualified Infectious Disease Product (QIDP) designations.
Mar 18CONVERT study (NCT02344004) on-going with estimated completion date of July 19.[20]
Sep 17Insmed announced positive top-line results from PIII CONVERT study (n=336) of ALIS (Amikacin Liposome Inhalation Suspension) in pts with treatment-refractory NTM Lung Disease caused by MAC. The study demonstrated that the addition of ALIS to guideline-based therapy (GBT) eliminated evidence of NTM lung disease caused by MAC in sputum by Month 6 in 29% of patients, compared to 9% of patients on GBT alone (p < 0.0001). serious treatment emergent adverse events were similar between treatment arms with no distinctions between treatment arms due to hearing loss or renal impairment. Overall the rate of reported adverse events in the ALIS plus GBT arm was higher and these events were mild or moderate in nature and transient. These findings are consistent with adverse events similar to those seen in other clinical studies of inhaled antibiotics.[21]
Nov 16CONVERT study = NCT02344004 [18].
Nov 16Insmed announces it has achieved its patient enrolment objective in the PIII CONVERT or INS-212 study, which is evaluating ARIKAYCE in treatment refractory NTM lung disease caused by MAC. The primary efficacy endpoint is the proportion of subjects who achieve culture conversion at Month 6 in the ARIKAYCE plus multi-drug regimen arm compared to the multi-drug regimen without ARIKAYCE arm [17].
Mar 15NCT02344004, a PIII randomized, open-label, multicenter study in adults with Nontuberculous Mycobacterial (NTM) infection caused by Mycobacterium avium complex (MAC) who are refractory to treatment was initiated Jan 15 [10]. Trial due to complete Oct 16 [11].
Mar 14Insmed reports that in a PII study, liposomal amikacin missed its primary endpoint of reducing bacterial density (used as a measure of infection). However, in a secondary endpoint, 11 of the 44 patients taking Arikayce turned in negative cultures at the end of the study, a statistically significant improvement over the placebo arm [8].
Feb 14Insmed remains on track to report top-line data from a PII trial in the US and Canada to treat NTM lung disease by end of 1Q 2014 [7].
Feb 12The Company plans to start a PII randomized study of approximately 100 adult patients with recalcitrant NTM lung disease in mid-2012. Patients who are NTM culture positive will continue with their antibiotic treatment regimen, and receive additionally, either ARIKACE 560mg, delivered once daily via an optimized, investigational eFlow® Nebulizer System (PARI Pharma GmbH), or placebo once daily. The primary efficacy endpoint is change in mycobacterial density from baseline to day 84 of treatment. Eligible patients will be able to receive ARIKACE 560mg once daily for an additional 84 days in an open-label design. The clinical trial design was previously agreed with the FDA [5].
Jan 12US FDA has lifted the clinical hold on ARIKACE® in patients with non-tuberculous mycobacteria (NTM) lung disease. Insmed continues to engage in discussions with FDA regarding the clinical hold placed on ARIKACE in Cystic Fibrosis (CF) patients with Pseudomonas lung infections. Insmed also announced that it will move ahead with the 9-month dog inhalation toxicity study of ARIKACE as previously requested by FDA to determine if the findings of the rat inhalation carcinogenicity study are observed in a non-rodent model. [4]
Oct 11The US FDA is continuing the clinical hold placed on the Phase III trial for Arikace in patients with non-tuberculous mycobacterial (NTM) lung disease. Based on its review of the information provided to date, including the rat inhalation carcinogenicity study results, the FDA has insufficient information to assess the risks of Arikace in NTM patients in the planned Phase III trial. FDA requires a Phase II trial in adult NTM patients intended to provide proof-of-concept efficacy and safety data for Arikace in NTM before a Phase III trial can proceed. [3]
Aug 11U.S. FDA has placed a clinical hold on Insmed´s P3 clinical trials for liposomal amikacin for inhalation in CF patients with Pseudomonas lung infections and patients with non-tuberculous mycobacterial (NTM) lung disease. A clinical hold is a notification issued by FDA to the sponsor to delay a proposed clinical trial or suspend an ongoing clinical trial. The decision was based on an initial review of the interim results of a long-term rat inhalation carcinogenicity study. In this study, rats received daily doses of liposomal amikacin by inhalation for up to two years. FDA has requested additional information and data from the rat study. Insmed anticipates being able to supply the currently requested information and data within the next 30 days. [2]
Mar 11A pivotal PIII study in nontuberculous mycobacteria lung infections has been agreed with the FDA. Development of the clinical program has been done in partnership with the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. Data from the study is expected 1H 2013 [1].