Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Teva B.V., Swensweg 5, 2031 GA Haarlem, The Netherland
Hypersensitivity to the active substance, colistin sulphate or polymyxin B.
Bronchospasm or coughing may occur on inhalation. These reactions usually disappear or significantly diminish with continued use and may be ameliorated by appropriate treatment with beta2-agonists prior to or following dry powder colistimethate sodium inhalation. If bronchospasm or coughing remain problematic, withdrawal of treatment should be considered.
Haemoptysis is a complication in cystic fibrosis and is more frequent in adults. The use of colistimethate sodium in patients with clinically significant haemoptysis should be undertaken or continued only if the benefits of treatment are considered to outweigh the risks of inducing further haemorrhage.
If acute respiratory exacerbations develop additional intravenous or oral antibacterial agent therapy should be considered.
After each inhalation of Colobreathe, the mouth should be rinsed with water. The rinse should not be swallowed. Rinsing may reduce the risk of developing oral fungal super-infection during treatment and may also reduce the unpleasant taste associated with colistimethate sodium.
There is very low transpulmonary absorption of colistimethate after inhalation of Colobreathe (see section 5.2). Care should still be taken in administering Colobreathe to patients who are known to have a propensity for nephrotoxic or neurotoxic events.
Caution should be taken with concomitant use of Colobreathe and parenteral or nebulised colistimethate sodium.
Caution should be taken with concomitant use of colistimethate sodium and potential nephrotoxic or neurotoxic medicinal products, including non-depolarising muscle relaxants (see section 4.5).
Colobreathe should be used with extreme caution in patients with myasthenia gravis because of potential for drug induced neuromuscular blockade.
Colistimethate sodium should be used with extreme caution in patients with porphyria.
Safety and efficacy have been assessed in controlled studies for up to 24 weeks. (see section 5.1).
There is no experience of using Colobreathe concurrently with other inhaled antibacterial agents.
Caution should be taken with concomitant use with other formulations of colistimethate sodium as there is little experience and there is a possibility of summative toxicity.
No in-vivo interaction studies have been performed.
Colistimethate sodium and colistin have been investigated in vitro to determine the effects on the expression of cytochrome P450 (CYP) enzymes on treating primary cultures of fresh human hepatocytes. Treatment with colistimethate sodium or colistin did not induce the activity of any enzyme tested (CYP1A2, 2B6, 2C8, 2C9, 2C19 and 3A4/5).
Concomitant use of inhaled colistimethate sodium with other medicinal products that are potentially nephrotoxic or neurotoxic, such as aminoglycosides, or neuromuscular blocking products, such as curariform agents should be undertaken with caution.
Co-treatment with colistimethate sodium and macrolides such as azithromycin and clarithromycin, or fluoroquinolones such as norfloxacin and ciprofloxacin should be undertaken with caution in patients with myasthenia gravis (see section 4.4).
There are no or limited amount of data from the use of inhaled colistimethate sodium in pregnant women. Studies in animals using parenteral administration have shown reproductive toxicity (see section 5.3). Single dose intravenous studies in human pregnancy show that colistimethate sodium crosses the placenta and consequently there is potential for foetal toxicity if administered during pregnancy.
Colistimethate sodium is not recommended during pregnancy and in women of childbearing potential not using contraception.
Physico-chemical data suggest excretion of colistimethate sodium in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from colistimethate sodium therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Colistimethate sodium has no notable effects on fertility in male or female rats or mice.
Based on the safety profile of colistimethate sodium, neurotoxity may occur with the possibility of dizziness, confusion or visual disturbances. Patients should be warned not to drive or operate machines if this occurs.
The safety of Colobreathe has been assessed in a total of 237 subjects (225 cystic fibrosis patients and 12 healthy volunteers). Of these, 187 patients aged 6 years and above were exposed to Colobreathe one capsule twice daily in a 24-week, phase 3 comparative study. There were 32 patients aged 6-12 years, 41 patients aged 13-17 years and 114 patients aged 18 years and older. The most commonly reported adverse reactions as a percent of all Colobreathe treated patients were: unpleasant taste (62%), cough (59.4%), throat irritation (43.9%), dyspnoea (16.6%) and dysphonia (10.7%). Inhalation may induce coughing or bronchospasm which may be controlled by pre-treatment with inhaled beta2 agonists.
Sore throat or mouth has been reported with nebulised colistimethate sodium and may occur with Colobreathe. This may be related to Candida albicans infection or hypersensitivity. Skin rash may also indicate hypersensitivity and if this occurs treatment should be withdrawn.
In the 24 week clinical study, the following adverse reactions were observed across all ages. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare ((≥1/10,000 to <1/1,000), very rare <1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Uncommon: Drug hypersensitivity
Uncommon: Weight fluctuation, decreased appetite
Uncommon: Anxiety
Common: Balance disorder, headache
Uncommon: Convulsions, somnolence
Common: Tinnitus
Uncommon: Ear congestion
Very Common: Dyspnoea, cough, dysphonia, throat irritation
Common: Haemoptysis, bronchospasm, asthma, wheezing, chest discomfort, lower respiratory tract infection, productive cough, crackles lung
Uncommon: Chest pain, dyspnoea exacerbated, pharyngolaryngeal pain, epistaxis, sputum purulent, abnormal chest sound, increased upper airway secretion
Very Common: Dysgeusia
Common: Vomiting, nausea
Uncommon: Diarrhoea, toothache, salivary hypersecretion, flatulence
Common: Arthralgia
Uncommon: Proteinuria
Common: Pyrexia, asthenia, fatigue
Uncommon: Thirst
Common: Forced expiratory volume decreased
Uncommon: Medication error
In the 24-week clinical study, where Colobreathe was administered twice daily to adults and children aged 6-17, the adverse reactions identified in the paediatric population were similar to that for the overall population. The most commonly reported adverse reactions as a percent of Colobreathe treated patients were: cough (55%), unpleasant taste (51%), throat irritation (34%), dyspnoea (10%) and dysphonia (10%).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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