Kaftrio

Kaftrio should only be prescribed by healthcare professionals with experience in the treatment of CF. 1). Kaftrio should only be used in patients diagnosed with CF. A diagnosis of CF should be made based on diagnostic guidelines and clinical judgement.

There are a limited number of patients who harbour mutations not listed in Table 5 that may be responsive to Kaftrio. In these cases, Kaftrio can be considered when the physician deems the potential benefits outweigh the potential risks and under close medical supervision.

1). Monitoring of transaminases (ALT and AST) and total bilirubin is recommended for all patients prior to initiating treatment, every 3 months during the first year of treatment and annually thereafter. 4). Posology Adults and paediatric patients aged 6 years and older should be dosed according to Table 1.

5 mg/tezacaftor 25 mg/elexacaftor 50 mg tablets One ivacaftor 75 mg tablet 6 to < 12 years ≥ 30 kg Two ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg tablets One ivacaftor 150 mg tablet 12 years and older - Two ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg tablets One ivacaftor 150 mg tablet The morning and evening dose should be taken approximately 12 hours apart, with fat-containing food (see Method of administration).

Missed dose If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule. If more than 6 hours have passed since: • the missed morning dose, the patient should take the missed dose as soon as possible and should not take the evening dose.

The next scheduled morning dose should be taken at the usual time. OR • the missed evening dose, the patient should not take the missed dose. The next scheduled morning dose should be taken at the usual time. Morning and evening doses should not be taken at the same time.

5). 5 mg/ tezacaftor 25 mg/elexacaftor 50 mg tablets on the first day • One ivacaftor 75 mg tablet on the next day No evening ivacaftor tablet dose. 5 mg/tezacaftor 25 mg/elexacaftor 50 mg tablets twice a week, approximately 3 to 4 days apart.

No evening ivacaftor tablet dose. 4 6 to < 12 years ≥ 30 kg Alternate each day: • Two ivacaftor 75 mg/ tezacaftor 50 mg/elexacaftor 100 mg tablets on the first day • One ivacaftor 150 mg tablet on the next day No evening ivacaftor tablet dose.

9%). 4). Tabulated list of adverse reactions Table 4 reflects adverse reactions observed with IVA/TEZ/ELX in combination with IVA, TEZ/IVA in combination with IVA, and IVA monotherapy. Adverse reactions are listed by MedDRA system organ class and frequency: 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 the order of decreasing seriousness. 12 Table 4: Adverse reactions MedDRA System Organ Class Adverse Reactions Frequency Infections and infestations Upper respiratory tract infection*, Nasopharyngitis very common Rhinitis*, Influenza* common Immune system disorders Hypersensitivity not known Metabolism and nutrition disorders Hypoglycaemia* common Psychiatric disorders Depression, Behavioural changes not known Nervous system disorders Headache*, Dizziness* very common Ear and labyrinth disorders Ear pain, Ear discomfort, Tinnitus, Tympanic membrane hyperaemia, Vestibular disorder common Ear congestion uncommon Respiratory, thoracic and mediastinal disorders Oropharyngeal pain, Nasal congestion* very common Rhinorrhoea*, Sinus congestion, Pharyngeal erythema, Abnormal breathing* common Wheezing* uncommon Gastrointestinal disorders Diarrhoea*, Abdominal pain* very common Nausea, Abdominal pain upper*, Flatulence* common Hepatobiliary disorders Transaminase elevations very common Alanine aminotransferase increased* very common Aspartate aminotransferase increased* very common Liver injury†, Total bilirubin increase† not known Skin and subcutaneous tissue disorders Rash* very common Acne*, Pruritus* common Reproductive system and breast disorders Breast mass common Breast inflammation, Gynaecomastia, Nipple disorder, Nipple pain uncommon Investigations Bacteria in sputum, Blood creatine phosphokinase increased* very common Blood pressure increased* uncommon *Adverse reactions observed during clinical studies with IVA/TEZ/ELX in combination with IVA.

Elevated transaminases and hepatic injury Cases of liver failure leading to transplantation have been reported within the first 6 months of treatment in patients with and without pre-existing advanced liver disease. Elevated transaminases are common in patients with CF.

In clinical studies, elevated transaminases were more frequently observed in patients treated with IVA/TEZ/ELX in combination with IVA compared to placebo. In patients taking IVA/TEZ/ELX in combination with IVA, these elevations have sometimes been associated with concomitant elevations in total bilirubin.

2). For patients with a history of liver disease or transaminase elevations, more frequent monitoring should be considered. Interrupt treatment and promptly measure serum transaminases and total bilirubin if a patient develops clinical signs or symptoms of liver injury.

Interrupt dosing in the event of ALT or AST >5 × the upper limit of normal (ULN), or ALT or AST >3 × ULN with total bilirubin >2 × ULN. Closely monitor the 7 laboratory tests until the abnormalities resolve. Following resolution, consider the benefits and risks of resuming treatment.

Patients who resume treatment after interruption should be monitored closely. 2). Hepatic impairment Treatment of patients with moderate hepatic impairment is not recommended. For patients with moderate hepatic impairment, the use of IVA/TEZ/ELX should only be considered when there is a clear medical need, and the benefits are expected to outweigh the risks.

If used, it should be used with caution at a reduced dose (see Table 3). 2). 8). In some cases, symptom improvement was reported after dose reduction or treatment discontinuation. Patients (and caregivers) should be alerted about the need to monitor for depressed mood, suicidal thoughts, unusual changes in behaviour, anxiety, or insomnia and to seek medical advice immediately if these symptoms present.

1.