Kalydeco

Kalydeco should only be prescribed by physicians with experience in the treatment of cystic fibrosis. 1). The phase of the poly-T variant identified with the R117H mutation should be determined in accordance with local clinical recommendations.

Kalydeco in combination with ivacaftor/tezacaftor/elexacaftor There are a limited number of patients who harbour mutations not listed in Table 6 that may be responsive to ivacaftor/tezacaftor/elexacaftor (IVA/TEZ/ELX). In these cases, ivacaftor (IVA) in combination with IVA/TEZ/ELX can be considered when the physician deems the potential benefits outweigh the potential risks and under close medical supervision.

1). Posology Adults, adolescents, and children 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 years 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 be advised to take it as soon as possible and then take the next dose at the regularly scheduled time. If more than 4 6 hours have passed since the time the dose is usually taken, the patient should be advised to wait until the next scheduled dose.

Patients receiving Kalydeco in a combination regimen should be advised not to take more than one dose of either medicinal product at the same time. Concomitant use of CYP3A inhibitors During concomitant administration with moderate or strong inhibitors of CYP3A, the ivacaftor dose should be adjusted as detailed in Table 2.

5).

Table 2:

Dosing recommendations for concomitant use with moderate or strong CYP3A inhibitors Age/ weight Moderate CYP3A inhibitors Strong CYP3A inhibitors Ivacaftor as monotherapy 6 years and older, ≥ 25 kg One morning tablet of ivacaftor 150 mg once daily.

No evening ivacaftor dose. One morning tablet of ivacaftor 150 mg twice a week, approximately 3 to 4 days apart. No evening ivacaftor dose. Ivacaftor in a combination regimen with tezacaftor/ivacaftor 6 years to < 12 years, < 30 kg Alternate each day: - one morning tablet of tezacaftor 50 mg/ivacaftor 75 mg on the first day - one morning tablet of ivacaftor 75 mg on the next day No evening ivacaftor dose.

8%). 5% of placebo-treated patients. 8%). 4). Tabulated list of adverse reactions Table 4 reflects the adverse reactions observed with ivacaftor monotherapy in clinical trials (placebo- controlled and uncontrolled studies) in which the length of exposure to ivacaftor ranged from 16 weeks to 144 weeks.

Additional adverse reactions observed with ivacaftor in a combination regimen with tezacaftor/ivacaftor and/or in a combination regimen with ivacaftor/tezacaftor/elexacaftor are also provided in Table 4. The frequency of adverse reactions is defined as follows: 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.

Table 4:

Adverse reactions System organ class Adverse reactions Frequency Infections and infestations Upper respiratory tract infection very common Nasopharyngitis very common Influenza† common Rhinitis common Metabolism and nutrition disorders Hypoglycaemia† common Psychiatric disorders Depression not known Nervous system disorders Headache very common Dizziness very common Ear and labyrinth disorders Ear pain common Ear discomfort common 14 System organ class Adverse reactions Frequency Tinnitus common Tympanic membrane hyperaemia common Vestibular disorder common Ear congestion uncommon Respiratory, thoracic and mediastinal disorders Oropharyngeal pain very common Nasal congestion very common Abnormal breathing† common Rhinorrhoea† common Sinus congestion common Pharyngeal erythema common Wheezing† uncommon Gastrointestinal disorders Abdominal pain very common Diarrhoea very common Abdominal pain upper† common Flatulence† common Nausea* common Hepatobiliary disorders Transaminase elevations very common Alanine aminotransferase increased† very common Aspartate aminotransferase increased† common Liver injury^ not known Total bilirubin increase^ not known Skin and subcutaneous tissue disorders Rash very common Acne† common Pruritus† common Reproductive system and breast disorders Breast mass common Breast inflammation uncommon Gynaecomastia uncommon Nipple disorder uncommon Nipple pain uncommon Investigations Bacteria in sputum very common Blood creatine phosphokinase increased† common Blood pressure increased† uncommon * Adverse reaction and frequency reported from clinical studies with ivacaftor in combination with tezacaftor/ivacaftor.

1). In study 770-111, four patients with the G970R mutation were included. In three of four patients the change in the sweat chloride test was < 5 mmol/L and this group did not demonstrate a clinically relevant improvement in FEV1 after 8 weeks of treatment.

1). 1). Therefore, use of ivacaftor as monotherapy in these patients is not recommended. 1). 1. 9 Elevated transaminases and hepatic injury In a patient with cirrhosis and portal hypertension, liver failure leading to transplantation has been reported while receiving ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor.

, cirrhosis, portal hypertension) and only if the benefits are expected to outweigh the risks. 2). Moderate transaminase (alanine transaminase [ALT] or aspartate transaminase [AST]) elevations are common in subjects with CF. Transaminase elevations have been observed in some patients treated with ivacaftor as monotherapy and in combination regimens with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor.

In patients taking ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor, these elevations have sometimes been associated with concomitant elevations in total bilirubin. Therefore, assessments of transaminases (ALT and AST) and total bilirubin are recommended for all patients prior to initiating ivacaftor, every 3 months during the first year of treatment and annually thereafter.

For all patients with a history of liver disease or transaminase elevations, more frequent monitoring of liver function tests should be considered. , patients with ALT or AST > 5 × the upper limit of normal (ULN), or ALT or AST > 3 × ULN with bilirubin > 2 × ULN), dosing should be interrupted, and laboratory tests closely followed until the abnormalities resolve.

2). Hepatic impairment Use of ivacaftor, either as monotherapy or in a combination regimen with tezacaftor/ivacaftor, is not recommended in patients aged 6 years and older with severe hepatic impairment unless the benefits are expected to outweigh the risks.

1.