Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
Only patients with CF who had a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R gating (class III) mutation or G970R in at least one allele of the CFTR gene were included in studies 1, 2, 5, and 6 (see section 5.1).

In study 5, 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 FEV 1 after 8 weeks of treatment. Clinical efficacy in patients with the G970R mutation of the CFTR gene could not be established (see section 5.1).

Efficacy results from a phase 2 study in patients with CF who are homozygous for the F508del mutation in the CFTR gene showed no statistically significant difference in FEV 1 over 16 weeks of ivacaftor KALY_50_75_150-SPC-0921-V1                      Page 4 of 19
treatment compared to placebo (see section 5.1). Therefore, use of Kalydeco in these patients is not recommended.

Effect on liver function tests
Moderate transaminase (alanine transaminase [ALT] or aspartate transaminase [AST]) elevations are common in patients with CF. Transaminase elevations have been observed in some patients treated with ivacaftor. Therefore, liver function tests 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 transaminase elevations, more frequent monitoring of liver function tests should be considered. In the event of significant elevations of transaminases (e.g., patients with ALT or AST > 5 x the upper limit of normal (ULN), or ALT or AST > 3 x ULN with bilirubin > 2 x ULN), dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following resolution of transaminase elevations, the benefits and risks of resuming treatment should be considered (see section 4.8).

Hepatic impairment
Use of Kalydeco is not recommended in patients with severe hepatic impairment unless the benefits are expected to outweigh the risks (see sections 4.2 and 5.2).

Renal impairment
Caution is recommended while using Kalydeco in patients with severe renal impairment or end-stage renal disease (see sections 4.2 and 5.2).

Patients after organ transplantation
Kalydeco has not been studied in patients with CF who have undergone organ transplantation. Therefore, use in transplanted patients is not recommended. See section 4.5 for interactions with cyclosporin or tacrolimus.

Interactions with medicinal products
CYP3A inducers
Exposure to ivacaftor is significantly decreased by the concomitant use of CYP3A inducers, potentially resulting in the loss of ivacaftor efficacy; therefore, co-administration of ivacaftor with strong CYP3A inducers is not recommended (see section 4.5).

CYP3A inhibitors
Exposure to ivacaftor is increased when co-administered with strong or moderate CYP3A inhibitors. The dose of ivacaftor must be adjusted when concomitantly used with strong or moderate CYP3A inhibitors (see Table 2 and sections 4.2 and 4.5).

Paediatric population
Cases of non-congenital lens opacities/cataracts without impact on vision have been reported in paediatric patients treated with ivacaftor. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation) a possible risk attributable to treatment with ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating ivacaftor treatment (see section 5.3).

Lactose content
Kalydeco contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium content
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7 Effects on ability to drive and use machines
Kalydeco has minor influence on the ability to drive or use machines. Ivacaftor may cause dizziness (see section 4.8) and, therefore, patients experiencing dizziness should be advised not to drive or use machines until symptoms abate.