Kalydeco 150 mg film-coated tablets

Each film-coated tablet contains 150 mg of ivacaftor.

Excipient with known effect: each film-coated tablet contains 167.2 mg lactose (as monohydrate)

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Light blue capsule-shaped tablets, printed with “V 150” in black ink on one side and plain on the other (16.5 mm x 8.4 mm in modified caplet shape).

Kalydeco is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have one of the following gating (class III) mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R (see sections 4.4 and 5.1).

Kalydeco should only be prescribed by physicians with experience in the treatment of cystic fibrosis. If the patient's genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of one of the above-listed gating (class III) mutations in at least one allele of the CFTR gene before starting treatment.

Posology

Adults, adolescents and children aged 6 years and older

The recommended dose is 150 mg taken orally every 12 hours (300 mg total daily dose).

Kalydeco should be taken with fat-containing food. Meals and snacks recommended in CF guidelines or meals recommended in standard nutritional guidelines contain adequate amounts of fat. Examples of meals that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats. Food containing grapefruit or Seville oranges should be avoided during treatment with Kalydeco (see section 4.5).

Special populations

Elderly

The efficacy and safety of Kalydeco in patients age 65 years or older have not been eva luated.

Renal impairment

No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended while using ivacaftor in patients with severe renal impairment (creatinine clearance less than or equal to 30 ml/min) or end-stage renal disease. (See sections 4.4 and 5.2.)

Hepatic impairment

No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dose of 150 mg once daily is recommended in patients with moderate hepatic impairment (Child-Pugh Class B). There is no experience of use of Kalydeco in patients with severe hepatic impairment. The use of Kalydeco in these patients is therefore not recommended unless the benefits outweigh the risks. In such case, the starting dose should be 150 mg every other day. Dosing intervals should be modified according to clinical response and tolerability (see sections 4.4 and 5.2).

Concomitant use of CYP3A inhibitors

When co-administered with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin and clarithromycin), Kalydeco should be administered at a dose of 150 mg twice a week (see sections 4.4 and 4.5).

When co-administered with moderate inhibitors of CYP3A (e.g., fluconazole, erythromycin), Kalydeco should be administered at a single daily dose of 150 mg (see sections 4.4 and 4.5).

Paediatric population

The safety and efficacy of Kalydeco in children aged less than 6 years have not been established. No data are available.

Method of administration

For oral use. Patients should be instructed to swallow the tablets whole (e.g., patients should not chew, break or dissolve the tablet).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Only patients with CF who had a G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R gating (Class III) mutation in at least one allele of the CFTR gene were included in studies 1, 2, and 5 (see section 5.1). Only limited data are available in patients carrying the G551D-CFTR mutation with percent predicted FEV₁ (forced expiratory volume exhaled in the first second) of less than 40% (12 patients). Patients with a percent predicted FEV₁ below 40% were not included in the study of patients with CF with non-G551D gating mutations, Study 5 (see section 5.1).

In study 5, four patients with the G970R mutation were included. In three of four patients the improvement 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. 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 FEV₁ over 16 weeks of ivacaftor treatment compared to placebo (see section 5.1). Ivacaftor has not been studied in other populations of patients with CF. 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 subjects with CF. Overall, the incidence and clinical features of transaminase elevations in clinical trials was similar between subjects in the ivacaftor and placebo treatment groups (see section 4.8). In the subset of patients with a medical history of elevated transaminases, increased ALT or AST have been reported more frequently in patients receiving ivacaftor compared to placebo. Therefore, liver function tests are recommended prior to initiating ivacaftor, every 3 months during the first year of treatment, and annually thereafter. Patients who develop unexplained increased transaminase levels during treatment should be closely monitored until the abnormalities resolve and consideration should be given to the continuation of treatment after assessment of the individual benefits and risks.

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).

Hepatic impairment

Use of Kalydeco is not recommended in patients with severe hepatic impairment unless the benefits are expected to outweigh the risks of overexposure. In such case, the starting dose interval should be 150 mg of Kalydeco every other day (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 cyclosporine or tacrolimus.

Interactions with medicinal products

Ivacaftor is a substrate of CYP3A4 and CYP3A5. Medicinal products that inhibit or induce CYP3A activity, may impact the pharmacokinetics of ivacaftor (see section 4.5). The dose of Kalydeco must be adjusted when concomitantly used with strong or moderate CYP3A inhibitors. Exposure to ivacaftor may be reduced by the concomitant use of CYP3A inducers, potentially resulting in loss of Kalydeco efficacy (see sections 4.2 and 4.5).

Ivacaftor is a weak CYP3A inhibitor and may modify the pharmacokinetics of medicinal products metabolised through the CYP3A system. In vitro studies indicated that ivacaftor has the potential to inhibit CYP2C9. Ivacaftor is a weak inhibitor of P-glycoprotein (P-gp) and may increase the exposure of medicinal products that are substrates for P-gp (see section 4.5).

Cataracts

Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patients aged up to 12 years old treated with ivacaftor. Although other risk factors were present in some cases (such as corticosteroid use, exposure to radiation) a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating ivacaftor treatment.

Lactose

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