Kalydeco 50mg and 75mg granules sachets
Vertex Pharmaceuticals (Europe) Limited
contact details
Active ingredient
ivacaftor
Legal Category
POM: Prescription only medicine
Kalydeco 50 mg granules in sachet
Kalydeco 75 mg granules in sachet
Kalydeco 50 mg granules in sachet
Each sachet contains 50 mg of ivacaftor.
Excipient with known effect
Each sachet contains 73.2 mg of lactose (as monohydrate)
Kalydeco 75 mg granules in sachet
Each sachet contains 75 mg of ivacaftor.
Excipient with known effect
Each sachet contains 109.8 mg of lactose (as monohydrate)
For the full list of excipients, see section 6.1.
Granules in sachet.
White to off-white granules approximately 2 mm in diameter.
Kalydeco granules are indicated for the treatment of children with cystic fibrosis (CF) aged 2 years and older and weighing less than 25 kg 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 before starting treatment to confirm the presence of one of the above-listed gating (class III) mutations in at least one allele of the CFTR gene.
Posology
Children aged 2 years and older, adolescents and adults should be dosed according to Table 1.
|
Table 1. Dosing recommendations for patients aged 2 years and older
|
|
Weight
|
Dose
|
Total daily dose
|
|
<14 kg
|
50 mg granules taken orally every 12 hours with fat-containing food
|
100 mg
|
|
≥14 kg to <25 kg
|
75 mg granules taken orally every 12 hours with fat-containing food
|
150 mg
|
|
≥25 kg
|
See Kalydeco tablets SmPC for further details.
|
Missed dose
If a dose is missed within 6 hours of the time it is usually taken, the patient should be told to take it as soon as possible and then take the next dose at the regularly scheduled time. If more than 6 hours have passed since the time the dose is usually taken, the patient should be told to wait until the next scheduled dose.
Concomitant use of CYP3A inhibitors
When co-administered with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin and clarithromycin), the Kalydeco dose should be reduced to 50 mg twice a week in patients aged 2 years and older with body weight less than 14 kg and 75 mg twice a week for those with body weight 14 kg to less than 25 kg (see sections 4.4 and 4.5).
When co-administered with moderate inhibitors of CYP3A (e.g., fluconazole, erythromycin), the Kalydeco dose is as above recommended, but administered once daily (see sections 4.4 and 4.5).
Special populations
Renal impairment
No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended while using Kalydeco 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). For patients with moderate hepatic impairment (Child-Pugh Class B), a reduced dose of 50 mg once daily is recommended in patients aged 2 years and older with body weight less than 14 kg and 75 mg once daily for those with body weight 14 kg to less than 25 kg. There is no experience of the use of Kalydeco in patients with severe hepatic impairment and therefore its use is not recommended unless the benefits outweigh the risks. In such cases, the starting dose should be as above recommended, but administered every other day. Dosing intervals should be modified according to clinical response and tolerability (see sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of Kalydeco in children aged less than 2 years have not been established. No data are available.
Method of administration
For oral use.
Each sachet is for single use only.
Each sachet of granules should be mixed with 5 mL of age-appropriate soft food or liquid and completely and immediately consumed. Food or liquid should be at room temperature or below. If not immediately consumed, the mixture has been shown to be stable for one hour and therefore should be ingested during this period. A fat-containing meal or snack should be consumed just before or just after dosing.
Food containing grapefruit or Seville oranges should be avoided during treatment with Kalydeco (see section 4.5).
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, 5 and 7 (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 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). 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. In placebo-controlled studies (studies 1 and 2), the incidence of transaminase elevations (>3 x upper limit of normal [ULN]) were 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 has been reported more frequently in patients receiving ivacaftor compared to placebo. 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.
Patients who develop increased transaminase levels should be monitored closely until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the ULN. Following resolution of transaminase elevations, the benefits and risks of resuming Kalydeco dosing should be considered.
Hepatic impairment
Use of ivacaftor is not recommended in patients with severe hepatic impairment unless the benefits are expected to outweigh the risks of overexposure. In such cases, the starting dose should be 50 mg every other day for patients aged 2 years and older with body weight less than 14 kg and 75 mg every other day for those with body weight 14 kg to less than 25 kg (see sections 4.2 and 5.2).
Renal impairment
Caution is recommended while using ivacaftor in patients with severe renal impairment or end-stage renal disease (see sections 4.2 and 5.2).
Patients after organ transplantation
Ivacaftor 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 ciclosporin or tacrolimus.
Interactions with medicinal products
CYP3A inducers
Exposure to ivacaftor may be reduced by the concomitant use of CYP3A inducers, potentially resulting in the loss of ivacaftor efficacy. Therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.5).
CYP3A inhibitors
The dose of Kalydeco must be adjusted when concomitantly used with strong or moderate CYP3A inhibitors (see sections 4.2 and 4.5).
Cataracts
Cases of non-congenital lens opacities 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 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 medicinal product.
Ivacaftor is a substrate of CYP3A4 and CYP3A5. It is a weak inhibitor of CYP3A and P-gp and a potential inhibitor of CYP2C9.
Medicinal products affecting the pharmacokinetics of ivacaftor:
CYP3A inducers
Co-administration of ivacaftor with rifampicin, a strong CYP3A inducer, decreased ivacaftor exposure (AUC) by 89% and decreased M1 to a lesser extent than ivacaftor. Co-administration with strong CYP3A inducers, such as rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John's wort (Hypericum perforatum), is not recommended (see section 4.4).
Concomitant use of weak to moderate inducers of CYP3A (e.g., dexamethasone, high-dose prednisone) may decrease the exposure of ivacaftor. No dose adjustment for ivacaftor is recommended. Patients should be monitored for reduced ivacaftor efficacy when ivacaftor is co-administered with moderate CYP3A inducers.
CYP3A inhibitors
Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, increased ivacaftor exposure (measured as area under the curve [AUC]) by 8.5-fold and increased hydroxymethyl-ivacaftor (M1) to a lesser extent than ivacaftor. A reduction of the Kalydeco dose to 50 mg twice a week in patients aged 2-years and older with body weight less than 14 kg and 75 mg twice a week for those with body weight 14 kg to less than 25 kg is recommended for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin and clarithromycin (see sections 4.2 and 4.4).
Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold and increased M1 to a lesser extent than ivacaftor. A reduction of the Kalydeco dose as above recommended, but administered once daily is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin (see sections 4.2 and 4.4).
Co-administration of ivacaftor with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure to ivacaftor. Food containing grapefruit or Seville oranges should be avoided during treatment with Kalydeco (see section 4.2).
Ciprofloxacin
Co-administration of ciprofloxacin with ivacaftor did not affect the exposure of ivacaftor. No dose adjustment is required when Kalydeco is co-administered with ciprofloxacin.
Medicinal products affected by ivacaftor:
CYP3A, P-gp or CYP2C9 substrates
Based on in vitro results, ivacaftor and its M1 metabolite have the potential to inhibit CYP3A and P-gp. Co-administration with (oral) midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor. Administration of ivacaftor may increase systemic exposure of medicinal products that are sensitive substrates of CYP3A and/or P-gp, which may increase or prolong their therapeutic effect and adverse reactions. When used concomitantly with midazolam, alprazolam, diazepam or triazolam, Kalydeco should be used with caution and patients should be monitored for benzodiazepine-related undesirable effects. Caution and appropriate monitoring are recommended when co-administering Kalydeco wi
