Presentation and Status in Health Basket
Presentation | Basket | Yarpa | Pharmasoft |
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Film Coated Tablets 56 X 150 mg |
56073 | 11256 | |
Granules 56 Sachets X 50 mg |
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Granules 56 Sachets X 75 mg |
18720 |
Related information
Dosage
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.
Adults, adolescents and children aged 2 years and older:
Weight <14 kg: 50 mg granules taken orally every 12 hours with fat containing food. Total daily dose: 100 mg.
Weight ≥14 kg to <25 kg: 75 mg granules taken orally every 12 hours with fat-containing food. Total daily dose: 150 mg.
Weight ≥25 kg: 150 mg tablet taken orally every 12 hours with fat-containing food. Total daily dose: 300 mg.
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 and 150 mg once daily with body weight more than or equal to 25 kg.
When co-administered with moderate inhibitors of CYP3A (e.g., fluconazole, erythromycin), the Kalydeco dose is as above recommended, but administered once daily.
Elderly: The efficacy and safety of Kalydeco in patients aged 65 years or older have not been evaluated.
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.
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 one tablet or one sachet once daily is recommended. 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 one tablet or one sachet every other day (see Table 1 at the attached doctor’s leaflet). Dosing intervals should be modified according to clinical response and tolerability.
Paediatric population: The safety and efficacy of Kalydeco in children aged less than 2 years have not been established. No data are available.
An appropriate dose for children weighing less than 25 kg cannot be achieved with Kalydeco tablets.
Method of administration: For oral use. Kalydeco should be taken with fat-containing food. Food or drink containing grapefruit or Seville oranges should be avoided during treatment.
Film-coated tablets: Patients should be instructed to swallow the tablets whole. The tablets should not be chewed, crushed, or broken before swallowing).
Granule in sachet: 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.
Indications
Kalydeco tablets are indicated for the treatment of patients with cystic fibrosis (CF) aged 6 years and older and weighing 25 kg or more who have one of the following gating (class III) mutations in the CFTR gene:
G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R.
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.
Limitations of use: Kalydeco is not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene.
Contra-Indications
Hypersensitivity to the active substance or to any of the excipients.
Special Precautions
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 6. 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. 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 4 treatment compared to placebo. 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.
Hepatic impairment: Use of Kalydeco is not recommended in patients with severe hepatic impairment unless the benefits are expected to outweigh the risks.
Renal impairment: Caution is recommended while using Kalydeco in patients with severe renal impairment or end-stage renal disease.
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.
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. CYP3A inhibitors: The dose of Kalydeco must be adjusted when concomitantly used with strong or moderate CYP3A inhibitors. 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 treatment 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, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Sodium: This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
Side Effects
The most common adverse reactions experienced by patients aged 6 years and older who received ivacaftor in the pooled 48-week placebo-controlled Phase 3 studies that occurred with an incidence of at least 3% and up to 9% higher than in the placebo arm were headache (23.9%), oropharyngeal pain (22.0%), upper respiratory tract infection (22.0%), nasal congestion (20.2%), abdominal pain (15.6%), nasopharyngitis (14.7%), diarrhoea (12.8%), dizziness (9.2%), rash (12.8%) and bacteria in sputum (12.8%). Transaminase elevations occurred in 12.8% of ivacaftor-treated patients versus 11.5% of placebo-treated patients.
In patients aged 2 to less than 6 years the most common adverse reactions were nasal congestion (26.5%), upper respiratory tract infection (23.5%), transaminase elevations (14.7%), rash (11.8%), and bacteria in sputum (11.8%).
Serious adverse reactions in patients who received ivacaftor included abdominal pain and transaminase elevations.
See prescribing information for full details.
Drug interactions
Ivacaftor is a substrate of CYP3A4 and CYP3A5. It is a weak inhibitor of CYP3A and P-gp and a potential inhibitor of CYP2C9. In vitro studies showed that ivacaftor is not a substrate for OATP1B1, OATP1B3, or P-gp. It is not known if ivacaftor and/or its metabolites are substrates of BCRP.
Medicinal products affecting the pharmacokinetics of ivacaftor:
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 is recommended for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin and clarithromycin.
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 is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin.
Co-administration of Kalydeco with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure to ivacaftor. Food or drink containing grapefruit or Seville oranges should be avoided during treatment with Kalydeco.
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 of Kalydeco with strong CYP3A inducers, such as rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John’s wort (Hypericum perforatum), is not recommended.
No dose adjustment is recommended when Kalydeco is used with moderate or weak CYP3A inducers.
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: Administration of ivacaftor may increase systemic exposure of medicinal products that are sensitive substrates of CYP3A, and/or P-gp, and/or CYP2C9 which may increase or prolong their therapeutic effect and adverse reactions.
CYP2C9 substrates: Ivacaftor may inhibit CYP2C9. Therefore, monitoring of the international normalised ratio (INR) is recommended during co-administration of warfarin with Kalydeco. Other medicinal products for which exposure may be increased include glimepiride and glipizide; these medicinal products should be used with caution.
Digoxin and other P-gp substrates: 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 Kalydeco may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index, such as ciclosporin, everolimus, sirolimus or tacrolimus, caution and appropriate monitoring should be used.
CYP3A substrates: Co-administration with (oral) midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. No dose adjustment of CYP3A substrates, such as midazolam, alprazolam, diazepam or triazolam, is required when these are co-administered with ivacaftor.
Hormonal contraceptives: Ivacaftor has been studied with an oestrogen/progesterone oral contraceptive and was found to have no significant effect on the exposures of the oral contraceptive Therefore, no dose adjustment of oral contraceptives is necessary.
Paediatric population: Interaction studies have only been performed in adults.
Pregnancy and Lactation
Pregnancy: There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ivacaftor in pregnant women.
As a precautionary measure, it is preferable to avoid the use of ivacaftor during pregnancy.
Lactation: It is unknown whether ivacaftor and/or its metabolites are excreted in human milk. Risks to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Kalydeco therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
See prescribing information for full details.
Overdose
No specific antidote is available for overdose with ivacaftor. Treatment of overdose consists of general supportive measures including monitoring of vital signs, liver function tests and observation of the clinical status of the patient.
Important notes
Granules in sachet: Once mixed with food, Kalydeco granules have been shown to be stable for one hour.