KALYDECO dosing and safety reference card Tablets and granules KALYDECO granules 50 mg KALYDECO granules 75 mg KALYDECO tablets NEW 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 gating (class III) mutations in the CFTR gene listed below. 1 KALYDECO tablets are indicated for the treatment of patients with CF aged 6 years and older and weighing 25 kg or more who have one of the gating (class III) mutations in the CFTR gene listed below.² NEW KALYDECO tablets are now also indicated for the treatment of patients with CF aged 18 years and older who have an R117H mutation in the CFTR gene. 2 G551D c.1652g>a p.gly551asp S549N c.1646g>a p.ser549asn G551S c.1651g>a p.gly551ser G1244E c.3731g>a p.gly1244glu S1255P c.3763t>c p.ser1255pro NEW R117H c.350g>a p.arg117his G178R c.532g>a p.gly178arg S549R c.1645a>c or c.1647t>g p.ser549arg S1251N c.3752g>a p.ser1251asn G1349D c.4046g>a p.gly1349asp Above shows CFTR mutation legacy name and cdna name (Human Genome Variation Society nomenclature). 3 Abbreviated prescribing information can be found on back cover. CFTR = cystic fibrosis transmembrane conductance regulator. KALYDECO is not indicated for patients with the G970R mutation in the CFTR gene.
Dosing recommendations for patients aged 2 years and older 1,2 Patients less than 14 kg in weight 50 mg granules taken orally every 12 hours (100 mg total daily dose) with fat-containing food Patients 14 kg to less than 25 kg in weight Patients 25 kg or more in weight and aged 6 years and above 75 mg granules taken orally every 12 hours (150 mg total daily dose) with fat-containing food KALYDECO tablets taken orally 150 mg every 12 hours (300 mg total daily dose) with fat-containing food GRANULES 56-count carton for 28 day supply (contains 4 individual wallets with 14 sachets per wallet of KALYDECO granules 50 mg per sachet or KALYDECO granules 75 mg per sachet) 1 KALYDECO granules 50 mg KALYDECO granules 75 mg TABLETS Blister pack containing 56 film-coated tablets for 28 day supply of KALYDECO tablets 150 mg 2
How to take KALYDECO granules and tablets GRANULES Each sachet is for single oral use only¹ Each sachet of KALYDECO granules should be mixed with 5 ml of age-appropriate soft food or liquid and completely and immediately consumed If not immediately consumed, the mixture has been shown to be stable for one hour and therefore should be ingested during this period Some examples of age-appropriate soft foods or liquids include puréed fruits or vegetables, yoghurt, water, milk or juice Food or liquid should be at room temperature or below TABLETS KALYDECO (150 mg) tablets should be taken orally every 12 hours (300 mg total daily dose) with fat-containing food² GRANULES & TABLETS 1,2 KALYDECO is fat-soluble which means it dissolves in fat. This makes it easier for the body to absorb/get into the bloodstream. In fact, studies have shown that the absorption of KALYDECO increased approximately 2 4 times when given with fatcontaining food. 1,2 Therefore, KALYDECO should be taken with fat-containing foods to help ensure the right amount of KALYDECO in the body. A fat-containing meal or snack should be given just before or just after dosing Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs. Other fat-containing foods include: Full fat cheese, whole milk, whole-milk dairy products, yoghurt, chocolate Meats, oily fish Avocados, hummus, soy-based products Nuts, fat-containing nutritional bars or drinks These are example foods only Food containing grapefruit or Seville oranges should be avoided during treatment with KALYDECO Missed dose 1,2 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 Do not give a double dose to make up for a missed dose
Important safety information 1,2 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 30 ml/min) or end-stage renal disease Hepatic impairment Mild hepatic impairment (Child-Pugh Class A, score 5 to 6): no dose adjustment is necessary for either with granules or tablets Moderate hepatic impairment (Child-Pugh Class B, score 7 to 9): For granules, reduce dose to 50 mg once daily in patients aged 2 years and older with body weight <14 kg and 75 mg once daily for those with body weight 14 kg to <25 kg. For tablets, reduce dose to 150 mg once daily Severe hepatic impairment (Child-Pugh Class C, score 10 to 15): the use of KALYDECO is not recommended unless the benefits outweigh the risks. In such cases, the starting dose should be a reduced dose of (and dosing intervals should be modified according to clinical response and tolerability): For granules, reduce dose to 50 mg every other day in patients aged 2 years and older with body weight <14 kg and 75 mg every other day for those with body weight 14 kg to <25 kg For tablets, reduce dose to 150 mg every other day Lactose KALYDECO contains lactose Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take KALYDECO Cataracts Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patients treated with KALYDECO Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to KALYDECO cannot be excluded Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating KALYDECO treatment Patients after organ transplantation KALYDECO has not been studied in patients with cystic fibrosis who have undergone organ transplantation; therefore, use in transplanted patients is not recommended Paediatric population The safety and efficacy of KALYDECO in children aged less than 2 years have not been established: no data are available Pregnancy No adequate and well-controlled studies of KALYDECO in pregnant women have been conducted. Developmental toxicity studies have been performed in rats and rabbits at daily doses up to 5 times the human daily dose and have revealed no evidence of harm to the foetus due to KALYDECO Because animal reproduction studies are not always predictive of human response, KALYDECO should be used during pregnancy only if clearly needed Breast-feeding The safe use of KALYDECO during breast-feeding has not been established. KALYDECO should only be used during breast-feeding if the potential benefit outweighs the potential risk Fertility KALYDECO impaired fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (resulting in exposures approximately 5 and 6 times, respectively, the exposure in humans at the maximum recommended human dose [MRHD] based on summed area under the curves (AUCs) of KALYDECO and its metabolites) when dams were dosed prior to and during early pregnancy No effects on male or female fertility and reproductive performance indices were observed at 100 mg/kg/day (resulting in exposures approximately 3 times the exposure in humans at the MRHD based on summed AUCs of KALYDECO and its metabolites) Special warnings and precautions for use Only patients with CF who had a G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, S549R gating (class III) or an R117H mutation in at least one allele of the CFTR gene were included in Phase 3 studies Only limited data are available in patients carrying the G551D-CFTR mutation with percent predicted FEV 1 <40% (12 patients) Patients with a percent predicted FEV 1 below 40% were not included in the study of patients with cystic fibrosis with non-g551d gating mutations Based on clinical (percent predicted FEV 1 ) and pharmacodynamic (sweat chloride) responses to KALYDECO, efficacy in patients with the G970R mutation could not be established Efficacy results from a Phase 2 study in patients with cystic fibrosis homozygous for the F508del mutation in the CFTR gene showed no statistically significant difference in FEV 1 over 16 weeks of KALYDECO treatment compared to placebo. Therefore, use of KALYDECO in these patients is not recommended Efficacy was not demonstrated in patients aged 6 to 11 years with CF who have an R117H mutation Less evidence of a positive effect of KALYDECO has been shown for patients with an R117H-7T mutation associated with less severe disease. Whenever possible the phase of the poly-t variant identified with the R117H mutation should be determined as this may be informative in considering treatment of patients with an R117H mutation Effects on ability to drive and use machines KALYDECO has minor influence on the ability to drive or use machines KALYDECO may cause dizziness and, therefore, patients experiencing dizziness should be advised not to drive or use machines until symptoms abate
Interactions with other medicinal products* and dose recommendations 1,2 Class Drug example(s) Recommendation Recommendation GRANULES TABLETS Medicinal products affecting the pharmacokinetics of KALYDECO: Strong CYP3A inhibitors Ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin 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 KALYDECO should be administered at a dose of 150 mg twice a week Moderate CYP3A inhibitors Fluconazole, erythromycin KALYDECO dose should be reduced to 50 mg once daily 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 KALYDECO should be administered at a single daily dose of 150 mg Strong CYP3A inducers Weak to moderate CYP3A inducers Rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John s wort (Hypericum perforatum) Dexamethasone, high-dose prednisone Co-administration with KALYDECO is not recommended Concomitant use may decrease the exposure of KALYDECO and thus may reduce KALYDECO efficacy Medicinal products affected by KALYDECO: CYP3A, P-gp or CYP2C9 substrates Midazolam, alprazolam, diazepam or triazolam Use with caution and monitor for benzodiazepine-related side effects during concomitant administration Digoxin, ciclosporin or tacrolimus Use with caution and monitor for benzodiazepine-related side effects during concomitant administration Warfarin Monitor the INR (International Normalised Ratio) during co-administration *Interaction studies have been performed only in adults.
Important safety information 1,2 Transaminase elevations Moderate transaminase (alanine transaminase [ALT] or aspartate transaminase [AST]) elevations are common in subjects with cystic fibrosis In placebo-controlled studies (STRIVE and ENVISION), the incidence of transaminase elevations (>3 x upper limit of normal [ULN]) were similar between subjects in the KALYDECO and placebo treatment groups In the subset of patients with a medical history of elevated transaminases, increased ALT or AST have been reported more frequently in patients receiving KALYDECO compared to placebo Monitoring Therefore, liver function tests are recommended for all patients prior to initiating KALYDECO, 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 >5x ULN Following resolution of transaminase elevations, the benefits and risks of resuming KALYDECO dosing should be considered Adverse reactions* in KALYDECO-treated patients aged 2 years and older 1,2 * 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) Table reflects the adverse reactions observed with KALYDECO in all clinical trials (placebo-controlled and uncontrolled studies) in which the length of exposure to KALYDECO ranged from 16 weeks to 144 weeks. 1,2 System organ class Adverse rections Frequency Infections and infestations Upper respiratory tract infection, nasopharyngitis Rhinitis Very common Common Nervous system disorders Headache, dizziness Very common Ear and labyrinth disorders Respiratory, thoracic and mediastinal disorders Ear pain, ear discomfort, tympanic membrane hyperaemia, tinnitus, vestibular disorder Ear congestion Oropharyngeal pain, nasal congestion Sinus congestion, pharyngeal erythema Common Uncommon Very common Common Gastrointestinal disorders Abdominal pain, diarrhoea Very common Hepatobiliary disorders Transaminase elevations Very common Skin and subcutaneous tissue disorders Rash Very common Reproductive system and breast disorders Breast mass Breast inflammation, gynaecomastia, nipple disorder, nipple pain Common Uncommon Investigations Bacteria in sputum Very common
KALYDECO potentiates CFTR protein channel opening at the cellular level 1,2 KALYDECO mechanism of action 1,2,4 Normal CFTR protein CFTR protein with a gating (class III) defect KALYDECO potentiates CFTR protein within licensed gating defects* Gating/opening of the CFTR protein allows CI - transport to occur normally 5,6 CFTR protein channel with a gating defect has decreased opening that restricts CI - transport 5,6 KALYDECO facilitates increased CI - transport by potentiating the gating of the defective CFTR protein 1,2,4 The exact mechanism leading KALYDECO to potentiate the gating activity of normal and some mutant CFTR forms in this system has not been completely elucidated. 1,2 *G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R or R117H.
UK Ireland Abbreviated Prescribing Information: KALYDECO (ivacaftor) (UK) (Refer to Summary of Product Characteristics for full information) This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. Presentation: Film-coated tablets: each tablet contains 150 mg ivacaftor. Granules in sachet: each sachet contains 50 mg or 75 mg ivacaftor. Therapeutic Indication: Kalydeco is indicated for the treatment of patients with cystic fibrosis (CF) aged 2 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. Kalydeco tablets are indicated for the treatment of CF patients 18 years or older who have an R117H mutation in the CFTR gene. Dosage and Administration: Kalydeco should only be prescribed by physicians with experience in the treatment of CF. 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 or an R117H mutation in at least one allele of the CFTR gene. For R117H, the phase of the poly-t variant should be determined in accordance with local clinical recommendations. Patients aged 2 years and older (<25 kg in weight): <14 kg - 50 mg granules taken orally every 12 hours (100 mg total daily dose); 14 kg to <25 kg - 75 mg granules taken orally every 12 hours (150 mg total daily dose). Patients aged 6 years and older ( 25 kg in weight): 150 mg tablet taken orally every 12 hours (300 mg total daily dose). Kalydeco should be taken with fat-containing food. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Special Warnings and Precautions: Only patients with CF who had a G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, S549R, or R117H mutation in at least one allele of the CFTR gene were included in Phase 3 studies. Efficacy in patients with the G970R mutation could not be established. Efficacy in patients less than 18 years of age with an R117H mutation could not be established. Less evidence of a positive effect has been shown for patients with an R117H-7T mutation (where possible the phase of the poly-t variant should be determined to aid treatment considerations for patients with an R117H mutation). 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 effect on lung function over 16 weeks of ivacaftor treatment. The use of Kalydeco in patients with CF who do not have any of the approved mutations is not recommended. Limited data are available in patients who have a G551D-CFTR mutation with percent predicted FEV 1 (forced expiratory volume exhaled in the first second) of less than 40%. Patients with a percent predicted FEV 1 below 40% were not included in the study of patients with CF with non-g551d gating mutations. Moderate transaminase (alanine transaminase [ALT] or aspartate transaminase [AST]) elevations are common in subjects with CF. In placebo-controlled studies, the incidence of transaminase elevations (>3 x ULN) were similar between subjects in the ivacaftor and placebo treatment groups. 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 for all patients prior to initiating ivacaftor, every 3 months during the first year of treatment, and annually thereafter. For 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. Caution is recommended while using ivacaftor in patients with severe renal impairment or end-stage renal disease. 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, 75 mg or 150 mg every other day. Ivacaftor has not been studied in patients with CF who have undergone organ transplantation. Therefore, use in transplanted patients is not recommended. Noncongenital lens opacities without impact on vision have been reported in paediatric patients treated with ivacaftor. In some cases other risk factors were present (e.g., corticosteroid use and exposure to radiation); however, a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating ivacaftor treatment. Kalydeco contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Pharmacokinetic 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. A reduction of the Kalydeco dose to 50 mg, 75 mg or 150 mg twice a week is recommended for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin. A reduction of the Kalydeco dose to 50 mg, 75 mg or 150 mg once daily is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin. No dose adjustment of Kalydeco is required when co-administered with ciprofloxacin. Food containing grapefruit or Seville oranges should be avoided during treatment with ivacaftor. Co-administration with strong CYP3A inducers, such as rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John s Wort (Hypericum perforatum) is not recommended. Concomitant use of weak to moderate inducers of CYP3A (e.g., dexamethasone, high-dose prednisone) may decrease the exposure of ivacaftor and thus may reduce ivacaftor efficacy. 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. Use with caution and monitor for benzodiazepine-related side effects when using concomitant midazolam, alprazolam, diazepam or triazolam. Use with caution and appropriate monitoring when using concomitant digoxin, cyclosporin, or tacrolimus. Ivacaftor may inhibit CYP2C9. Therefore, monitoring of the INR during co-administration with warfarin is recommended. Pregnancy: No adequate and well-controlled studies of Kalydeco in pregnant women have been conducted. Developmental toxicity studies have been performed in rats and rabbits at daily doses up to 5 times the human daily dose and have revealed no evidence of harm to the foetus due to ivacaftor. Because animal reproduction studies are not always predictive of human response, Kalydeco should be used during pregnancy only if clearly needed. Lactation: It is unknown whether ivacaftor and/or its metabolites are excreted in human milk. Ivacaftor was shown to be excreted into the milk of lactating female rats. The safe use of Kalydeco during breast-feeding has not been established. Kalydeco should only be used during breastfeeding if the potential benefit outweighs the potential risk. Undesirable Effects: The most common adverse reactions in ivacaftor-treated patients aged 6 years and older in the pooled placebo-controlled Phase 3 studies (occurring at an incidence of 3% to 9% higher than placebo) were headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhoea, dizziness, rash and bacteria in sputum. 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, upper respiratory tract infection, transaminase elevations, rash, and bacteria in sputum. Serious adverse reactions included abdominal pain and transaminase elevations. Other adverse reactions were rhinitis, ear discomfort, ear pain, tinnitus, tympanic membrane hyperaemia, ear congestion, vestibular disorder, pharyngeal erythema, sinus congestion, breast inflammation, breast mass, gynaecomastia, nipple disorder, and nipple pain. The safety profile is generally consistent among children and adolescents and is also consistent with adult patients. For full details of these and other side-effects, please see the Summary of Product Characteristics. List of Excipients: Film-coated tablets: Cellulose, microcrystalline. Lactose monohydrate. Hypromellose acetate succinate. Croscarmellose sodium. Sodium laurilsulfate. Colloidal silicon dioxide. Magnesium stearate. Polyvinyl alcohol. Titanium dioxide (E171). Macrogol (PEG 3350). Talc. Indigo carmine aluminum lake (E132). Carnauba wax. Shellac. Iron oxide black (E172). Propylene glycol. Ammonium hydroxide. Granules in sachet: Colloidal silicon dioxide. Croscarmellose sodium. Hypromellose acetate succinate. Lactose monohydrate. Magnesium stearate. Mannitol. Sucralose. Sodium laurilsulfate. Storage and Use: Store below 30 C. No special requirements for disposal. For oral use. Film-coated tablets: Patients should be instructed to swallow the tablets whole. Granules 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. Once mixed, the product has been shown to be stable for one hour. Legal Category: POM, prescription-only medicine. Price information: 14,000 per 28 days (56 tablets or 56 sachets of granules). Marketing Authorisation Holder: Vertex Pharmaceuticals (Europe) Limited, 2 Kingdom Street, London W2 6BD, United Kingdom. Marketing Authorisation Number(s): Kalydeco 150 mg film-coated tablets: EU/1/12/782/001-002. Kalydeco 50 mg granules in sachet: EU/1/12/782/003. Kalydeco 75 mg granules in sachet: EU/1/12/782/004 Date of First Authorisation: 23 July 2012. Date of Revision of the Text: November 2015. Kalydeco is a trademark of Vertex Pharmaceuticals Incorporated, from whom further information is available.reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions using the below method: Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Vertex Pharmaceuticals (UK) Ltd on 0800 0282616 References: 1. KALYDECO granules Summary of Product Characteristics. November 2015. Vertex Pharmaceuticals (Europe) Limited. 2. KALYDECO tablets Summary of Product Characteristics. February 2016. Vertex Pharmaceuticals (Europe) Limited. 3. The Clinical and Functional TRanslation of CFTR (CFTR2). Last modified 13 August 2015. Available at: http://cftr2.org/files/cftr2_13august2015.pdf. Accessed March 2016. 4. Yu H, et al. J Cyst Fibros 2012;11(3):237-245. 5. Welsh MJ et al. In: Valle D, Beaudet A, Vogelstein B et al, eds. The Online Metabolic & Molecular Bases of Inherited Disease. The McGraw-Hill Companies Inc; 2004:part 21, chap 201. www.ommbid.com. 6. Orenstein DM, et al. Cystic Fibrosis: A Guide for Patient and Family. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004. KALYDECO is manufactured for Vertex Pharmaceuticals Incorporated. KALYDECO, Vertex and the Vertex triangle logo are trademarks of Vertex Pharmaceuticals Incorporated. 2016 Vertex Pharmaceuticals Incorporated. VXR-UK-02-00171a Date of preparation: May 2016
UK Ireland Abbreviated Prescribing Information: KALYDECO (ivacaftor) (Ireland) (Refer to Summary of Product Characteristics for full information) This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. Presentation: Film-coated tablets: each tablet contains 150 mg ivacaftor. Granules in sachet: each sachet contains 50 mg or 75 mg ivacaftor. Therapeutic Indication: Kalydeco is indicated for the treatment of patients with cystic fibrosis (CF) aged 2 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. Kalydeco tablets are indicated for the treatment of CF patients 18 years or older who have an R117H mutation in the CFTR gene. Dosage and Administration: Kalydeco should only be prescribed by physicians with experience in the treatment of CF. 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 or an R117H mutation in at least one allele of the CFTR gene. For R117H, the phase of the poly-t variant should be determined in accordance with local clinical recommendations. Patients aged 2 years and older (<25 kg in weight): <14 kg - 50 mg granules taken orally every 12 hours (100 mg total daily dose); 14 kg to <25 kg - 75 mg granules taken orally every 12 hours (150 mg total daily dose). Patients aged 6 years and older ( 25 kg in weight): 150 mg tablet taken orally every 12 hours (300 mg total daily dose). Kalydeco should be taken with fat-containing food. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Special Warnings and Precautions: Only patients with CF who had a G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, S549R, or R117H mutation in at least one allele of the CFTR gene were included in phase III studies. Efficacy in patients with the G970R mutation could not be established. Efficacy in patients less than 18 years of age with an R117H mutation could not be established. Less evidence of a positive effect has been shown for patients with an R117H-7T mutation (where possible the phase of the poly-t variant should be determined to aid treatment considerations for patients with an R117H mutation). 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 effect on lung function over 16 weeks of ivacaftor treatment. The use of Kalydeco in patients with CF who do not have any of the approved mutations is not recommended. Limited data are available in patients who have a G551D- CFTR mutation with percent predicted FEV 1 (forced expiratory volume exhaled in the first second) of less than 40%. Patients with a percent predicted FEV 1 below 40% were not included in the study of patients with CF with non-g551d gating mutations. Moderate transaminase (alanine transaminase [ALT] or aspartate transaminase [AST]) elevations are common in subjects with CF. In placebo-controlled studies, the incidence of transaminase elevations (>3 x ULN) were similar between subjects in the ivacaftor and placebo treatment groups. 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 for all patients prior to initiating ivacaftor, every 3 months during the first year of treatment, and annually thereafter. For 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. Caution is recommended while using ivacaftor in patients with severe renal impairment or end-stage renal disease. 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, 75 mg or 150 mg every other day. Ivacaftor has not been studied in patients with CF who have undergone organ transplantation. Therefore, use in transplanted patients is not recommended. Non-congenital lens opacities without impact on vision have been reported in paediatric patients treated with ivacaftor. In some cases other risk factors were present (e.g., corticosteroid use and exposure to radiation); however, a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating ivacaftor treatment. Kalydeco contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine. Pharmacokinetic 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. A reduction of the Kalydeco dose to 50 mg, 75 mg or 150 mg twice a week is recommended for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin. A reduction of the Kalydeco dose to 50 mg, 75 mg or 150 mg once daily is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin. No dose adjustment of Kalydeco is required when co-administered with ciprofloxacin. Food containing grapefruit or Seville oranges should be avoided during treatment with ivacaftor. Co-administration with strong CYP3A inducers, such as rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John s Wort (Hypericum perforatum) is not recommended. Concomitant use of weak to moderate inducers of CYP3A (e.g., dexamethasone, high-dose prednisone) may decrease the exposure of ivacaftor and thus may reduce ivacaftor efficacy. 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. Use with caution and monitor for benzodiazepine-related side effects when using concomitant midazolam, alprazolam, diazepam or triazolam. Use with caution and appropriate monitoring when using concomitant digoxin, cyclosporin, or tacrolimus. Ivacaftor may inhibit CYP2C9. Therefore, monitoring of the INR during co-administration with warfarin is recommended. Pregnancy: No adequate and well-controlled studies of Kalydeco in pregnant women have been conducted. Developmental toxicity studies have been performed in rats and rabbits at daily doses up to 5 times the human daily dose and have revealed no evidence of harm to the foetus due to ivacaftor. Because animal reproduction studies are not always predictive of human response, Kalydeco should be used during pregnancy only if clearly needed. Lactation: It is unknown whether ivacaftor and/or its metabolites are excreted in human milk. Ivacaftor was shown to be excreted into the milk of lactating female rats. The safe use of Kalydeco during breast-feeding has not been established. Kalydeco should only be used during breast-feeding if the potential benefit outweighs the potential risk. Undesirable Effects: The most common adverse reactions in ivacaftor-treated patients aged 6 years and older in the pooled placebo-controlled Phase 3 studies (occurring at an incidence of 3% to 9% higher than placebo) were headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhoea, dizziness, rash and bacteria in sputum. 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, upper respiratory tract infection, transaminase elevations, rash, and bacteria in sputum. Serious adverse reactions included abdominal pain and transaminase elevations. Other adverse reactions were rhinitis, ear discomfort, ear pain, tinnitus, tympanic membrane hyperaemia, ear congestion, vestibular disorder, pharyngeal erythema, sinus congestion, breast inflammation, breast mass, gynaecomastia, nipple disorder, and nipple pain. The safety profile is generally consistent among children and adolescents and is also consistent with adult patients. For full details of these and other side-effects, please see the Summary of Product Characteristics. List of Excipients: Film-coated tablets: Cellulose, microcrystalline. Lactose monohydrate. Hypromellose acetate succinate. Croscarmellose sodium. Sodium laurilsulfate. Colloidal silicon dioxide. Magnesium stearate. Polyvinyl alcohol. Titanium dioxide (E171). Macrogol (PEG 3350). Talc. Indigo carmine aluminum lake (E132). Carnauba wax. Shellac. Iron oxide black (E172). Propylene glycol. Ammonium hydroxide. Granules in sachet: Colloidal silicon dioxide. Croscarmellose sodium. Hypromellose acetate succinate. Lactose monohydrate. Magnesium stearate. Mannitol. Sucralose. Sodium laurilsulfate. Storage and Use: Store below 30 C. No special requirements for disposal. For oral use. Film-coated tablets: Patients should be instructed to swallow the tablets whole. Granules 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. Once mixed, the product has been shown to be stable for one hour. Legal Category: POM, prescription-only medicine. Price information: 18,000 per 28 days (56 tablets or 56 sachets of granules). Marketing Authorisation Holder: Vertex Pharmaceuticals (Europe) Limited, 2 Kingdom Street, London W2 6BD, United Kingdom. Marketing Authorisation Number(s): Kalydeco 150 mg film-coated tablets: EU/1/12/782/001-002. Kalydeco 50 mg granules in sachet: EU/1/12/782/003. Kalydeco 75 mg granules in sachet: EU/1/12/782/004 Date of First Authorisation: 23 July 2012. Date of Revision of the Text: November 2015. Kalydeco is a trademark of Vertex Pharmaceuticals Incorporated, from whom further information is available. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions. Medical Information Contact: 1800 924568 References: 1. KALYDECO granules Summary of Product Characteristics. November 2015. Vertex Pharmaceuticals (Europe) Limited. 2. KALYDECO tablets Summary of Product Characteristics. February 2016. Vertex Pharmaceuticals (Europe) Limited. 3. The Clinical and Functional TRanslation of CFTR (CFTR2). Last modified 13 August 2015. Available at: http://cftr2.org/files/cftr2_13august2015.pdf. Accessed March 2016. 4. Yu H, et al. J Cyst Fibros 2012;11(3):237-245. 5. Welsh MJ et al. In: Valle D, Beaudet A, Vogelstein B et al, eds. The Online Metabolic & Molecular Bases of Inherited Disease. The McGraw-Hill Companies Inc; 2004:part 21, chap 201. www.ommbid.com. 6. Orenstein DM, et al. Cystic Fibrosis: A Guide for Patient and Family. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004. KALYDECO is manufactured for Vertex Pharmaceuticals Incorporated. KALYDECO, Vertex and the Vertex triangle logo are trademarks of Vertex Pharmaceuticals Incorporated. 2016 Vertex Pharmaceuticals Incorporated. VXR-IE-02-00081 Date of preparation: May 2016