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近日,Ivacaftor(商品名：Kalydeco)由Vertex制药公司研制，是FDA首个获批的用于改善囊性纤维化病情的药物。Kalydeco最早在2012年01月获准用于年龄6岁或以上、至少有一个拷贝G551D突变的CF患者，2014年03月，FDA批准Kalydeco一项新药补充申请，用于年龄6岁或以上、在囊性纤维化跨膜电导调节基因中其余8种之一有突变的囊性纤维化(CF)患者。由于这项补充申请的获准，Kalydeco现在可用于有下列9种突变的CF患者：G551D、G178R、S549N、S549R、G551S、G1244E、S1251N、S1255P和G1349D。在美国，目前大约有150名6岁及以上年龄段、有其余8种之一突变基因的CF患者，Kalydeco正是适应了他们的治疗需要。
2.4 Dosing Information in Pediatric Patients less than 2 Years A safe and efficacious dose of KALYDECO for pediatric patients less than 2 years of age has not been established. The use of KALYDECO (oral granules) in children under the age of 2 years is not recommended. 2.5 Dosage Adjustment for Patients with Hepatic Impairment The dose of KALYDECO should be reduced to one tablet or one packet of oral granules once daily for patients with moderate hepatic impairment (Child-Pugh Class B). KALYDECO should be used with caution in patients with severe hepatic impairment (Child-Pugh Class C) at a dose of one tablet or one packet of oral granules once daily or less frequently [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. 2.6 Dosage Adjustment for Patients Taking Drugs that are CYP3A Inhibitors When KALYDECO is being co-administered with strong CYP3A inhibitors (e.g., ketoconazole), the dose should be reduced to one tablet or one packet of oral granules twice a week. The dose of KALYDECO should be reduced to one tablet or one packet of granules once daily when co-administered with moderate CYP3A inhibitors (e.g., fluconazole). Food containing grapefruit or Seville oranges should be avoided [see Drug Interactions (7.1), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. 3 DOSAGE FORMS AND STRENGTHS Tablets: 150 mg; supplied as light blue, film-coated, capsule-shaped tablets containing 150 mg of ivacaftor. Each tablet is printed with the characters "V 150" on one side and plain on the other Oral granules: Unit-dose packets containing 50 mg or 75 mg per packet; supplied as small, white to off-white granules and enclosed in unit-dose packets 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Transaminase (ALT or AST) Elevations Elevated transaminases have been reported in patients with CF receiving KALYDECO. It is recommended that ALT and AST be assessed prior to initiating KALYDECO, 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 closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO dosing [see Adverse Reactions (6) and Use in Specific Populations (8.6)]. 5.2 Concomitant Use with CYP3A Inducers Use of KALYDECO with strong CYP3A inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which may reduce the therapeutic effectiveness of KALYDECO. Therefore, co-administration of KALYDECO with strong CYP3A inducers (e.g., rifampin, St. John's wort) is not recommended [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. 5.3 Cataracts Cases of non-congenital lens opacities/cataracts have been reported in pediatric patients treated with KALYDECO. Although other risk factors were present in some cases (such as corticosteroid use and/or exposure to radiation), a possible risk attributable to KALYDECO cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating KALYDECO treatment. 6 ADVERSE REACTIONS The following adverse reaction is discussed in greater detail in other sections of the label: Transaminase Elevations [see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The overall safety profile of KALYDECO is based on pooled data from three placebo-controlled clinical trials conducted in 353 patients 6 years of age and older with CF who had a G551D mutation in the CFTR gene (Trials 1 and 2) or were homozygous for the F508del mutation (Trial 3). In addition, the following clinical trials have also been conducted [see Clinical Pharmacology (12) and Clinical Studies (14)]: An 8-week crossover design trial (Trial 4) involving 39 patients between the ages of 6 and 57 years with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. A 24-week placebo-controlled trial (Trial 5) involving 69 patients between the ages of 6 and 68 years with an R117H mutation in the CFTR gene. A 24-week open-label trial (Trial 6) in 34 patients 2 to less than 6 years of age. Patients eligible for Trial 6 were those with the G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. Of 34 patients enrolled, 32 had the G551D mutation and 2 had the S549N mutation. Of the 353 patients included in the pooled analyses of patients with CF who had either a G551D mutation or were homozygous for the F508del mutation in the CFTR gene, 50% of patients were female and 97% were Caucasian; 221 received KALYDECO, and 132 received placebo from 16 to 48 weeks. The proportion of patients who prematurely discontinued study drug due to adverse reactions was 2% for KALYDECO-treated patients and 5% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in KALYDECO-treated patients included abdominal pain, increased hepatic enzymes, and hypoglycemia. The most common adverse reactions in the 221 patients treated with KALYDECO were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%), nausea (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%). The incidence of adverse reactions below is based upon two double-blind, placebo-controlled, 48-week clinical trials (Trials 1 and 2) in a total of 213 patients with CF ages 6 to 53 who have a G551D mutation in the CFTR gene and who were treated with KALYDECO 150 mg orally or placebo twice daily. Table 2 shows adverse reactions occurring in ≥8% of KALYDECO-treated patients with CF who have a G551D mutation in the CFTR gene that also occurred at a higher rate than in the placebo-treated patients in the two double-blind, placebo-controlled trials. Table 2: Incidence of Adverse Drug Reactions in ≥8% of KALYDECO-Treated Patients with a G551D Mutation in the CFTR Gene and Greater than Placebo in 2 Placebo-Controlled Phase 3 Clinical Trials of 48 Weeks Duration
Infections and infestations: rhinitis Investigations: aspartate aminotransferase increased, bacteria in sputum, blood glucose increased, hepatic enzyme increased Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, myalgia Nervous system disorders: sinus headache Respiratory, thoracic and mediastinal disorders: pharyngeal erythema, pleuritic pain, sinus congestion, wheezing Skin and subcutaneous tissue disorders: acne The safety profile for the CF patients enrolled in the other clinical trials (Trials 3-6) was similar to that observed in the 48-week, placebo-controlled trials (Trials 1 and 2). Laboratory Abnormalities Transaminase Elevations: In Trials 1, 2, and 3 the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 × ULN was 2%, 2%, and 6% in KALYDECO-treated patients and 2%, 2%, and 8% in placebo-treated patients, respectively. Two patients (2%) on placebo and 1 patient (0.5%) on KALYDECO permanently discontinued treatment for elevated transaminases, all >8 × ULN. Two patients treated with KALYDECO were reported to have serious adverse reactions of elevated liver transaminases compared to none on placebo. Transaminase elevations were more common in patients with a history of transaminase elevations [see Warnings and Precautions (5.1)]. During the 24-week, open-label, clinical trial in 34 patients ages 2 to less than 6 years (Trial 6), where patients received either 50 mg (less than 14 kg) or 75 mg (14 kg or greater) ivacaftor granules twice daily, the incidence of patients experiencing transaminase elevations (ALT or AST) >3 × ULN was 14.7% (5/34). All 5 patients had maximum ALT or AST levels >8 × ULN, which returned to baseline levels following interruption of KALYDECO dosing. Transaminase elevations were more common in patients who had abnormal transaminases at baseline. KALYDECO was permanently discontinued in one patient [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS Potential for other drugs to affect ivacaftor 7.1 Inhibitors of CYP3A Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold. Based on simulations of these results, a reduction of the KALYDECO dose is recommended when co-administered with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin, as follows: in patients 6 years and older reduce dose to one 150 mg tablet twice a week; in patients 2 to less than 6 years with body weight less than 14 kg, reduce dose to one 50 mg packet of granules twice a week; and in patients 2 to less than 6 years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules twice a week. Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO dose is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin, as follows: in patients 6 years and older reduce dose to one 150 mg tablet once daily; in patients 2 to less than 6 years with body weight less than 14 kg, reduce dose to one 50 mg packet of granules once daily; and in patients 2 to less than 6 years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules once daily. Co-administration of KALYDECO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, food containing grapefruit or Seville oranges should be avoided during treatment with KALYDECO [see Clinical Pharmacology (12.3)]. 7.2 Inducers of CYP3A Co-administration with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's wort is not recommended [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. 7.3 Ciprofloxacin Co-administration of KALYDECO with ciprofloxacin had no effect on the exposure of ivacaftor. Therefore, no dose adjustment is necessary during concomitant administration of KALYDECO with ciprofloxacin [see Clinical Pharmacology (12.3)]. Potential for ivacaftor to affect other drugs 7.4 CYP3A and/or P-gp Substrates Ivacaftor and its M1 metabolite have the potential to inhibit CYP3A and P-gp. Co-administration with 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 KALYDECO may increase systemic exposure of drugs that are substrates of CYP3A and/or P-gp, which may increase or prolong their therapeutic effect and adverse events. Therefore, caution and appropriate monitoring are recommended when co-administering KALYDECO with sensitive CYP3A and/or P-gp substrates, such as digoxin, cyclosporine, and tacrolimus [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic effects: Pregnancy Category B. There are no adequate and well-controlled studies of KALYDECO in pregnant women. Ivacaftor was not teratogenic in rats at approximately 6 times the maximum recommended human dose (MRHD) (based on summed AUCs for ivacaftor and its metabolites at a maternal dose of 200 mg/kg/day). Ivacaftor was not teratogenic in rabbits at approximately 12 times the MRHD (on an ivacaftor AUC basis at a maternal dose of 100 mg/kg/day, respectively). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. Because animal reproduction studies are not always predictive of human response, KALYDECO should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers Ivacaftor is excreted into the milk of lactating female rats. Excretion of ivacaftor into human milk is probable. There are no human studies that have investigated the effects of ivacaftor on breast-fed infants. Caution should be exercised when KALYDECO is administered to a nursing woman. 8.4 Pediatric Use The safety and efficacy of KALYDECO in patients 6 to 17 years of age with CF who have a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene have been demonstrated [see Adverse Reactions (6) and Clinical Studies (14)]. The safety and efficacy of KALYDECO in patients 6 to 17 years of age with CF who have an R117H mutation in the CFTR gene have been demonstrated [see Adverse Reactions (6) and Clinical Studies (14)]. The efficacy of KALYDECO in children 2 to less than 6 years of age is extrapolated from efficacy in patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and children 2 to less than 6 years of age [see Clinical Pharmacology (12.3)]. The safety of KALYDECO in children 2 to less than 6 years of age (mean age 3 years) is derived from a 24-week, open-label, clinical trial in 34 patients ages 2 to less than 6 years administered either 50 mg or 75 mg of ivacaftor granules twice daily (Trial 6). Eligible patients were those with the G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. Of 34 patients enrolled, 32 had the G551D mutation and 2 had the S549N mutation. The type and frequency of adverse reactions in this trial were similar to those in patients 6 years and older. Transaminase elevations were more common in patients who had abnormal transaminases at baseline. For patients with a history of transaminase elevations, more frequent monitoring of liver function tests should be considered [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. The safety and efficacy of KALYDECO in patients with CF younger than 2 years of age have not been studied. The use of KALYDECO in children under the age of 2 years is not recommended. 8.5 Geriatric Use CF is largely a disease of children and young adults. Clinical trials of KALYDECO did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dose of KALYDECO is recommended in patients with moderate hepatic impairment (Child-Pugh Class B), as follows: in patients 6 years and older, one 150 mg tablet once daily; in patients 2 to less than 6 years with body weight less than 14 kg, one 50 mg packet of granules once daily; and in patients 2 to less than 6 years with body weight 14 kg or greater, one 75 mg packet of granules once daily. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a dose of one tablet or one packet of granules once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment [see Pharmacokinetics (12.3)]. 8.7 Renal Impairment KALYDECO has not been studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease. No dose adjustment is necessary for patients with mild to moderate renal impairment; however, 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. 8.8 Patients with CF who are Homozygous for the F508del Mutation in the CFTR Gene Efficacy results from a double-blind, placebo-controlled trial in patients with CF who are homozygous for the F508del mutation in the CFTR gene showed no statistically significant difference in forced expiratory volume exhaled in one second (FEV1) over 16 weeks of KALYDECO treatment compared to placebo [see Clinical Studies (14.4)]. Therefore, KALYDECO should not be used in patients homozygous for the F508del mutation in the CFTR gene. 10 OVERDOSAGE There have been no reports of overdose with KALYDECO. The highest single dose used in a clinical study was 800 mg in a solution formulation without any treatment-related adverse events. The highest repeated dose was 450 mg (in a tablet formulation) every 12 hours for 4.5 days (9 doses) in a trial evaluating the effect of KALYDECO on ECGs in healthy subjects. Adverse events reported at a higher incidence compared to placebo included dizziness and diarrhea. No specific antidote is available for overdose with KALYDECO. Treatment of overdose with KALYDECO consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. 11 DESCRIPTION The active ingredient in KALYDECO tablets and oral granules is ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, which has the following chemical name: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. Its molecular formula is C24H28N2O3 and its molecular weight is 392.49. Ivacaftor has the following structural formula: Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 microgram/mL). KALYDECO is available as a light blue, capsule-shaped, film-coated tablet for oral administration containing 150 mg of ivacaftor. Each KALYDECO tablet contains 150 mg of ivacaftor and the following inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains carnauba wax, FD&C Blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. KALYDECO is also available as white to off-white granules for oral administration (sweetened but unflavored) and enclosed in a unit-dose packet containing 50 mg of ivacaftor or 75 mg of ivacaftor. Each unit-dose packet of KALYDECO oral granules contains 50 mg of ivacaftor or 75 mg of ivacaftor and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, mannitol, sucralose, and sodium lauryl sulfate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ivacaftor is a potentiator of the CFTR protein. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein. In vitro, ivacaftor increased CFTR-mediated transepithelial current (IT) in rodent cells expressing the G551D-CFTR protein following addition of a cyclic adenosine monophosphate (cAMP) agonist with an EC50 of 100 ± 47 nM; however, ivacaftor did not increase IT in the absence of cAMP agonist. Ivacaftor also increased IT in human bronchial epithelial cells expressing G551D-CFTR protein following addition of a cAMP agonist by 10-fold with an EC50 of 236 ± 200 nM. Ivacaftor increased the open probability of G551D-CFTR protein in single channel patch clamp experiments using membrane patches from rodent cells expressing G551D-CFTR protein by 6-fold versus untreated cells after addition of PKA and ATP. In addition to G551D-CFTR, ivacaftor increased the channel-open probability of other mutant CFTR forms expressed in rodent cells, resulting in enhanced CFTR-mediated IT. These mutant CFTR forms included G178R-, S549N-, S549R-, G551S-, G970R-, G1244E-, S1251N-, S1255P-, and G1349D-CFTR. Ivacaftor also potentiated the channel-open probability of R117H-CFTR, which has low channel-open probability (gating) and reduced channel current amplitude (conductance) compared to normal CFTR. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit. 12.2 Pharmacodynamics Sweat Chloride Evaluation Changes in sweat chloride response to KALYDECO were evaluated in six clinical trials. In two randomized, double-blind, placebo-controlled clinical trials in patients with a G551D mutation in the CFTR gene, one in patients 12 and older (Trial 1) and the other in patients 6-11 years of age (Trial 2), the treatment difference (between KALYDECO and placebo) in mean change in sweat chloride from baseline through Week 24 was -48 mmol/L (95% CI -51, -45) and -54 mmol/L (95% CI -62, -47), respectively. These changes persisted through 48 weeks. In a 16-week, randomized, double-blind, placebo-controlled, parallel-group clinical trial in patients with CF age 12 years and older who were homozygous for the F508del mutation in the CFTR gene (Trial 3), the treatment difference in mean change in sweat chloride from baseline through 8 weeks of treatment was -3 mmol/L (95% CI -6, -0.2). In a two-part, randomized, double-blind, placebo-controlled, crossover clinical trial in patients with CF who had a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene (Trial 4), the treatment difference in mean change in sweat chloride from baseline through 8 weeks of treatment was -49 mmol/L (95% CI -57, -41). In Trial 4, mean changes in sweat chloride for the mutations for which KALYDECO is indicated ranged from -51 to -8, whereas the range for individual subjects with the G970R mutation was -1 to -11 mmol/L. In a randomized, double-blind, placebo-controlled clinical trial in patients with CF who had an R117H mutation in the CFTR gene (Trial 5), the mean baseline sweat chloride for all patients was 70 mmol/L. The treatment difference in mean change in sweat chloride from baseline through 24 weeks of treatment was -24 mmol/L (95% CI -28, -20) [see Clinical Studies (14)]. In an open-label clinical trial in 34 patients ages 2 to less than 6 years administered either 50 mg or 75 mg of ivacaftor twice daily (Trial 6), the mean absolute change from baseline in sweat chloride through 24 weeks of treatment was -45 mmol/L (95% CI -53, -38) [see Pediatric Use (8.4)]. There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (FEV1). ECG Evaluation The effect of multiple doses of ivacaftor 150 mg and 450 mg twice daily on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia's correction method (QTcF) was below 10 ms, the threshold for regulatory concern. 12.3 Pharmacokinetics The pharmacokinetics of ivacaftor is similar between healthy adult volunteers and patients with CF. After oral administration of a single 150 mg dose to healthy volunteers in a fed state, peak plasma concentrations (Tmax) occurred at approximately 4 hours, and the mean (±SD) for AUC and Cmax were 10600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively. After every 12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9. Absorption The exposure of ivacaftor increased approximately 2.5- to 4-fold when given with food that contains fat. Therefore, KALYDECO should be administered with fat-containing food. Examples of fat-containing foods include eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc. The median (range) Tmax is approximately 4.0 (3.0; 6.0) hours in the fed state. KALYDECO granules (2 × 75 mg) had similar bioavailability as the 150 mg tablet when given with fat-containing food in adult subjects. The effect of food on ivacaftor absorption is similar for KALYDECO granules and the 150 mg tablet formulation. Distribution Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells. After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L. Metabolism Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active. Elimination Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent. The apparent terminal half-life was approximately 12 hours following a single dose. The mean apparent clearance (CL/F) of ivacaftor was similar for healthy subjects and patients with CF. The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects. Specific populations Pediatric patients The following conclusions about exposures between adults and the pediatric population are based on population PK analyses: Pediatric patients 2 to less than 6 years of age who weigh less than 14 kg Following oral administration of KALYDECO granules, 50 mg every 12 hours, the mean (±SD) steady state AUC (AUCss) was 10500 (4260) ng/mL*h and is similar to the mean AUCss of 10700 (4100) ng/mL*h in adult patients administered KALYDECO tablets, 150 mg every 12 hours. Pediatric patients 2 to less than 6 years of age who weigh 14 kg or greater Following oral administration of KALYDECO granules, 75 mg every 12 hours, the mean (±SD) AUC (AUCss) was 11300 (3820) ng/mL*h and is similar to the mean AUC in adult patients administered KALYDECO tablets, 150 mg every 12 hours. Pediatric patients 6 to less than 12 years of age Following oral administration of KALYDECO tablets, 150 mg every 12 hours, the mean (±SD) AUCss was 20000 (8330) ng/mL*h and is 87% higher than the mean AUC in adult patients administered KALYDECO tablets, 150 mg every 12 hours. Pediatric patients 12 to less than 18 years of age Following oral administration of KALYDECO tablets, 150 mg every 12 hours, the mean (±SD) AUCss was 9240 (3420) ng/mL*h and is similar to the mean AUCss in adult patients administered KALYDECO tablets, 150 mg every 12 hours. Hepatic impairment Adult subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 -9) had similar ivacaftor Cmax, but an approximately two-fold increase in ivacaftor AUC0-∞ compared with healthy subjects matched for demographics. Based on simulations of these results, a reduced KALYDECO dose to one tablet or packet of granules once daily is recommended for patients with moderate hepatic impairment. The impact of mild hepatic impairment (Child-Pugh Class A) on the pharmacokinetics of ivacaftor has not been studied, but the increase in ivacaftor AUC0-∞ is expected to be less than two-fold. Therefore, no dose adjustment is necessary for patients with mild hepatic impairment. The impact of severe hepatic impairment (Child-Pugh Class C, score 10-15) on the pharmacokinetics of ivacaftor has not been studied. The magnitude of increase in exposure in these patients is unknown, but is expected to be substantially higher than that observed in patients with moderate hepatic impairment. When benefits are expected to outweigh the risks, KALYDECO should be used with caution in patients with severe hepatic impairment at a dose of one tablet or one packet of granules given once daily or less frequently [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)]. Renal impairment KALYDECO has not been studied in patients with mild, moderate, or severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or in patients with end-stage renal disease. No dose adjustments are recommended for mild and moderate renal impairment patients because of minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine in a human PK study); however, caution is recommended when administering KALYDECO to patients with severe renal impairment or end-stage renal disease. Gender The effect of gender on KALYDECO pharmacokinetics was evaluated using population pharmacokinetics of data from clinical studies of KALYDECO. No dose adjustments are necessary based on gender. Drug Interactions Drug interaction studies were performed with KALYDECO and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7)]. Dosing recommendations based on clinical studies or potential drug interactions with KALYDECO are presented below. Potential for Ivacaftor to Affect Other Drugs Based on in vitro results, ivacaftor and metabolite M1 have the potential to inhibit CYP3A and P-gp. Clinical studies showed that KALYDECO is a weak inhibitor of CYP3A and P-gp, but not an inhibitor of CYP2C8. In vitro studies suggest that ivacaftor and M1 may inhibit CYP2C9. In vitro, ivacaftor, M1, and M6 were not inducers of CYP isozymes. Dosing recommendations for co-administered drugs with KALYDECO are shown in Figure 1. Figure 1: Impact of KALYDECO on Other Drugs Note: The data obtained with substrates but without co-administration of KALYDECO are used as reference. *NE: Norethindrone; **EE: Ethinyl Estradiol The vertical lines are at 0.8, 1.0, and 1.25, respectively. Potential for Other Drugs to Affect Ivacaftor In vitro studies showed that ivacaftor and metabolite M1 were substrates of CYP3A enzymes (i.e., CYP3A4 and CYP3A5). Exposure to ivacaftor is reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors [see Dosage and Administration (2.6) and Drug Interactions (7)]. KALYDECO dosing recommendations for co-administration with other drugs are shown in Figure 2. Figure 2: Impact of Other Drugs on KALYDECO Note: The data obtained for KALYDECO without co-administration of inducers or inhibitors are used as reference. The vertical lines are at 0.8, 1.0 and 1.25, respectively. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year studies were conducted in mice and rats to assess carcinogenic potential of KALYDECO. No evidence of tumorigenicity was observed in mice or rats at ivacaftor oral doses up to 200 mg/kg/day and 50 mg/kg/day, respectively (approximately equivalent to 3 to 5 times the MRHD, respectively, based on summed AUCs of ivacaftor and its metabolites). Ivacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test. Ivacaftor impaired fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (approximately 5 and 6 times, respectively, the MRHD based on summed AUCs of ivacaftor and its metabolites). Increases in prolonged diestrus were observed in females at 200 mg/kg/day. Ivacaftor also increased the number of females with all nonviable embryos and decreased corpora lutea, implantations, and viable embryos in rats at 200 mg/kg/day (approximately 6 times the MRHD based on summed AUCs of ivacaftor and its metabolites) when dams were dosed prior to and during early pregnancy. These impairments of fertility and reproductive performance in male and female rats at 200 mg/kg/day were attributed to severe toxicity. No effects on male or female fertility and reproductive performance indices were observed at ≤100 mg/kg/day (approximately 3 times the MRHD based on summed AUCs of ivacaftor and its metabolites). 13.2 Animal Toxicology and/or Pharmacology Cataracts were seen in juvenile rats dosed with ivacaftor from postnatal day 7-35 at dose levels of 10 mg/kg/day and higher (approximately 0.12 times the MRHD based on summed AUCs of ivacaftor and its metabolites). This finding has not been observed in older animals. 14 CLINICAL STUDIES 14.1 Trials in Patients with CF who have a G551D Mutation in the CFTR Gene Dose Ranging: Dose ranging for the clinical program consisted primarily of one double-blind, placebo-controlled, crossover trial in 39 adult (mean age 31 years) Caucasian patients with CF who had FEV1 ≥40% predicted. Twenty patients with median predicted FEV1 at baseline of 56% (range: 42% to 109%) received KALYDECO 25, 75, 150 mg or placebo every 12 hours for 14 days and 19 patients with median predicted FEV1 at baseline of 69% (range: 40% to 122%) received KALYDECO 150, 250 mg or placebo every 12 hours for 28 days. The selection of the 150 mg every 12 hours dose was primarily based on nominal improvements in lung function (pre-dose FEV1) and changes in pharmacodynamic parameters (sweat chloride and nasal potential difference). The twice-daily dosing regimen was primarily based on an apparent terminal plasma half-life of approximately 12 hours. Efficacy: The efficacy of KALYDECO in patients with CF who have a G551D mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled clinical trials in 213 clinically stable patients with CF (109 receiving KALYDECO 150 mg twice daily). All eligible patients from these trials were rolled over into an open-label extension study. Trial 1 evaluated 161 patients with CF who were 12 years of age or older (mean age 26 years) with FEV1 at screening between 40-90% predicted [mean FEV1 64% predicted at baseline (range: 32% to 98%)]. Trial 2 evaluated 52 patients who were 6 to 11 years of age (mean age 9 years) with FEV1 at screening between 40-105% predicted [mean FEV1 84% predicted at baseline (range: 44% to 134%)]. Patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the upper limit of normal were excluded. Patients in both trials were randomized 1:1 to receive either 150 mg of KALYDECO or placebo every 12 hours with food containing fat for 48 weeks in addition to their prescribed CF therapies (e.g., tobramycin, dornase alfa). The use of inhaled hypertonic saline was not permitted. The primary efficacy endpoint in both studies was improvement in lung function as determined by the mean absolute change from baseline in percent predicted pre-dose FEV1 through 24 weeks of treatment. In both studies, treatment with KALYDECO resulted in a significant improvement in FEV1. The treatment difference between KALYDECO and placebo for the mean absolute change in percent predicted FEV1 from baseline through Week 24 was 10.6 percentage points (P < 0.0001) in Trial 1 and 12.5 percentage points (P < 0.0001) in Trial 2 (Figure 3). These changes persisted through 48 weeks. Improvements in percent predicted FEV1 were observed regardless of age, disease severity, sex, and geographic region. Figure 3: Mean Absolute Change from Baseline in Percent Predicted FEV1 * Primary endpoint was assessed at the 24-week time point Other efficacy variables included absolute change from baseline in sweat chloride [see Clinical Pharmacology (12.2)], time to first pulmonary exacerbation (Trial 1 only), absolute change from baseline in weight, and improvement from baseline in Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain score, a measure of respiratory symptoms relevant to patients with CF such as cough, sputum production, and difficulty breathing. For the purpose of the study, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Patients treated with KALYDECO demonstrated statistically significant improvements in risk of pulmonary exacerbations, CF symptoms (in Trial 1 only), and gain in body weight (Table 3). Weight data, when expressed as body mass index normalized for age and sex in patients <20 years of age, were consistent with absolute change from baseline in weight. Table 3: Effect of KALYDECO on Other Efficacy Endpoints in Trials 1 and 2
* Treatment difference = effect of KALYDECO – effect of Placebo † Hazard ratio for time to first pulmonary exacerbation 14.2 Trial in Patients with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R Mutation in the CFTR Gene The efficacy and safety of KALYDECO in patients with CF who have a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene were evaluated in a two-part, randomized, double-blind, placebo-controlled, crossover design clinical trial in 39 patients with CF (Trial 4). Patients who completed Part 1 of this trial continued into the 16-week open-label Part 2 of the study. The mutations studied were G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D. See Clinical Studies (14.1) for efficacy in patients with a G551D mutation. Patients were 6 years of age or older (mean age 23 years) with FEV1 ≥40% at screening [mean FEV1 at baseline 78% predicted (range: 43% to 119%)]. Patients with evidence of colonization with Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the upper limit of normal at screening were excluded. Patients were randomized 1:1 to receive either 150 mg of KALYDECO or placebo every 12 hours with food containing fat for 8 weeks in addition to their prescribed CF therapies during the first treatment period and crossed over to the other treatment for the second 8 weeks. The two 8-week treatment periods were separated by a 4- to 8-week washout period. The use of inhaled hypertonic saline was not permitted. The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV1 through 8 weeks of treatment. Other efficacy variables included absolute change from baseline in sweat chloride through 8 weeks of treatment [see Clinical Pharmacology (12.2)], absolute change from baseline in body mass index (BMI) at 8 weeks of treatment (including body weight at 8 weeks), and improvement in CFQ-R respiratory domain score through 8 weeks of treatment. For the overall population of the 9 mutations studied, treatment with KALYDECO compared to placebo resulted in significant improvement in percent predicted FEV1 [10.7 through Week 8 (P<0.0001)], BMI [0.66 kg/m2 at Week 8 (P<0.0001)], and CFQ-R respiratory domain score [9.6 through Week 8 (P=0.0004)]; however, there was a high degree of variability of efficacy responses among the 9 mutations (Table 4). Based on clinical and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the G970R mutation could not be established [see Clinical Pharmacology (12.2)]. Table 4: Effect of KALYDECO for Efficacy Variables in the Overall Populations and for Specific CFTR Mutations
n=36 for the analysis of absolute change in sweat chloride. Statistical testing was not performed due to small numbers for individual mutations. Reflects results from the one patient with the G551S mutation with data at the 8-week time point. n=3 for the analysis of absolute change in sweat chloride. 14.3 Trial in Patients with CF who have an R117H Mutation in the CFTR Gene The efficacy and safety of KALYDECO in patients with CF who have an R117H mutation in the CFTR gene were evaluated in a randomized, double-blind, placebo-controlled, parallel-group clinical trial (Trial 5). Fifty-nine of 69 patients completed 24 weeks of treatment. Two patients discontinued and 8 patients did not complete treatment due to study termination. Trial 5 evaluated 69 clinically stable patients with CF who were 6 years of age or older (mean age 31 years). Patients who were 12 years and older had FEV1 at screening between 40-90% predicted, and patients who were 6-11 years of age had FEV1 at screening between 40-105% predicted. The overall mean FEV1 was 73% predicted at baseline (range: 33% to 106%). The patients had well preserved BMIs (mean overall: 23.76 kg/m2) and a high proportion were pancreatic sufficient as assessed by a low rate of pancreatic enzyme replacement therapy use (pancreatin: 11.6%; pancrelipase: 5.8%). Patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening, and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the ULN, were excluded. Patients were randomized 1:1 to receive either 150 mg of KALYDECO (n=34) or placebo (n=35) every 12 hours with food containing fat for 24 weeks in addition to their prescribed CF therapies. The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV1 through 24 weeks of treatment. The treatment difference for absolute change in percent predicted FEV1 through Week 24 was 2.1 percentage points (analysis conducted with the full analysis set which included all 69 patients), and did not reach statistical significance (Table 5). Other efficacy variables that were analyzed included absolute change in sweat chloride from baseline through Week 24, improvement in cystic fibrosis respiratory symptoms through Week 24 as assessed by the CFQ-R respiratory domain score (Table 5), absolute change in body mass index (BMI) at Week 24, and time to first pulmonary exacerbation. The overall treatment difference for the absolute change from baseline in BMI at Week 24 was 0.3 kg/m2 and the calculated hazard ratio for time to first pulmonary exacerbation was 0.93, which were not statistically significant. Statistically significant improvements in clinical efficacy (FEV1, CFQ-R respiratory domain) were seen in several subgroup analyses, and decreases in sweat chloride were observed in all subgroups. Subgroups analyzed included those based on age, lung function, and poly-T status (Table 5). Table 5: Effect of KALYDECO on Overall Population (Percent Predicted FEV1, CFQ-R Respiratory Domain Score, and Sweat Chloride) and in Relevant Subgroups Through 24 Weeks
(n=54) Poly-T status confirmed by genotyping 14.4 Trial in Patients Homozygous for the F508del Mutation in the CFTR Gene Trial 3 was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial in 140 patients with CF age 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥40% predicted. Patients were randomized 4:1 to receive KALYDECO 150 mg (n=112) every 12 hours or placebo (n=28) in addition to their prescribed CF therapies. The mean age of patients enrolled was 23 years and the mean baseline FEV1 was 79% predicted (range 40% to 129%). As in Trials 1 and 2, patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the upper limit of normal were excluded. The use of inhaled hypertonic saline was not permitted. The primary endpoint was improvement in lung function as determined by the mean absolute change from baseline through Week 16 in percent predicted FEV1. Treatment with KALYDECO resulted in no improvement in FEV1 relative to placebo in patients with CF homozygous for the F508del mutation in the CFTR gene [mean absolute change from baseline through Week 16 in percent predicted FEV1 was 1.5% and -0.2% for patients in the KALYDECO and placebo-treated groups, respectively (P=0.15)]. There were no meaningful differences between patients treated with KALYDECO compared to placebo for secondary endpoints (change in CF symptoms, change in weight, or change in sweat chloride concentration [see Pharmacodynamics (12.2)]). 16 HOW SUPPLIED/STORAGE AND HANDLING KALYDECO (ivacaftor) tablets are supplied as light blue, film-coated, capsule-shaped tablets containing 150 mg of ivacaftor. Each tablet is printed with the characters "V 150" on one side and plain on the other, and is packaged as follows:
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Transaminase (ALT or AST) Elevations and Monitoring Inform patients that elevation in liver tests have occurred in patients treated with KALYDECO. Liver function tests will be performed prior to initiating KALYDECO, every 3 months during the first year of treatment and annually thereafter. More frequent monitoring of liver function tests should be considered in patients with a history of transaminase elevations [see Warnings and Precautions (5.1)]. Drug Interactions with CYP3A Inducers and Inhibitors Ask patients to tell you all the medications they are taking including any herbal supplements or vitamins. Co-administration of KALYDECO with strong CYP3A inducers (e.g., rifampin, St. John's wort) is not recommended, as they may reduce the therapeutic effectiveness of KALYDECO. Reduction of the dose of KALYDECO to one tablet or one packet of granules twice a week is recommended when co-administered with strong CYP3A inhibitors, such as ketoconazole. Dose reduction to one tablet or one packet of granules once daily is recommended when co-administered with moderate CYP3A inhibitors, such as fluconazole. Food containing grapefruit or Seville oranges should be avoided [see Drug Interactions (7.1, 7.2) and Clinical Pharmacology (12.3)]. Use in Patients with Hepatic Impairment Inquire and/or assess whether patients have liver impairment. Reduce the dose of KALYDECO in patients with moderately impaired hepatic function (Child-Pugh Class B, score 7 -9) to one tablet or one packet of granules once daily. KALYDECO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C, score 10-15); however, exposure is expected to be substantially higher than that observed in patients with moderate hepatic impairment. When benefits are expected to outweigh the risks, KALYDECO should be used with caution in patients with severe hepatic impairment at a dose of one tablet or one packet of granules given once daily or less frequently. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A, score 5-6) [see Use in Specific Populations (8.6)]. Administration KALYDECO® (ivacaftor) tablets 150 mg Inform patients that KALYDECO is best absorbed by the body when taken with food that contains fat. A typical CF diet will satisfy this requirement. Examples include eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, and yogurt),etc. KALYDECO® (ivacaftor) oral granules 50 mg or 75 mg Inform patients and caregivers that KALYDECO oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and completely consumed to ensure delivery of the entire dose. Food or liquid should be at or below room temperature. Once mixed, the product has been shown to be stable for one hour, and therefore should be consumed during this period. Some examples of appropriate soft foods or liquids may include puréed fruits or vegetables, yogurt, applesauce, water, milk, or juice. Inform patients and caregivers that KALYDECO is best absorbed by the body when taken with food that contains fat; therefore, KALYDECO oral granules should be taken just before or just after consuming food that contains fat. A typical CF diet will satisfy this requirement. Examples include eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc. Patients should be informed about what to do in the event they miss a dose of KALYDECO: In case a dose of KALYDECO is missed within 6 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of KALYDECO with fat-containing food as soon as possible. If more than 6 hours have passed since KALYDECO is usually taken, the missed dose should NOT be taken and the patient should resume the usual dosing schedule. Patients should be advised to contact their health care provider if they have questions. Cataracts Inform patients that abnormality of the eye lens (cataract) has been noted in some children and adolescents receiving KALYDECO. Baseline and follow-up ophthalmological examinations should be performed in pediatric patients initiating KALYDECO treatment [see Warnings and Precautions (5.3)]. 欧盟批准Vertex囊性纤维化药物Kalydeco用于8种非G551D门控突变 2014年8月3日，福泰制药（Vertex）研发的Kalydeco（ivacaftor）获欧盟委员会（EC）批准，用于囊性纤维化跨膜电导调节因子（CFTR）基因中存在8种非G551D门控突变（non-G551D gating mutations）之一的6岁及以上囊性纤维化患者的治疗。 此次获批，是基于二部分、随机、双盲、安慰剂对照III期研究的第一部分数据，该研究在39例携带非G551D门控突变的6岁及以上囊性纤维化（CF）患者中开展。第一部分数据表明，Kalydeco使肺功能（FEV1）、汗液氯化物、身体质量指数、CFQ-R得分均取得了统计学意义的显著改善。该项研究的第二部分数据已于2014年6月提交至欧洲囊性纤维化协会会议，数据表明，Kalydeco在研究的第一部分中所取得的改善，在整个治疗24周中均能够维持。该项研究中的安全性与在G551D门控突变患者中开展的III期研究一致。 Kalydeco是首个靶向囊性纤维化（CF）根本病因的药物，可使G551D突变患者体内缺陷性CFTR蛋白发挥正常功能。G551D突变是一种最常见的门控突变，该突变损害了ATP介导的通道调节。 此次获批的8种非G551D门控突变包括：G178R，S549N，S549R，G551S，G1244E，S1251N，S1255P和G1349D。在欧洲，约有250例患者携带这8种非G551D门控突变。 关于Kalydeco： Kalydeco于2012年首次获FDA及EMA批准，用于治疗CFTR基因存在至少单拷贝G551D突变的6岁及以上囊性纤维化（CF）患者。此外，FDA于2014年6月批准Kalydeco用于携带9种非G551D门控突变中任意一种突变的6岁及以上CF患者，包括：G178R，S549N，S549R，G551S，G1244E，S1251N，S1255P，G1349D或G970R。 关于囊性纤维化（CF）： 囊性纤维化（CF）是由囊性纤维化跨膜电导调节因子（CFTR）基因突变导致CFTR蛋白功能缺陷或缺失所致的罕见遗传性疾病，该病困扰着全球约7万人。CFTR蛋白通常调节细胞膜的离子运输，基因突变能导致蛋白产物功能的破坏或丧失。当细胞膜离子运输被中断，某些器官粘液涂层的粘度将变稠。该病的一个主要特征是呼吸道积聚厚厚的粘液，导致呼吸困难及反复感染。 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
