DRUG INTERACTIONS

Potential for other drugs to affect tezacaftor/ivacaftor 

 

1. Inducers of CYP3A

Tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A). Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced SYMDEKO efficacy. Co-administration of ivacaftor with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (area under the curve [AUC]) by 89%.

Tezacaftor exposures can also be expected to decrease significantly during co-administration with strong CYP3A inducers.

 

Therefore, co-administration of SYMDEKO with strong CYP3A inducers is not recommended. 

 

Examples of strong CYP3A inducers include:  rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum) 

 

2. Inhibitors of CYP3A

Co-administration with itraconazole, a strong CYP3A inhibitor, increased tezacaftor exposure (AUC) by 4.0-fold and ivacaftor by 15.6-fold.

When co-administered with strong CYP3A inhibitors, the dosing regimen of SYMDEKO should be adjusted . 

 

Examples of strong CYP3A inhibitors include: ketoconazole, itraconazole, posaconazole, and voriconazole ,telithromycin and clarithromycin 

 

Examples of moderate CYP3A inhibitors include: fluconazole ? erythromycin 

 

3. Co-administration of SYMDEKO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of tezacaftor and ivacaftor; therefore, food or drink containing grapefruit or Seville oranges should be avoided during treatment with SYMDEKO 

 

4.Ciprofloxacin Co-administration of SYMDEKO with ciprofloxacin had no significant effect on the exposure of tezacaftor or ivacaftor. Therefore, no dose adjustment is necessary during concomitant administration of SYMDEKO with ciprofloxacin . 

 

Potential for tezacaftor/ivacaftor to affect other drugs 

 

5.CYP3A Substrates Co-administration of SYMDEKO with midazolam (oral), a sensitive CYP3A substrate, did not affect midazolam exposure. No dose adjustment of CYP3A substrates is required when co-administered with SYMDEKO. 

 

6. Digoxin and Other P-gp Substrates Co-administration of SYMDEKO with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold consistent with weak inhibition of P-gp by ivacaftor.

 

 

 

 

 

Name of the  Drug-      Symdeko

 

Active Ingredient -       Tezacaftor,Ivacaftor

 

Pharmacological Classification- 

 

                       To treat cystic fibrosis age 12 years and older

                       

                                                     

Date of Approval-          2-13-2018

 

(Ref- FDA approved List 2018)     

 

 

 

-----------------------WARNINGS AND PRECAUTIONS--------------------- ? Elevated transaminases (ALT or AST): Transaminases (ALT and AST) should be assessed prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. In patients with a history of transaminase elevations, more frequent monitoring should be considered. Dosing should be interrupted in patients with significant elevations of transaminases, e.g., patients with ALT or AST >5 x upper limit of normal (ULN), or ALT or AST >3 x ULN with bilirubin >2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming treatment. (5.1, 6) ? Use with CYP3A inducers: Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John’s wort) substantially decrease exposure of ivacaftor and may decrease the exposure of tezacaftor, which may reduce therapeutic effectiveness. Therefore, co-administration is not recommended. (5.2, 7.1, 12.3) ? Cataracts: Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with SYMDEKO. Baseline and follow-up examinations are recommended in pediatric patients initiating SYMDEKO treatment. (5.3, 8.4) 

 

------------------------------ADVERSE REACTIONS---------------------------- The most common adverse drug reactions to SYMDEKO (occurring in =3% of patients) were headache, nausea, sinus congestion, and dizziness. (6.1) 

 

To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA1088 or www.fda.gov/medwatch. 

 

-----------------------------DRUG INTERACTIONS ---------------------------- CYP3A inhibitors: Reduce SYMDEKO dose when co-administered with strong (e.g., ketoconazole) or moderate (e.g., fluconazole) CYP3A inhibitors. Avoid food containing grapefruit or Seville oranges. (2.3, 7.2, 12.3) 

 

See 

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 has occurred in patients treated with SYMDEKO or with ivacaftor alone. Transaminases (ALT and AST) should be assessed prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. More frequent monitoring 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 SYMDEKO with strong CYP3A inducers (e.g., rifampin, St. John’s wort) is not recommended, as they may reduce the therapeutic effectiveness of SYMDEKO. Adjustment of the dose to one tablet of tezacaftor 100 mg/ivacaftor 150 mg twice a week, taken approximately 3 to 4 days apart is recommended when co-administered with strong CYP3A inhibitors, such as ketoconazole. Advise the patient not to take the evening dose of ivacaftor 150 mg. Dose reduction to one tablet of tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg, taken on alternate days in the morning is recommended when co-administered with moderate CYP3A inhibitors, such as fluconazole. Advise the patient not to take the evening dose of ivacaftor 150 mg. Food or drink containing grapefruit or Seville oranges should be avoided [see Warnings and Precautions (5), Drug Interactions (7) and Clinical Pharmacology (12.3)].  

 

Cataracts Inform patients that abnormality of the eye lens (cataract) has been noted in some children and adolescents receiving SYMDEKO or with ivacaftor alone. Baseline and follow-up ophthalmological examinations should be performed in pediatric patients initiating treatment with SYMDEKO [see Warnings and Precautions (5.3)]. 

 

Use in Patients with Hepatic Impairment Inquire and/or assess whether patients have liver impairment. Adjust the dose in patients with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) to one tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning and advise the patient not to take the evening dose of ivacaftor 150 mg. SYMDEKO 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, SYMDEKO should be used with caution in patients with severe hepatic impairment at a dose of one tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning or less frequently. Advise the patient not to take the evening dose of ivacaftor 150 mg. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A, score 5-6) [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. 

 

Reference ID: 4220295

SYMDEKO™ (tezacaftor/ivacaftor; ivacaftor) Tablets 

 

13 

 

Administration Inform patients that SYMDEKO 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. [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. 

 

Patients should be informed about what to do in the event they miss a dose of SYMDEKO or ivacaftor: ? If 6 hours or less have passed since the time SYMDEKO is usually taken, patients should be instructed to take the prescribed dose of SYMDEKO with fat-containing food as soon as possible. ? If more than 6 hours have passed since the time SYMDEKO 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. 

 

 

Manufactured for Vertex Pharmaceuticals Incorporated 50 Northern Avenue Boston, MA 02210 

 

Approved February 2018 

 

VERTEX and the VERTEX triangle logo are registered trademarks and SYMDEKO is a trademark of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2018 Vertex Pharmaceuticals Incorporated ALL RIGHTS RESE

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tezacaftor facilitates the cellular processing and trafficking of normal and select mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. For ivacaftor to function CFTR protein must be present at the cell surface. Ivacaftor can potentiate the CFTR protein delivered to the cell surface by tezacaftor, leading to a further enhancement of chloride transport than either agent alone. The combined effect of tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increases in chloride transport. 

 

CFTR Chloride Transport Assay in Fisher Rat Thyroid (FRT) cells expressing mutant CFTR The chloride transport response of mutant CFTR protein to tezacaftor/ivacaftor was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations. The FRT assay was conducted in ivacaftor-responsive mutations and F508del. Tezacaftor/ivacaftor increased chloride transport in FRT cells expressing CFTR mutations that result in CFTR protein being delivered to the cell surface.  

 

The minimum response threshold was designated as a net increase of at least 10% of untreated normal over baseline. The tezacaftor/ivacaftor incubation resulted in either similar or increased chloride transport compared to ivacaftor alone. In vitro data may not accurately predict added clinical benefit of SYMDEKO (tezacaftor/ivacaftor combination) over KALYDECO (ivacaftor) alone for individual mutations. In addition, the magnitude of the net change over baseline in CFTR-mediated chloride transport is not correlated with the magnitude of clinical response for individual mutations.  

 

Figure 1: Net Change Over Baseline (% of untreated normal) in CFTR-Mediated Chloride Transport Following Addition of SYMDEKO (tezacaftor/Ivacaftor combination) in FRT Cells Expressing Mutant CFTR proteins (Ussing Chamber Electrophysiology Data)   

 

*Clinical data exist for these mutations [see Clinical Studies (14.1 and 14.2)]. #F508del represents data from one allele. A patient must have two copies of F508del mutation to be indicated for tezacaftor/ivacaftor (see Table 4). 

 

Splice mutations cannot be studied in the FRT assay and are not included in Figure 1.  

Reference ID: 4220295

SYMDEKO™ (tezacaftor/ivacaftor; ivacaftor) Tablets 

 

7 

 

 

Table 4 lists responsive CFTR mutations based on (1) a clinical FEV1 response and/or (2) in vitro data in FRT cells, indicating that tezacaftor/ivacaftor increases chloride transport to at least 10% of untreated normal over baseline. CFTR gene mutations that are not responsive to ivacaftor alone are not expected to respond to SYMDEKO except for F508del homozygotes.  

 

Table 4: List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to SYMDEKO E56K R117C A455E  S945L  R1070W  3272-26A?G  P67L E193K F508del* S977F  F1074L  3849+10kbC?T  R74W L206W D579G  F1052V  D1152H   D110E R347H 711+3A?G  K1060T  D1270N   D110H R352Q  E831X  A1067T  2789+5G?A   *A patient must have two copies of the F508del mutation or at least one copy of a responsive mutation presented in Table 4 to be indicated. 

 

12.2 Pharmacodynamics Effects on Sweat Chloride In Trial 1 (patients homozygous for the F508del mutation), the treatment difference between SYMDEKO and placebo in mean absolute change from baseline in sweat chloride through Week 24 was -10.1 mmol/L (95% CI: -11.4, -8.8). 

 

In Trial 2 (patients heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor), the treatment difference in mean absolute change from baseline in sweat chloride through Week 8 was -9.5 mmol/L (95% CI: -11.7, -7.3) between SYMDEKO and placebo, and -4.5 mmol/L (95% CI: -6.7, -2.3) between ivacaftor and placebo. 

 

Cardiac Electrophysiology At a dose 3 times the maximum approved recommended dose, tezacaftor does not prolong the QT interval to any clinically relevant extent. 

 

In a separate study of ivacaftor evaluating doses up to 3 times the maximum approved recommended dose, ivacaftor does not prolong the QT interval to any clinically relevant extent.  

 

12.3 Pharmacokinetics The pharmacokinetics of tezacaftor and ivacaftor are similar between healthy adult volunteers and patients with CF. Following once-daily dosing of tezacaftor and twice-daily dosing of ivacaftor in patients with CF, plasma concentrations of tezacaftor and ivacaftor reach steady-state within 8 days and within 3 to 5 days, respectively, after starting treatment. At steady-state, the accumulation ratio is approximately 1.5 for tezacaftor and 2.2 for ivacaftor. Exposures of tezacaftor (administered alone or in combination with ivacaftor) increase in an approximately dose-proportional manner with increasing doses from 10 mg to 300 mg once daily.  Key pharmacokinetic parameters for tezacaftor and ivacaftor at steady state are shown in Table 5.  

 

Table 5: Mean (SD) Pharmacokinetic Parameters of Tezacaftor and Ivacaftor at Steady State in Patients with CF  Drug Cmax (mcg/mL) Effective t½ (h) AUC0-24h or AUC0-12h (mcg·h/mL)* Tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours Tezacaftor 5.95 (1.50) 15.0 (3.44) 84.5 (27.8) Ivacaftor 1.17 (0.424) 13.7 (6.06) 11.3 (4.60) *AUC0-24h for tezacaftor and AUC0-12h for ivacaftor 

 

Absorption After a single dose in healthy subjects in the fed state, tezacaftor was absorbed with a median (range) time to maximum concentration (tmax) of approximately 4.0 hours (2 to 6 hours). The median (range) tmax of ivacaftor was approximately 6.0 hours (3 to 10 hours) in the fed state.  When a single dose of tezacaftor/ivacaftor was administered with fat-containing foods, tezacaftor exposure was similar and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state. 

 

Distribution Tezacaftor is approximately 99% bound to plasma proteins, primarily to albumin. Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent volume of distribution of tezacaftor and ivacaftor was 271 (157) L and 206 (82.9) L, respectively. Neither tezacaftor nor ivacaftor partition preferentially into human red blood cells. 

 

Elimination After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent clearance values of tezacaftor and ivacaftor were 1.31 (0.41) and 15.7 (6.38) L/h, respectively. After steady-state dosing of tezacaftor in combination with ivacaftor in CF patients, the effective half-lives of tezacaftor and ivacaftor were approximately 15.0 (3.44) and 13.7 (6.06) hours, respectively. 

 

Metabolism Tezacaftor is metabolized extensively in humans. In vitro data suggested that tezacaftor is metabolized mainly by CYP3A4 and CYP3A5. Following oral administration of a single dose of 100 mg 14C-tezacaftor to healthy male subjects, M1, M2, and M5 were the 3 major circulating metabolites of tezacaftor in humans. M1 has the similar potency to that of tezacaftor and is considered pharmacologically active. M2 is much less pharmacologically active than tezacaftor or M1, and M5 is not considered pharmacologically active. Another minor circulating metabolite, M3, is formed by direct glucuronidation of tezacaftor. 

 

Ivacaftor is also metabolized extensively in humans. In vitro and in vivo data indicate that ivacaftor is metabolized primarily by CYP3A4 and CYP3A5. 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 is not considered pharmacologically active. 

 

Reference ID: 4220295

SYMDEKO™ (tezacaftor/ivacaftor; ivacaftor) Tablets 

 

8 

 

Excretion Following oral administration of 14C-tezacaftor, the majority of the dose (72%) was excreted in the feces (unchanged or as the M2 metabolite) and about 14% was recovered in urine (mostly as M2 metabolite), resulting in a mean overall recovery of 86% up to 21 days after the dose. Less than 1% of the administrated dose was excreted in urine as unchanged tezacaftor, showing that renal excretion is not the major pathway of tezacaftor elimination in humans. 

 

Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine), and there was negligible urinary excretion of ivacaftor as unchanged drug. 

 

Specific populations Pediatric patients 12 to less than 18 years of age The following conclusions about exposures between adults and the pediatric population are based on population PK analyses: Following oral administration of SYMDEKO tablets, tezacaftor 100 mg once daily / ivacaftor 150 mg every 12 hours, the mean (±SD) AUCss was 97.3 (35.7) mcg·h/mL and 11.4 (5.46) mcg·h/mL, respectively for tezacaftor and ivacaftor, similar to the mean AUCss in adult patients administered SYMDEKO tablets, tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours. 

 

Patients with Hepatic Impairment Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had an approximately 36% increase in AUC and a 10% increase in Cmax for tezacaftor, and a 1.5-fold increase in ivacaftor AUC compared with healthy subjects matched for demographics. In a separate study, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had similar ivacaftor Cmax, but an approximately 2.0-fold increase in ivacaftor AUC0-8 compared with healthy subjects matched for demographics. 

 

Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5 to 6) or severe hepatic impairment (Child-Pugh Class C, score 10 to 15) receiving SYMDEKO. The magnitude of increase in exposure in patients with severe hepatic impairment is unknown, but is expected to be higher than that observed in patients with moderate hepatic impairment [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Patient Counseling Information (17)]. 

 

Patients with Renal Impairment SYMDEKO has not been studied in patients with moderate or severe renal impairment (creatinine clearance =30 mL/min) or in patients with end-stage renal disease. In a human pharmacokinetic study with tezacaftor alone, there was minimal elimination of tezacaftor and its metabolites in urine (only 13.7% of total radioactivity was recovered in the urine with 0.79% as unchanged drug). 

 

In a human pharmacokinetic study with ivacaftor alone, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). 

 

In population pharmacokinetic analysis, data from 665 patients on tezacaftor or tezacaftor in combination with ivacaftor in Phase 2/3 clinical trials indicated that mild renal impairment (N=147; eGFR 60 to less than 90 mL/min/1.73 m2) and moderate renal impairment (N=7; eGFR 30 to less than 60 mL/min/1.73 m2) did not affect the clearance of tezacaftor significantly [see Use in Specific Populations (8.7)]. 

 

Male and Female Patients The pharmacokinetic parameters of tezacaftor and ivacaftor are similar in males and females. 

 

Drug Interactions Studies Drug interaction studies were performed with SYMDEKO and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7)]. 

 

Potential for Tezacaftor/Ivacaftor to Affect Other Drugs Clinical studies (with rosiglitazone and desipramine – see Table 6) showed that ivacaftor is not an inhibitor of CYP2C8 or CYP2D6. Based on in vitro results, ivacaftor has the potential to inhibit CYP3A and P-gp, and may also inhibit CYP2C9. In vitro, ivacaftor was not an inducer of CYP isozymes. Ivacaftor is not an inhibitor of transporters OATP1B1, OATP1B3, OCT1, OCT2, OAT1, or OAT3. 

 

Based on in vitro results, tezacaftor has a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tezacaftor has a low potential to induce CYP3A, but it is not an inducer of CYP1A2 and CYP2B6. Tezacaftor has a low potential to inhibit transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, or OAT3.  

 

Clinical studies with midazolam showed that SYMDEKO is not an inhibitor of CYP3A. Co-administration of SYMDEKO with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold. Co administration of SYMDEKO with an ethinyl estradiol/ norethindrone oral contraceptive had no significant effect on the exposures of the hormonal contraceptives. 

 

The effects of tezacaftor and ivacaftor (or ivacaftor alone) on the exposure of co-administered drugs are shown in Table 6 [see Drug Interactions (7)]. 

 

Potential for Other Drugs to Affect Tezacaftor/Ivacaftor In vitro studies showed that ivacaftor and tezacaftor were substrates of CYP3A enzymes (i.e., CYP3A4 and CYP3A5). Exposure to ivacaftor and tezacaftor will be reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors. 

 In vitro studies showed that tezacaftor is a substrate for the uptake transporter OATP1B1, and efflux transporters P-gp and BCRP. Tezacaftor is not a substrate for OATP1B3. In vitro studies showed that ivacaftor is not a substrate for OATP1B1, OATP1B3, or P-gp. 

 

The effects of co-administered drugs on the exposure of tezacaftor and ivacaftor (or ivacaftor alone) are shown in Table 7 [see Dosage and Administration (2.3) and Drug Interactions (7)]. 

 

 

 USE IN SPECIFIC POPULATIONS

 

1. Pregnancy Risk Summary

There are limited and incomplete human data from clinical trials and post-marketing reports on the use of SYMDEKO or its individual components, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk.

 

Although there are no animal reproduction studies with the concomitant administration of tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with tezacaftor and ivacaftor in pregnant rats and rabbits.

 

The background risk of major birth defects and miscarriage for the indicated population is unknown.

 

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 

 

2. Lactation Risk Summary -

There is no information regarding the presence of tezacaftor or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production.

 

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYMDEKO and any potential adverse effects on the breastfed child from SYMDEKO or from the underlying maternal condition. 

 

3.Pediatric Use-

SYMDEKO is indicated for the treatment of CF in pediatric patients ages 12-17 years who are homozygous for the F508del mutation or who have at least one mutation in the CFTR gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence .

 

The safety and efficacy of SYMDEKO in patients with CF younger than 12 years of age have not been studied.  

 

4.Geriatric Use-

Clinical trials of SYMDEKO did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients. 

 

5.Hepatic Impairment -

No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dose of SYMDEKO is recommended in patients with moderate hepatic impairment (Child-Pugh Class B).

 

There is no experience in patients with severe hepatic impairment (Child-Pugh Class C), but tezacaftor/ivacaftor exposure is expected to be higher than in patients with moderate hepatic impairment.

 

Therefore, use with caution at a reduced dose in patients with severe hepatic impairment after weighing the risks and benefits of treatment.

 

6.Renal Impairment-

SYMDEKO has not been studied in patients with moderate or severe renal impairment or in patients with end-stage renal disease. No dose adjustment is recommended for mild and moderate renal impairment.

 

Caution is recommended in patients with severe renal impairment or end-stage renal disease.

 

 

OVERDOSAGE-

No specific antidote is available for overdose with SYMDEKO. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.