Ivacaftor/Tezacaftor - Symdeko-@- ( Feb- 2018)
Drug Name:Ivacaftor/Tezacaftor - Symdeko-@- ( Feb- 2018)
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
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.
Indication:
U.S. FDA APPROVED DRUGS DURING 2018
Sr.No- 3
Name of the Drug- Symdeko
Active Ingredient - Tezacaftor/Ivacaftor
Pharmacological Classification-
To treat cystic fibrosis in patients age 12 years and older
Date of Approval- 2-13-2018
(Ref- FDA approved List 2018)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
SYMDEKO safely and effectively. See full prescribing information for SYMDEKO.
SYMDEKO™ (tezacaftor/ivacaftor) tablets; (ivacaftor) tablets, for oral use
Initial U.S. Approval: 2018
INDICATIONS AND USAGE
SYMDEKO is a combination of tezacaftor and ivacaftor, indicated for the treatment of patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.
Adverse Reaction:
ADVERSE REACTIONS
The most common adverse drug reactions to SYMDEKO (occurring in =3% of patients) were headache, nausea, sinus congestion, and dizziness.
Contra-Indications:
CONTRAINDICATIONS
None.
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.
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.
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.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
SYMDEKO is a combination of tezacaftor and ivacaftor, indicated for the treatment of patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.
DOSAGE AND ADMINISTRATION-
Adults and pediatric patients ages 12 years and older: one tablet (containing tezacaftor 100 mg/ivacaftor 150 mg) in the morning and one tablet (containing ivacaftor 150 mg) in the evening, approximately 12 hours apart.
SYMDEKO should be taken with fat-containing food.
Reduce dose in patients with moderate and severe hepatic impairment.
Reduce dose when co-administered with drugs that are moderate or strong CYP3A inhibitors.
DOSAGE FORMS AND STRENGTHS
Tablets: SYMDEKO is co-packaged as tezacaftor 100 mg/ivacaftor 150 mg fixed dose combination tablets and ivacaftor 150 mg tablets.
Patient Information:
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 [s
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.
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
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)
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.
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
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
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.
2. 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.
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
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.
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).
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
Pregnancy and lactation:
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. Both tezacaftor and ivacaftor are excreted into the milk of lactating rats
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.
