SYMDEKO (Page 8 of 9)

14.3 Trial in Patients with CF Who Were Heterozygous for the F508del Mutation and a Second Mutation Not Predicted to be Responsive to Tezacaftor/Ivacaftor (Trial 3)

Trial 3 evaluated 168 patients with CF (83 SYMDEKO and 85 placebo) age 12 years and older (mean age 26.1 years) who were heterozygous for the F508del mutation and had a second CFTR mutation predicted to be unresponsive to tezacaftor/ivacaftor. CF patients with the F508del mutation and one of the following mutations in the CFTR gene were enrolled in the study (listed in decreasing frequency): W1282X, G542X, N1303K, 621+1G>T, 1717-1G>A, 1898+1G>A, CFTRdele2,3 , 2183delAA>G , 2184insA , R1162X , R553X, 3659delC, 3905insT, G970R, I507del, R1066C, R347P, 1154insTC, 1811+1.6kbA>G, 2184delA, 405+1G>A, E60X, G85E, L1077P, Q39X, S466X, Y1092X, 1078delT, 1248+1G>A, 1677delTA, 1812-1G>A, 2869INSG, 3120+1G>A, 394delTT, 457TAT>G, 711+1G>T, 711+5G>A, 712-1G>T, G673x, L1065P, Q220X, Q493X, R709X, V520F. The mean ppFEV1 at baseline was 57.5% [range: 31.0 to 96.7]. The primary efficacy endpoint was change from baseline in absolute ppFEV1 through Week 12. The overall treatment difference between SYMDEKO and placebo for the mean absolute change in ppFEV1 from baseline through Week 12 was 1.2 percentage points (95% CI: -0.3, 2.6). This study was terminated following the planned interim analysis because the pre-specified futility criteria were met.

16 HOW SUPPLIED/STORAGE AND HANDLING

SYMDEKO (tezacaftor 50 mg/ivacaftor 75 mg fixed-dose combination tablet co-packaged with ivacaftor 75 mg tablet):

  • Tezacaftor 50 mg/ivacaftor 75 mg fixed-dose combination tablets are supplied as white, capsule shaped tablets containing 50 mg of tezacaftor and 75 mg of ivacaftor. Each tablet is debossed with “V50” on one side and plain on the other.
  • Ivacaftor 75 mg tablets are supplied as light blue, film-coated, capsule-shaped tablets containing 75 mg of ivacaftor. Each tablet is printed with the characters “V 75” on one side and plain on the other.
  • 56-count tablet carton containing a 4-week supply (4 weekly wallets, each with 14 tablets) NDC 51167-113-01

SYMDEKO (tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination tablets co-packaged with ivacaftor 150 mg tablet):

  • Tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination tablets are supplied as yellow, capsule-shaped tablets containing 100 mg of tezacaftor and 150 mg of ivacaftor. Each tablet is debossed with “V100” on one side and plain on the other.
  • Ivacaftor 150 mg 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.
  • 56-count tablet carton containing a 4-week supply (4 weekly wallets, each with 14 tablets) NDC 51167-661-01

Store at 68°F to 77°F (20°C to 25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature].

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/ivacaftor 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. Dose reduction to one tablet of tezacaftor/ivacaftor or ivacaftor, 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. Food or drink containing grapefruit 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/ivacaftor once daily in the morning and advise the patient not to take the evening dose of ivacaftor. 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/ivacaftor once daily in the morning or less frequently. Advise the patient not to take the evening dose of ivacaftor. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A, score 5-6) [see Dosage and Administration (2.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

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.

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

Approved June 2022

SYMDEKO, VERTEX and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated.
All other trademarks referenced herein are the property of their respective owners.
©2022 Vertex Pharmaceuticals IncorporatedALL RIGHTS RESERVED

Patient Information is perforated for dispensing to the patient.

PATIENT INFORMATIONSYMDEKO (SIM-deh-koh)(tezacaftor/ivacaftor tablets; ivacaftor tablets)for oral use
What is SYMDEKO?
  • SYMDEKO is a prescription medicine used for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have two copies of the F508del mutation, or who have at least one mutation in the CF gene that is responsive to treatment with SYMDEKO.
  • Talk to your doctor to learn if you have an indicated CF gene mutation.
It is not known if SYMDEKO is safe and effective in children under 6 years of age.
Do not take SYMDEKO if you take certain medicines or herbal supplements such as:
  • antibiotics such as rifampin (RIFAMATE® , RIFATER®) or rifabutin (MYCOBUTIN®)
  • seizure medicines such as phenobarbital, carbamazepine (TEGRETOL® , CARBATROL® , EQUETRO®), or phenytoin (DILANTIN® , PHENYTEK®)
  • St. John’s wort
Talk to your doctor before taking SYMDEKO if you take any of the medicines or herbal supplements listed above.
Before taking SYMDEKO, tell your doctor about all of your medical conditions, including if you:
  • have or have had liver problems.
  • have kidney problems.
  • are pregnant or plan to become pregnant. It is not known if SYMDEKO will harm your unborn baby. You and your doctor should decide if you will take SYMDEKO while you are pregnant.
  • are breastfeeding or planning to breastfeed. It is not known if SYMDEKO passes into your breast milk. You and your doctor should decide if you will take SYMDEKO while you are breastfeeding.
SYMDEKO may affect the way other medicines work, and other medicines may affect how SYMDEKO works.Tell your doctor about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements, because the dose of SYMDEKO may need to be adjusted when taken with certain medicines.Ask your doctor or pharmacist for a list of these medicines if you are not sure.Especially tell your doctor if you take:
  • antifungal medicines such as ketoconazole (e.g. , NIZORAL®), itraconazole (e.g. , SPORANOX®), posaconazole (e.g. , NOXAFIL®), voriconazole (e.g. , VFEND®), or fluconazole (e.g. , DIFLUCAN®)
  • antibiotics such as telithromycin (e.g. , KETEK®), clarithromycin (e.g. , BIAXIN®), or erythromycin (e.g. , ERY-TAB®)
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I take SYMDEKO?
  • Take SYMDEKO exactly as your doctor tells you to take it.
  • Take SYMDEKO by mouth only.
  • SYMDEKO consists of 2 different tablets.
  • SYMDEKO Tablets (age 6 to less than 12 years weighing less than 30 kg):
    • The white tablet is marked with ‘V50’ and contains the medicines tezacaftor and ivacaftor. Take 1 white tablet in the morning.
    • The light blue tablet is marked with ‘V 75’ and contains the medicine ivacaftor. Take 1 light blue tablet in the evening.
  • SYMDEKO Tablets (age 6 to less than 12 years weighing 30 kg or more and age 12 years and older):
    • The yellow tablet is marked with ‘V100’ and contains the medicines tezacaftor and ivacaftor. Take 1 yellow tablet in the morning.
    • The light blue tablet is marked with ‘V 150’ and contains the medicine ivacaftor. Take 1 light blue tablet in the evening.
  • Take the morning and the evening tablet about 12 hours apart.
  • Always take SYMDEKO with food that contains fat. Examples of fat-containing foods include eggs, butter, peanut butter, cheese pizza, and whole-milk dairy products such as whole milk, cheese, and yogurt.
  • If you miss a dose of SYMDEKO and:
    • it is 6 hours or less from the time you usually take the yellow tablet in the morning or the light blue tablet in the evening, take the missed dose with food that contains fat as soon as you can. Then take your next dose at your usual time.
    • it is more than 6 hours from the time you usually take the yellow tablet in the morning or the light blue tablet in the evening, do not take the missed dose. Take your next dose at the usual time with food that contains fat.
  • Do not take more than your usual dose of SYMDEKO to make up for a missed dose.
What should I avoid while taking SYMDEKO?
  • SYMDEKO can cause dizziness in some people who take it. Do not drive a car, use machinery, or do anything that needs you to be alert until you know how SYMDEKO affects you.
  • Avoid food or drink that contains grapefruit while you are taking SYMDEKO.
What are the possible side effects of SYMDEKO?SYMDEKO can cause serious side effects, including:
  • High liver enzymes in the blood have been reported in people treated with SYMDEKO or treated with ivacaftor alone. Your doctor will do blood tests to check your liver:
    • before you start SYMDEKO
    • every 3 months during your first year of taking SYMDEKO
    • every year while you are taking SYMDEKO
Your doctor may do blood tests to check the liver more often if you have had high liver enzymes in your blood in the past.Call your doctor right away if you have any of the following symptoms of liver problems:
  • pain or discomfort in the upper right stomach (abdominal) area
  • yellowing of your skin or the white part of your eyes
  • loss of appetite
  • nausea or vomiting
  • dark, amber-colored urine
  • Abnormality of the eye lens (cataract) in some children and adolescents treated with SYMDEKO or treated with ivacaftor alone. If you are a child or adolescent, your doctor should perform eye examinations before and during treatment with SYMDEKO to look for cataracts.
The most common side effects of SYMDEKO include:
  • headache
  • nausea
  • sinus congestion
  • dizziness
These are not all the possible side effects of SYMDEKO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store SYMDEKO?
  • Store SYMDEKO at room temperature between 68°F to 77°F (20°C to 25°C).
  • Do not use SYMDEKO after the expiration date on the package.
Keep SYMDEKO and all medicines out of the reach of children.
General information about the safe and effective use of SYMDEKO. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SYMDEKO for a condition for which it was not prescribed. Do not give SYMDEKO to other people, even if they have the same symptoms you have. It may harm them.You can ask your pharmacist or doctor for information about SYMDEKO that is written for health professionals.
What are the ingredients in SYMDEKO?tezacaftor/ivacaftor tablets:Active ingredients: tezacaftor and ivacaftorInactive ingredients: hypromellose acetate succinate, sodium lauryl sulfate, hypromellose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, HPMC/hypromellose 2910, hydroxypropyl cellulose, titanium dioxide, talc, and iron oxide yellow (in tezacaftor 100 mg/ivacaftor 150 mg tablets only).ivacaftor tablets:Active ingredients: ivacaftorInactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, carnauba wax, FD&C Blue #2, PEG 3350, polyvinyl alcohol, talc, titanium dioxide, ammonium hydroxide, iron oxide black, propylene glycol, and shellac.

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Manufactured for: Vertex Pharmaceuticals Incorporated; 50 Northern Avenue, Boston, MA 02210 SYMDEKO, VERTEX and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2019 Vertex Pharmaceuticals Incorporated For more information, go to www.symdeko.com or call 1-877-752-5933.
This Patient Information has been approved by the U.S. Food and Drug Administration.Approved December2020

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