Symdeko (tezacaftor/ivacaftor) Cystic Fibrosis Drug Warnings

Generic drug: tezacaftor/ivacaftor

Brand name: Symdeko

What is Symdeko (tezacaftor/ivacaftor), and how does it work?

• Symdeko (tezacaftor/ivacaftor) 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.

What are the 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.

What is the dosage for Symdeko?

General Dosing Information

Swallow the tablets whole.

Symdeko
should be taken with fat-containing food, such as food recommended in standard
nutritional guidelines. Examples of meals or snacks that contain fat are those
prepared with butter or oils or those containing eggs, cheeses, nuts, whole
milk, or meats, etc.

Recommended Dosage In Adults, Adolescents, And Children Age 6 Years And Older

Adults, adolescents, and children age 6 years and older should be dosed according to Table 1. The morning and the evening dose should be taken approximately 12 hours apart.

Table 1: Recommended Dosage for Patients Age 6 Years and Older

AgeMorning (one tablet)Evening (one tablet)6 to <12 years weighing <30 kgtezacaftor 50 mg/ivacaftor 75 mgivacaftor 75 mg6 to <12 years weighing ≥30 kgtezacaftor 100 mg/ivacaftor 150 mgivacaftor 150 mg≥12 yearstezacaftor 100 mg/ivacaftor 150 mgivacaftor 150 mg

Information For Missed Doses

If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule. If more than 6 hours have passed since the missed morning or evening dose, the patient should not take the missed dose. The next scheduled dose can be taken at the usual time. More than one dose should not be taken at the same time.

Recommended Dosage For Patients With Hepatic Impairment

For dose adjustment for patients with hepatic impairment, refer to Table 2.

Studies have not been conducted in patients with severe hepatic impairment
(Child-Pugh Class C), but exposure of tezacaftor and ivacaftor is expected to be
higher than in patients with moderate hepatic impairment. Therefore, Symdeko
should be used with caution at an adjusted dose after weighing the risks and
benefits of treatment in these patients.

Table 2: Recommended Dosage for Patients with Hepatic Impairment

Hepatic ImpairmentMorningEveningPatients Age 6 to <12 Years Weighing <30kgPatients Age 6 to <12 Years Weighing ≥30 kg and Patients Age ≥12 YearsAll PatientsMild (Child-Pugh Class A)No dose adjustmentNo dose adjustmentNo dose adjustmentModerate (Child-Pugh Class B)One tablet of tezacaftor 50 mg/ivacaftor 75 mg once dailyOne tablet of tezacaftor 100 mg/ivacaftor 150 mg once dailyNo ivacaftor doseSevere (Child-Pugh Class C)One tablet of tezacaftor 50 mg/ivacaftor 75 mg once daily (or less frequently)One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily (or less frequently)

Dosage Adjustment For Patients Taking Drugs That Are CYP3A Inhibitors

The dosing regimen of
Symdeko should be adjusted when co-administered with moderate and strong CYP3A inhibitors.

Moderate CYP3A Inhibitors

When co-administered with moderate CYP3A inhibitors (e.g., fluconazole,
erythromycin), the dosing regimen should be adjusted as in Table 3.

Table 3: Dosing Schedule for Concomitant Use of
Symdeko with Moderate CYP3A Inhibitors

Day 1Day 2Day 3Day 4*Patients Age 6 to <12 Years Weighing <30 kgMorning  Tezacaftor 50 mg/ivacaftor 75 mg tablet√-√-  Ivacaftor 75 mg tablet-√-√Evening  Ivacaftor 75 mg tablet—-Patients Age 6 to <12 Years Weighing ≥30 kg
and
Patients Age ≥12 YearsMorning  Tezacaftor 100 mg/ivacaftor 150 mg tablet√-√-  Ivacaftor 150 mg tablet-√-√Evening  Ivacaftor 150 mg tablet—-*Continue dosing with tezacaftor/ivacaftor or ivacaftor tablets on alternate days.

Strong CYP3A inhibitors

When co-administered with strong CYP3A inhibitors (e.g., ketoconazole,
itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin),
the dosing regimen should be adjusted as in Table 4.

Table 4: Dosing Schedule for Concomitant Use of
Symdeko with Strong CYP3A Inhibitors

Day 1Day 2 and Day 3Day 4*Patients Age 6 to <12 Years Weighing <30 kgMorning  Tezacaftor 50 mg/ivacaftor 75 mg tablet√-√Evening^†  Ivacaftor 75 mg tablet—Patients Age 6 to <12 Years Weighing ≥30 kg
and
Patients Age ≥12 YearsMorning  Tezacaftor 100 mg/ivacaftor 150 mg tablet√-√Evening^†  Ivacaftor 150 mg tablet—^* Continue dosing with tezacaftor/ivacaftor tablets twice a week, taken approximately 3 to 4 days apart.
^† The evening dose of ivacaftor should not be taken on any day.

Food or drink containing grapefruit should be avoided during treatment with
Symdeko.

What drugs interact with Symdeko?

Potential For Other Drugs To Affect Tezacaftor/Ivacaftor

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)

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
• Co-administration of fluconazole increased ivacaftor exposure (AUC) by
  3.0-fold. Simulation suggested co-administration with fluconazole, a
  moderate CYP3A inhibitor, may increase tezacaftor exposure (AUC) by
  approximately 2.0-fold.
• When co-administered with moderate CYP3A inhibitors, the dosing regimen
  of Symdeko should be adjusted.
• Examples of moderate CYP3A inhibitors include:
  • fluconazole
  • erythromycin
• 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
  should be avoided during treatment with Symdeko.

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

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 .

CYP2C9 Substrates

• Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international
  normalized ratio (INR) during co administration of Symdeko with warfarin is
  recommended.
•  Other medicinal products for which exposure may be increased by
  Symdeko include glimepiride and glipizide; these medicinal products should
  be used with caution.

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.
• Administration of Symdeko may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions.
• When used concomitantly with digoxin or other substrates of P-gp with a
  narrow therapeutic index such as cyclosporine, everolimus, sirolimus, and
  tacrolimus, caution and appropriate monitoring should be used.

Hormonal Contraceptives

• Symdeko has been studied with an ethinyl estradiol/norethindrone oral
  contraceptive and was found to have no significant effect on the exposures
  of the hormonal contraceptive. Symdeko is not expected to modify the
  efficacy of hormonal contraceptives.

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Is Symdeko safe to use while pregnant or breastfeeding?

• 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.
• 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.