Symdeko (tezacaftor/ivacaftor)

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.

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

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

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

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

Food or drink containing grapefruit should be avoided during treatment 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.

• 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.