Kalydeco (ivacaftor)

Kalydeco can cause serious side effects.

High liver enzymes in the blood have been reported in patients receiving Kalydeco. Your doctor will do blood tests to check your liver:

• before you start Kalydeco
• every 3 months during your first year of taking Kalydeco
• every year while you are taking Kalydeco

For patients who have had high liver enzymes in the past, the doctor may do blood tests to check the liver more often.

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) has been noted in some children and adolescents receiving Kalydeco.

Your doctor should perform eye examinations prior to and during treatment with Kalydeco to look for cataracts.

The most common side effects of Kalydeco include:

• headache
• upper respiratory tract infection (common cold), including:
  • sore throat
  • nasal or sinus congestion
  • runny nose
• stomach (abdominal) pain
• diarrhea
• rash
• nausea
• dizziness

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Kalydeco. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General Dosing Information

Kalydeco should be taken with fat-containing food. Examples include eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, yogurt, breast milk or infant formula), etc.

Recommended Dosage In Adults And Pediatric Patients Aged 6 Years And Older

The recommended dosage of Kalydeco for adults and pediatric patients ages 6 years and older is one 150 mg tablet taken orally every 12 hours (300 mg total daily dose) with fat-containing food.

Recommended Dosage In Pediatric Patients Aged 4 Months To Less Than 6 Years

The recommended dosage of Kalydeco (oral granules) for patients ages 4 months to less than 6 years is weight-based according to Table 1.

Table 1: Dosage of Kalydeco Oral Granules by Body Weight in Pediatric Patients Ages 4 months to less than 6 Years

Instructions For Administration Of Oral Granules

• The entire contents of each packet of oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and completely consumed.
• Food or liquid should be at or below room temperature.
• Once mixed, the product has been shown to be stable for one hour, and therefore should be consumed during this period.
• Some examples of soft foods or liquids may include puréed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, or juice.
• Each dose should be administered just before or just after fat-containing food [see General Dosing Information above].

Dosage Adjustment For Patients With Hepatic Impairment Aged 6 Months And Older

• The dosage of Kalydeco should be reduced to one tablet or one packet of oral granules once daily for patients aged 6 months and older with moderate hepatic impairment (Child-Pugh Class B).
• Kalydeco should be used with caution in patients aged 6 months and older with severe hepatic impairment (Child-Pugh Class C), at a dosage of one tablet or one packet of oral granules once daily or less frequently.
• Use is not recommended in patients with hepatic impairment below 6 months of age.

Dosage Adjustment For Patients Aged 6 Months And Older Taking Drugs That Are CYP3A Inhibitors

• When Kalydeco is being co-administered with strong CYP3A inhibitors (e.g., ketoconazole) in patients aged 6 months or older, the dose should be reduced to one tablet or one packet of oral granules twice a week.
• The dose of Kalydeco should be reduced to one tablet or one packet of granules once daily when co-administered with moderate CYP3A inhibitors (e.g., fluconazole).
• Concomitant use of moderate or strong CYP3A inhibitors is not recommended in patients below 6 months of age.
• Food containing grapefruit should be avoided.

Potential For Other Drugs To Affect Ivacaftor

Inhibitors Of CYP3A

• Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold.
• Based on simulations of these results, a reduction of the Kalydeco dose is recommended for patients taking concomitant strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin.
• Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold.
• Therefore, a reduction of the Kalydeco dose is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin.
• Co-administration of Kalydeco with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, avoid food containing grapefruit during treatment with Kalydeco.

Inducers Of CYP3A

• Co-administration with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold.
• Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's wort is not recommended.

Ciprofloxacin

• Co-administration of Kalydeco with ciprofloxacin had no effect on the exposure of ivacaftor.
•  Therefore, no dose adjustment is necessary during concomitant administration of Kalydeco with ciprofloxacin.

Potential For Ivacaftor To Affect Other Drugs

CYP2C9 Substrates

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

CYP3A And/Or P-gp Substrates

• Ivacaftor and its M1 metabolite have the potential to inhibit CYP3A and P-gp.
• Co-administration with oral midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor.
• Co-administration 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 Kalydeco may increase systemic exposure of drugs that are substrates of CYP3A and/or P-gp, which may increase or prolong their therapeutic effect and adverse events.
• Therefore, caution and appropriate monitoring are recommended when co-administering Kalydeco with sensitive CYP3A and/or P-gp substrates, such as digoxin, cyclosporine, and tacrolimus.

• There are limited and incomplete human data from clinical trials and post marketing reports on use of Kalydeco in pregnant women.
• There is no information regarding the presence of 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 Kalydeco, and any potential adverse effects on the breastfed child from Kalydeco or from the underlying maternal condition.