SYMDEKO

/ Vertex

6 to <12 years weighing <30 kg
Morning (one tablet): tezacaftor 50 mg/ivacaftor 75 mg
Evening (one tablet): ivacaftor 75 mg
6 to <12 years weighing ≥30 kg
Morning (one tablet): tezacaftor 100 mg/ivacaftor 150 mg
Evening (one tablet): ivacaftor 150 mg
≥12 years
Morning (one tablet): tezacaftor 100 mg/ivacaftor 150 mg
Evening (one tablet): ivacaftor 150 mg
The morning and the evening doses should be taken approximately 12 hours apart. 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.
See prescribing information for full details.

Treatment of patients with cystic fibrosis (CF) aged 6 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.

Hypersensitivity to the active substances or to any of the excipients

Transaminase (AST/ALT) Elevations
Elevated transaminases have been observed in patients with CF treated with this medical product, as well as with ivacaftor monotherapy. Assessments of transaminases (ALT and AST) are recommended for all patients prior to initiating treatment, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations more frequent monitoring should be considered. In the event of 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, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve.
Hypersensitivity Reactions, Including Anaphylaxis
Hypersensitivity reactions, including cases of anaphylaxis, have been reported. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment.
Intracranial Hypertension
Cases of intracranial hypertension (IH) have been reported in the postmarketing setting with the use of drugs containing the same or similar active ingredients. Clinical manifestations of IH include headache, blurred vision, diplopia, and potential vision loss; papilledema can be found on fundoscopy If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt therapy and refer the patient for prompt medical evaluation. Consider the benefits and risks for the individual patient to determine whether to resume treatment. Patients with elevated vitamin A levels may be at increased risk.
Concomitant Use with CYP3A Inducers
Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of CYP3A inducers, which may reduce the therapeutic effectiveness.
Cataracts
Cases of non-congenital lens opacities have been reported in pediatric patients treated with this medical product, as well as with ivacaftor monotherapy. Although other risk factors were present in some cases (such as corticosteroid use, exposure to radiation), a possible risk attributable to treatment cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment

The safety profile was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV1 (ppFEV1), and geographic regions.
adverse reactions occurring in ≥3% of treated patients that also occurred at a higher rate than in the placebo-treated patients in the 12- and 24-week placebo-controlled, parallel-group trials.
See prescribing information for full details.

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 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 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 this medical product 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 this medical product should be adjusted.
Examples of moderate CYP3A inhibitors include: fluconazole, erythromycin.
Co-administration 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.
Potential for tezacaftor/ivacaftor to affect other drugs
CYP2C9 Substrates
Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co-administration with warfarin is recommended. Other medicinal products for which exposure may be increased by this medical product include glimepiride and glipizide; these medicinal products should be used with caution.
Digoxin and Other P-gp Substrates
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 this medical product 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.
See prescribing information for full details.

Pregnancy: There are limited and incomplete human data from clinical trials and postmarketing reports on the use of this medical product or its individual components, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk.
Lactation: 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 this medical product and any potential adverse effects on the breastfed child from this medical product or from the underlying maternal condition.
See prescribing information for full details.

No specific antidote is available for overdose. Treatment of overdosage consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.