Trikafta

/ Vertex

The morning and the evening dose should be taken approximately 12 hours apart.
2 to less than 6 years
Less than 14 kg- One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) granules + One packet (containing ivacaftor 59.5 mg) granules
14 kg or more- One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) granules + One packet (containing ivacaftor 75 mg) granules
6 to less than 12 years
Less than 30 kg- Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) + One tablet of ivacaftor 75 mg
30 kg or more- Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) + One tablet of ivacaftor 150 mg
12 years and older
Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) + One tablet of ivacaftor 150 mg.
See prescribing information for full details.

Treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least one F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive based on in vitro data.

Hypersensitivity to the active substances (elexacaftor, ivacaftor or tezacaftor) or to any of the excipients.

Elevated Transaminases and Hepatic Injury:
Liver failure leading to transplantation has been reported in a patient with cirrhosis and portal hypertension while receiving this medical product. Avoid use in patients with pre-existing advanced liver disease (e.g., as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment.
Isolated elevations of transaminases or bilirubin have been observed in patients with CF treated with this medical product. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or international normalized ratio (INR) and have resulted in patients being hospitalized for intervention, including in patients without a history of pre-existing liver disease.
Assessments of liver function tests (ALT, AST, and bilirubin) are recommended for all patients prior to initiating treatment, every 3 months during the first year of treatment, and annually thereafter. In the event of significant elevations in liver function tests, e.g., ALT or AST >5 x the 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. Following the resolution of liver function test elevations, consider the benefits and risks of resuming treatment. For patients with a history of hepatobiliary disease or liver function test elevations, more frequent monitoring should be considered.
Hypersensitivity Reactions, Including Anaphylaxis:
Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the post-marketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue treatment with this medical product 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 post-marketing setting. 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 this medical product and refer for prompt medical evaluation. Consider the benefits and risks for the individual patient to determine whether to resume treatment. Patients should be monitored until IH resolution and for recurrence. 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 elexacaftor and tezacaftor are expected to decrease by the concomitant use of strong CYP3A inducers, which may reduce the therapeutic effectiveness. Therefore, co-administration with strong CYP3A inducers is not recommended.
Concomitant Use with CYP3A Inhibitors: Exposure to elexacaftor, tezacaftor and ivacaftor are increased when co-administered with strong or moderate CYP3A inhibitors. Therefore, the dose of this medical product should be reduced when used concomitantly with moderate or strong CYP3A inhibitors.
Cataracts: Cases of non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor-containing regimens. Although other risk factors were present in some cases (such as corticosteroid use, exposure to radiation), a possible risk attributable to treatment with ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In one Trial, the proportion of patients who discontinued study drug prematurely due to adverse events was 1% for treated patients and 0% for placebo-treated patients. Serious adverse reactions that occurred more frequently in treated patients compared to placebo were rash (1% vs <1%) and influenza (1% vs 0%). There were no deaths in Trials 1, 2, 3 and 4.
See prescribing information for full details.

Inducers of CYP3A: Elexacaftor, 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 area under the curve (AUC) by 89%. Elexacaftor and tezacaftor exposures are expected to decrease during co-administration with strong CYP3A inducers. Therefore, co-administration with strong CYP3A inducers is not recommended.
Inhibitors of CYP3A: Co-administration with itraconazole, a strong CYP3A inhibitor, increased elexacaftor AUC by 2.8-fold and tezacaftor AUC by 4.0- to 4.5-fold. When
co-administered with itraconazole and ketoconazole, ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively. The dosage of this medical product should be reduced when co-administered with strong CYP3A inhibitors.
Examples of strong CYP3A inhibitors include: ketoconazole, itraconazole, posaconazole and voriconazole, telithromycin and clarithromycin.
Simulations indicated that co-administration with moderate CYP3A inhibitors may increase elexacaftor and tezacaftor AUC by approximately 1.9- to 2.3-fold and 2.1-fold, respectively. Co-administration of fluconazole increased ivacaftor AUC by 2.9-fold. The dosage of this medical product should be reduced when co-administered with moderate CYP3A inhibitors.
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 elexacaftor, tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment.
Potential for elexacaftor/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.
Transporters: Co-administration of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin AUC 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 on the use of this medical product or its individual components, elexacaftor, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk.
Lactation: There is no information regarding the presence of elexacaftor, 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 or from the underlying maternal condition.
See prescribing information for full details.

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