Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Vertex Pharmaceuticals (Ireland) Limited, Unit 49, Block F2, Northwood Court, Santry, Dublin 9, D09 T665, Ireland
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
In a patient with cirrhosis and portal hypertension liver failure leading to transplantation has been reported while receiving IVA/TEZ/ELX in combination with ivacaftor. IVA/TEZ/ELX in combination with IVA should be used with caution in patients with pre-existing advanced liver disease (e.g., cirrhosis, portal hypertension) and only if the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment (see sections 4.2, 4.8, and 5.2).
Elevated transaminases are common in patients with CF and have been observed in some patients treated with IVA/TEZ/ELX in combination with IVA. In patients taking IVA/TEZ/ELX in combination with IVA, these elevations have sometimes been associated with concomitant elevations in total bilirubin. Assessments of transaminases (ALT and AST) and total bilirubin 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 liver disease or transaminase elevations, more frequent monitoring should be considered. In the event of 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 transaminase elevations, the benefits and risks of resuming treatment should be considered (see sections 4.2, 4.8, and 5.2).
Treatment of patients with moderate hepatic impairment is not recommended. For patients with moderate hepatic impairment, the use of IVA/TEZ/ELX should only be considered when there is a clear medical need, and the benefits are expected to outweigh the risks. If used, it should be used with caution at a reduced dose (see Table 3).
Patients with severe hepatic impairment should not be treated with IVA/TEZ/ELX (see sections 4.2, 4.8, and 5.2).
Depression (including suicidal ideation and suicide attempt) has been reported in patients treated with IVA/TEZ/ELX, usually occurring within three months of treatment initiation and in patients with a history of psychiatric disorders. In some cases, symptom improvement was reported after dose reduction or treatment discontinuation. Patients (and caregivers) should be alerted about the need to monitor for depressed mood, suicidal thoughts, or unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
There is no experience in patients with severe renal impairment/end-stage renal disease therefore caution is recommended in this population (see sections 4.2 and 5.2).
IVA/TEZ/ELX in combination with IVA has not been studied in patients with CF who have undergone organ transplantation. Therefore, use in transplanted patients is not recommended. See section 4.5 for interactions with commonly used immunosuppressants.
The incidence of rash events was higher in females than in males, particularly in females taking hormonal contraceptives. A role for hormonal contraceptives in the occurrence of rash cannot be excluded. For patients taking hormonal contraceptives who develop rash, interrupting treatment with IVA/TEZ/ELX in combination with IVA and hormonal contraceptives should be considered. Following the resolution of rash, it should be considered if resuming IVA/TEZ/ELX in combination with IVA without hormonal contraceptives is appropriate. If rash does not recur, resumption of hormonal contraceptives can be considered (see section 4.8).
Clinical studies of IVA/TEZ/ELX in combination with IVA did not include sufficient number of patients aged 65 years and older to determine whether response in these patients is different from younger adults. Dose recommendations are based on the pharmacokinetic profile and knowledge from studies with tezacaftor/ivacaftor (TEZ/IVA) in combination with ivacaftor (IVA), and ivacaftor (IVA) monotherapy (see sections 4.2 and 5.2).
Exposure to IVA is significantly decreased and exposures to ELX and TEZ are expected to decrease by the concomitant use of CYP3A inducers, potentially resulting in the reduced efficacy of IVA/TEZ/ELX and IVA; therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.5).
Exposures of ELX, TEZ and IVA are increased when co-administered with strong or moderate CYP3A inhibitors. The dose of IVA/TEZ/ELX and IVA should be adjusted when used concomitantly with strong or moderate CYP3A inhibitors (see section 4.5 and Table 2 in section 4.2).
Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patients treated with IVA-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 IVA cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating treatment with IVA/TEZ/ELX in combination with IVA (see section 5.3).
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
ELX, TEZ and IVA are substrates of CYP3A (IVA is a sensitive substrate of CYP3A). Concomitant use of strong CYP3A inducers may result in reduced exposures and thus reduced IVA/TEZ/ELX efficacy. Co-administration of IVA with rifampicin, a strong CYP3A inducer, significantly decreased IVA area under the curve (AUC) by 89%. ELX and TEZ exposures are also expected to decrease during co-administration with strong CYP3A inducers; therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.4).
Examples of strong CYP3A inducers include:
Co-administration with itraconazole, a strong CYP3A inhibitor, increased ELX AUC by 2.8-fold and TEZ AUC by 4.0- to 4.5-fold. When co-administered with itraconazole and ketoconazole, IVA AUC increased by 15.6-fold and 8.5-fold, respectively. The dose of IVA/TEZ/ELX and IVA should be reduced when co-administered with strong CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4).
Examples of strong CYP3A inhibitors include:
Simulations indicated that co-administration with moderate CYP3A inhibitors fluconazole, erythromycin and verapamil, may increase ELX and TEZ AUC by approximately 1.9- to 2.3-fold. Coadministration of fluconazole increased IVA AUC by 2.9-fold. The dose of IVA/TEZ/ELX and IVA should be reduced when co-administered with moderate CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4).
Examples of moderate CYP3A inhibitors include:
Co-administration with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ELX, TEZ and IVA. Food or drink containing grapefruit should be avoided during treatment with IVA/TEZ/ELX and IVA (see section 4.2).
In vitro studies showed that ELX is a substrate for the efflux transporters P-gp and Breast Cancer Resistance Protein (BCRP) but is not a substrate for OATP1B1 or OATP1B3. Exposure to ELX is not expected to be affected significantly by concomitant use of P-gp and BCRP inhibitors due to its high intrinsic permeability and low likelihood of being excreted intact.
In vitro studies showed that TEZ is a substrate for the uptake transporter OATP1B1 and efflux transporters P-gp and BCRP. TEZ is not a substrate for OATP1B3. Exposure to TEZ is not expected to be affected significantly by concomitant inhibitors of OATP1B1, P-gp, or BCRP due to its high intrinsic permeability and low likelihood of being excreted intact. However, exposure to M2-TEZ (TEZ metabolite) may be increased by inhibitors of P-gp. Therefore, caution should be used when Pgp inhibitors (e.g., ciclosporin) are used with IVA/TEZ/ELX.
In vitro studies showed that IVA is not a substrate for OATP1B1, OATP1B3, or P-gp. IVA and its metabolites are substrates of BCRP in vitro. Due to its high intrinsic permeability and low likelihood of being excreted intact, co-administration of BCRP inhibitors is not expected to alter exposure of IVA and M1-IVA, while any potential changes in M6-IVA exposures are not expected to be clinically relevant.
IVA may inhibit CYP2C9; therefore, monitoring of the international normalised ratio (INR) during co-administration of warfarin with IVA/TEZ/ELX and IVA is recommended. Other medicinal products for which exposure may be increased include glimepiride and glipizide; these medicinal products should be used with caution.
Co-administration of IVA or TEZ/IVA with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by IVA. Administration of IVA/TEZ/ELX and IVA 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 ciclosporin, everolimus, sirolimus and tacrolimus, caution and appropriate monitoring should be used.
ELX and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. TEZ/IVA increased the AUC of pitavastatin, an OATP1B1 substrate, by 1.2-fold. Co-administration with IVA/TEZ/ELX in combination with IVA may increase exposures of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide. When used concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used. Bilirubin is an OATP1B1 and OATP1B3 substrate. In study 445-102, mild increases in mean total bilirubin were observed (up to 4.0 µmol/L change from baseline). This finding is consistent with the in vitro inhibition of bilirubin transporters OATP1B1 and OATP1B3 by ELX and M23-ELX.
ELX and IVA are inhibitors of BCRP. Co-administration of IVA/TEZ/ELX, and IVA may increase exposures of medicinal products that are substrates of BCRP, such as rosuvastatin. When used concomitantly with substrates of BCRP, appropriate monitoring should be used.
IVA/TEZ/ELX in combination with IVA has been studied with ethinyl estradiol/levonorgestrel and was found to have no clinically relevant effect on the exposures of the oral contraceptive. IVA/TEZ/ELX and IVA is not expected to have an impact on the efficacy of oral contraceptives.
Interaction studies have only been performed in adults.
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ELX, TEZ or IVA in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of IVA/TEZ/ELX during pregnancy.
It is unknown whether ELX, TEZ, IVA, or their metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of ELX, TEZ and IVA into the milk of lactating female rats (see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from IVA/TEZ/ELX therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
There are no data available on the effect of ELX, TEZ and IVA on fertility in humans. TEZ had no effects on fertility and reproductive performance indices in male and female rats at clinically relevant exposures. ELX and IVA had an effect on fertility in rats (see section 5.3).
IVA/TEZ/ELX in combination with IVA has a minor influence on the ability to drive or use machines. Dizziness has been reported in patients receiving IVA/TEZ/ELX in combination with IVA, TEZ/IVA in combination with IVA as well as IVA (see section 4.8). Patients experiencing dizziness should be advised not to drive or use machines until symptoms abate.
The most common adverse reactions experienced by patients aged 12 years and older who received IVA/TEZ/ELX in combination with IVA were headache (17.3%), diarrhoea (12.9%) and upper respiratory tract infection (11.9%).
Serious adverse reactions of rash experienced by patients aged 12 years and older were reported in 1.5% patients treated with IVA/TEZ/ELX in combination with IVA (see section 4.4).
Table 4 reflects adverse reactions observed with IVA/TEZ/ELX in combination with IVA, TEZ/IVA in combination with IVA, and IVA monotherapy. Adverse reactions are listed by MedDRA system organ class and frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 4. Adverse reactions:
| MedDRA System Organ Class | Adverse Reactions | Frequency |
|---|---|---|
| Infections and infestations | Upper respiratory tract infection*, Nasopharyngitis | very common |
| Rhinitis*, Influenza* | common | |
| Metabolism and nutrition disorders | Hypoglycaemia* | common |
| Psychiatric disorders | Depression | not known |
| Nervous system disorders | Headache*, Dizziness* | very common |
| Ear and labyrinth disorders | Ear pain, Ear discomfort, Tinnitus, Tympanic membrane hyperaemia, Vestibular disorder | common |
| Ear congestion | uncommon | |
| Respiratory, thoracic and mediastinal disorders | Oropharyngeal pain, Nasal congestion* | very common |
| Rhinorrhoea*, Sinus congestion, Pharyngeal erythema, Abnormal breathing* | common | |
| Wheezing* | uncommon | |
| Gastrointestinal disorders | Diarrhoea*, Abdominal pain* | very common |
| Nausea, Abdominal pain upper*, Flatulence* | common | |
| Hepatobiliary disorders | Transaminase elevations | very common |
| Alanine aminotransferase increased* | very common | |
| Aspartate aminotransferase increased* | common | |
| Liver injury† | not known | |
| Total bilirubin increase† | not known | |
| Skin and subcutaneous tissue disorders | Rash* | very common |
| Acne*, Pruritus* | common | |
| Reproductive system and breast disorders | Breast mass | common |
| Breast inflammation, Gynaecomastia, Nipple disorder, Nipple pain | uncommon | |
| Investigations | Bacteria in sputum | very common |
| Blood creatine phosphokinase increased* | common | |
| Blood pressure increased* | uncommon |
* Adverse reactions observed during clinical studies with IVA/TEZ/ELX in combination with IVA.
† Liver injury (ALT and AST and total bilirubin increase) reported from post-marketing data with IVA/TEZ/ELX in combination with IVA. This also included liver failure leading to transplantation in a patient with pre-existing cirrhosis and portal hypertension. Frequency cannot be estimated from the available data.
Safety data from the following studies were consistent with the safety data observed in study 445-102.
In study 445-102, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 x the ULN was 1.5%, 2.5% and 7.9% in IVA/TEZ/ELX-treated patients and 1.0%, 1.5% and 5.5% in placebo-treated patients. The incidence of adverse reactions of transaminase elevations was 10.9% in IVA/TEZ/ELX-treated patients and 4.0% in placebo-treated patients.
Post-marketing cases of treatment discontinuation due to elevated transaminases have been reported (see section 4.4).
In study 445-102, the incidence of rash events (e.g., rash, rash pruritic) was 10.9% in IVA/TEZ/ELX- and 6.5% in placebo-treated patients. The rash events were generally mild to moderate in severity. The incidence of rash events by patient sex was 5.8% in males and 16.3% in females in IVA/TEZ/ELX-treated patients and 4.8% in males and 8.3% in females in placebo-treated patients. In patients treated with IVA/TEZ/ELX, the incidence of rash events was 20.5% in females taking hormonal contraceptive and 13.6% in females not taking hormonal contraceptive (see section 4.4).
In study 445-102, the incidence of maximum creatine phosphokinase >5 x the ULN was 10.4% in IVA/TEZ/ELX- and 5.0% in placebo-treated patients. The observed creatine phosphokinase elevations were generally transient and asymptomatic and many were preceded by exercise. No IVA/TEZ/ELX-treated patients discontinued treatment for increased creatine phosphokinase.
In study 445-102, the maximum increase from baseline in mean systolic and diastolic blood pressure was 3.5 mmHg and 1.9 mmHg, respectively for IVA/TEZ/ELX-treated patients (baseline: 113 mmHg systolic and 69 mmHg diastolic) and 0.9 mmHg and 0.5 mmHg, respectively for placebo-treated patients (baseline: 114 mmHg systolic and 70 mmHg diastolic).
The proportion of patients who had systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg on at least two occasions was 5.0% and 3.0%, respectively in IVA/TEZ/ELX-treated patients compared with 3.5% and 3.5%, respectively in placebo-treated patients.
The safety data of IVA/TEZ/ELX in combination with IVA in studies 102, 103, 104,106 and 111 was evaluated in 228 patients between 2 to less than 18 years of age. The safety profile is generally consistent among paediatric and adult patients.
During study 445-106 in patients aged 6 to less than 12 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 x ULN were 0.0%, 1.5%, and 10.6%, respectively. No IVA/TEZ/ELX-treated patients had transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN or discontinued treatment due to transaminase elevations (see section 4.4).
During study 445-111 in patients aged 2 to less than 6 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 x ULN were 1.3%, 2.7%, and 8.0% respectively. No IVA/TEZ/ELXtreated patients had transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN or discontinued treatment due to transaminase elevations (see section 4.4).
During study 445-111 in patients aged 2 to less than 6 years, 15 (20.0%) subjects had at least 1 rash event, 4 (9.8%) females and 11 (32.4%) males.
One patient had an adverse event of lenticular opacity.
With the exception of sex differences in rash, the safety profile of IVA/TEZ/ELX in combination with IVA was generally similar across all subgroups of patients, including analysis by age, baseline percent predicted forced expiratory volume in one second (ppFEV1) and geographic regions.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
