Ivacaftor, Tezacaftor and Elexacaftor interacts in the following cases:
Elexacaftor and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. Tezacaftor/ivacaftor increased the AUC of pitavastatin, an OATP1B1 substrate, by 1.2-fold. Co-administration with ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor 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 elexacaftor and M23-ELX.
Elexacaftor and ivacaftor are inhibitors of BCRP. Co-administration of ivacaftor/tezacaftor/elexacaftor, and ivacaftor 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.
Co-administration with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor. Food or drink containing grapefruit should be avoided during treatment with ivacaftor/tezacaftor/elexacaftor and ivacaftor.
In vitro studies showed that elexacaftor 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 elexacaftor 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 tezacaftor is a substrate for the uptake transporter OATP1B1 and efflux transporters P-gp and BCRP. Tezacaftor is not a substrate for OATP1B3. Exposure to tezacaftor 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 (tezacaftor metabolite) may be increased by inhibitors of P-gp. Therefore, caution should be used when P-gp inhibitors (e.g., ciclosporin) are used with ivacaftor/tezacaftor/elexacaftor.
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 dose of ivacaftor/tezacaftor/elexacaftor and ivacaftor should be reduced when co-administered with strong CYP3A inhibitors.
Examples of strong CYP3A inhibitors include:
Dosing schedule for concomitant use with moderate and strong CYP3A inhibitors:
| Age | Weight | Strong CYP3A Inhibitors |
|---|---|---|
| 2 years to less than 6 years | 10 kg to <14 kg | IVA 60 mg/TEZ 40 mg/ELX 80 mg twice a week, approximately 3 to 4 days apart. No evening dose of IVA. |
| 2 years to less than 6 years | ≥14 kg | IVA 75 mg/TEZ 50 mg/ELX 100 mg twice a week, approximately 3 to 4 days apart. No evening dose of IVA. |
| 6 to <12 years | <30 kg | IVA 75 mg/TEZ 50 mg/ELX 100 mg twice a week, approximately 3 to 4 days apart. No evening IVA dose. |
| 6 to <12 years | ≥30 kg | IVA 150 mg/TEZ 100 mg/ELX 200 mg twice a week, approximately 3 to 4 days apart. No evening IVA dose. |
| 12 years and older | - | IVA 150 mg/TEZ 100 mg/ELX 200 mg twice a week, approximately 3 to 4 days apart. No evening IVA dose. |
Simulations indicated that co-administration with moderate CYP3A inhibitors fluconazole, erythromycin and verapamil, may increase elexacaftor and tezacaftor AUC by approximately 1.9- to 2.3-fold. Coadministration of fluconazole increased ivacaftor AUC by 2.9-fold. The dose of ivacaftor/tezacaftor/elexacaftor and ivacaftor should be reduced when co-administered with moderate CYP3A inhibitors.
Examples of moderate CYP3A inhibitors include:
Dosing schedule for concomitant use with moderate CYP3A inhibitors:
| Age | Weight | Moderate CYP3A Inhibitors |
|---|---|---|
| 2 years to less than 6 years | 10 kg to <14 kg | Alternate each day: • ivacaftor 60 mg/tezacaftor 40 mg/ elexacaftor 80 mg (IVA/TEZ/ELX) on the first day • ivacaftor 59.5 mg (IVA) on the next day No evening IVA dose. |
| 2 years to less than 6 years | ≥14 kg | Alternate each day: • ivacaftor 75 mg/tezacaftor 50 mg/ elexacaftor 100 mg (IVA/TEZ/ELX) on the first day • ivacaftor 75 mg (IVA) on the next day No evening IVA dose. |
| 6 to <12 years | <30 kg | Alternate each day: • ivacaftor 75 mg/tezacaftor 50 mg/ elexacaftor 100 mg (IVA/TEZ/ELX) on the first day • ivacaftor 75 mg (IVA) on the next day No evening dose of IVA. |
| 6 to <12 years | ≥30 kg | Alternate each day: • ivacaftor 150 mg/tezacaftor 100 mg/ elexacaftor 200 mg (IVA/TEZ/ELX) on the first day • ivacaftor 150 mg (IVA) on the next day. No evening dose IVA dose. |
| 12 years and older | - | Alternate each day: • ivacaftor 150 mg/tezacaftor 100 mg/ elexacaftor 200 mg (IVA/TEZ/ELX) on the first day • ivacaftor 150 mg (IVA) on the next day No evening IVA dose. |
Elexacaftor, tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A). Concomitant use of strong CYP3A inducers may result in reduced exposures and thus reduced ivacaftor/tezacaftor/elexacaftor efficacy. Co-administration of ivacaftor with rifampicin, a strong CYP3A inducer, significantly decreased ivacaftor area under the curve (AUC) by 89%. Elexacaftor and tezacaftor exposures are also expected to decrease during co-administration with strong CYP3A inducers; therefore, co-administration with strong CYP3A inducers is not recommended.
Examples of strong CYP3A inducers include:
Treatment of patients with moderate hepatic impairment (Child-Pugh Class B) is not recommended. For patients with moderate hepatic impairment, the use of ivacaftor/tezacaftor/elexacaftor 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.
Recommendation for use in patients aged 6 years and older with hepatic impairment:
| Age | Weight | Moderate (Child-Pugh Class B) |
|---|---|---|
| 2 years to less than 6 years | 10 kg to <14 kg | Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks. If used, ivacaftor/tezacaftor/elexacaftor should be used with caution at a reduced dose, as follows: • Days 1-3: IVA 60 mg/TEZ 40 mg/ELX 80 mg each day • Day 4: no dose • Days 5-6: IVA 60 mg/TEZ 40 mg/ELX 80 mg each day • Day 7: no dose Repeat above dosing schedule each week. The evening dose of the IVA should not be taken. |
| 2 years to less than 6 years | ≥14 kg | Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks. If used, ivacaftor/tezacaftor/elexacaftor should be used with caution at a reduced dose, as follows: • Days 1-3: IVA 75 mg/TEZ 50 mg/ELX 100 mg each day • Day 4: no dose • Days 5-6: IVA 75 mg/TEZ 50 mg/ELX 100 mg each day • Day 7: no dose Repeat above dosing schedule each week. The evening dose of the IVA should not be taken. |
| 6 to <12 years | <30 kg | Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks. If used, ivacaftor/tezacaftor/elexacaftor should be used with caution at a reduced dose, as follows: • Day 1: IVA 75 mg/TEZ 50 mg/ELX 100 mg in the morning • Day 2: IVA 37.5 mg/TEZ 25 mg/ELX 50 mg in the morning Continue alternating Day 1 and Day 2 dosing thereafter. The evening dose of the IVA should not be taken. |
| 6 to <12 years | ≥30 kg | Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks. If used, ivacaftor/tezacaftor/elexacaftor should be used with caution at a reduced dose, as follows: • Day 1: IVA 150 mg/TEZ 100 mg/ELX 200 mg in the morning • Day 2: IVA 75 mg/TEZ 50 mg/ELX 100 mg in the morning Continue alternating Day 1 and Day 2 dosing thereafter. The evening dose of the IVA should not be taken |
| 12 years and older | - | Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks. If used, ivacaftor/tezacaftor/elexacaftor should be used with caution at a reduced dose, as follows: • Day 1: IVA 150 mg/TEZ 100 mg/ELX 200 mg in the morning • Day 2: IVA 75 mg/TEZ 50 mg/ELX 100 mg in the morning Continue alternating Day 1 and Day 2 dosing thereafter. The evening dose of the IVA should not be taken. |
In a patient with cirrhosis and portal hypertension liver failure leading to transplantation has been reported while receiving ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor. Ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor 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.
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of elexacaftor, tezacaftor or ivacaftor in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of ivacaftor/tezacaftor/elexacaftor during pregnancy.
It is unknown whether elexacaftor, tezacaftor, ivacaftor, or their metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of elexacaftor, tezacaftor and ivacaftor into the milk of lactating female rats. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ivacaftor/tezacaftor/elexacaftor 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 elexacaftor, tezacaftor and ivacaftor on fertility in humans. Tezacaftor had no effects on fertility and reproductive performance indices in male and female rats at clinically relevant exposures. Elexacaftor and ivacaftor had an effect on fertility in rats.
Ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor has a minor influence on the ability to drive or use machines. Dizziness has been reported in patients receiving ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor, tezacaftor/ivacaftor in combination with ivacaftor as well as ivacaftor. 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 ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor 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 ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor.
The table below reflects adverse reactions observed with ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor, tezacaftor/ivacaftor in combination with ivacaftor, and ivacaftor 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.
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 ivacaftor/tezacaftor/elexacaftor in combination with IVA.
† Liver injury (ALT and AST and total bilirubin increase) reported from post-marketing data with ivacaftor/tezacaftor/elexacaftor 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 ivacaftor/tezacaftor/elexacaftor-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 ivacaftor/tezacaftor/elexacaftor-treated patients and 4.0% in placebo-treated patients.
Post-marketing cases of treatment discontinuation due to elevated transaminases have been reported.
In study 445-102, the incidence of rash events (e.g., rash, rash pruritic) was 10.9% in ivacaftor/tezacaftor/elexacaftor- 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 ivacaftor/tezacaftor/elexacaftor-treated patients and 4.8% in males and 8.3% in females in placebo-treated patients. In patients treated with ivacaftor/tezacaftor/elexacaftor, the incidence of rash events was 20.5% in females taking hormonal contraceptive and 13.6% in females not taking hormonal contraceptive.
In study 445-102, the incidence of maximum creatine phosphokinase >5 x the ULN was 10.4% in ivacaftor/tezacaftor/elexacaftor- and 5.0% in placebo-treated patients. The observed creatine phosphokinase elevations were generally transient and asymptomatic and many were preceded by exercise. No ivacaftor/tezacaftor/elexacaftor-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 ivacaftor/tezacaftor/elexacaftor-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 ivacaftor/tezacaftor/elexacaftor-treated patients compared with 3.5% and 3.5%, respectively in placebo-treated patients.
The safety data of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor 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 ivacaftor/tezacaftor/elexacaftor-treated patients had transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN or discontinued treatment due to transaminase elevations.
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 ivacaftor/tezacaftor/elexacaftortreated patients had transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN or discontinued treatment due to transaminase elevations.
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 ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor 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.
© 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.
