Ivacaftor / Tezacaftor: prescribing information – dosing, contraindications, interactions, side effects

Symkevi is indicated in a combination regimen with ivacaftor tablets for the treatment of patients with cystic fibrosis (CF) aged 6 years and older who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, and 3849+10kbC→T.

Symkevi should only be prescribed by physicians with experience in the treatment of CF. If the patient’s genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of an indicated mutation using a genotyping assay.

Posology

Adults, adolescents and children aged 6 years and older should be dosed according to Table 1.

Table 1: Dosing recommendations for patients aged 6 years and older
Age/Weight
Morning
(1 tablet)
Evening
(1 tablet)
6 to < 12 years weighing < 30 kg tezacaftor 50 mg/ivacaftor 75 mg ivacaftor 75 mg 6 to < 12 years weighing ≥ 30 kg tezacaftor 100 mg/ivacaftor 150 mg ivacaftor 150 mg ≥ 12 years tezacaftor 100 mg/ivacaftor 150 mg ivacaftor 150 mg

The morning and evening dose should be taken approximately 12 hours apart with fat-containing food (see Method of administration).

Missed dose

If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule.

If more than 6 hours have passed since the missed morning or evening dose, the patient should not take the missed dose. The next scheduled dose can be taken at the usual time.

More than one dose of either tablet should not be taken at the same time.

Concomitant use of CYP3A inhibitors

The dose of Symkevi and ivacaftor should be adjusted when co-administered with moderate and strong CYP3A inhibitors.

When co-administered with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin, verapamil), or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin), the dose should be reduced according to Table 2 (see sections 4.4 and 4.5).

Table 2: Dosing recommendations for concomitant use with moderate or strong CYP3A inhibitors Age/Weight Moderate CYP3A inhibitors Strong CYP3A inhibitors 6 years to < 12 years, < 30 kg Alternate each morning:
- one tablet of tezacaftor
50 mg/ivacaftor 75 mg once daily on the first day
- one tablet of ivacaftor
75 mg on the next day.
Continue alternating tablets each day.

No evening dose.
One morning tablet of tezacaftor 50 mg/ivacaftor
75 mg twice a week, approximately 3 to 4 days apart.

No evening dose.
6 years to < 12 years,
≥ 30 kg
Alternate each morning:
- one tablet of tezacaftor
100 mg/ivacaftor 150 mg once daily on the first day
- one tablet of ivacaftor
150 mg on the next day.
Continue alternating tablets each day.

No evening dose.
One morning tablet of tezacaftor 100 mg/ivacaftor
150 mg twice a week, approximately 3 to 4 days apart.

No evening dose.

Table 2: Dosing recommendations for concomitant use with moderate or strong CYP3A inhibitors Age/Weight Moderate CYP3A inhibitors Strong CYP3A inhibitors 12 years and older Alternate each morning:
- one tablet of tezacaftor
100 mg/ivacaftor 150 mg once daily on the first day
- one tablet of ivacaftor
150 mg on the next day.
Continue alternating tablets each day.

No evening dose.
One morning tablet of tezacaftor 100 mg/ivacaftor
150 mg twice a week, approximately 3 to 4 days apart.

No evening dose.

Special populations

Elderly people

The safety, efficacy and pharmacokinetics of Symkevi have been examined in a limited number of elderly patients. No dose adjustment specific to this patient population is required (see section 5.2).

Renal impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment. Caution is recommended in patients with severe renal impairment or end-stage renal disease (see sections 4.4 and 5.2).

Hepatic impairment

For dose adjustment for patients with hepatic impairment, (see Table 3). There is no experience of the use of Symkevi in patients with severe hepatic impairment (Child-Pugh Class C); therefore, its use is not recommended unless the benefits outweigh the risks. In such cases, Symkevi should be used at a reduced dose (see sections 4.4 and 5.2). No dose adjustment is necessary for Symkevi in patients with mild hepatic impairment (Child-Pugh Class A).

Table 3: Dosing recommendations for use in patients with hepatic impairment
Age/Weight
Moderate (Child-Pugh Class B)
Severe (Child-Pugh Class C)
6 years to < 12 years,
< 30 kg
One morning tablet of tezacaftor
50 mg/ivacaftor 75 mg once daily.

No evening dose.
One morning tablet of tezacaftor 50 mg/ivacaftor
75 mg once daily or less frequently.

Dosing intervals should be modified according to clinical response and tolerability.

No evening dose.
6 years to < 12 years,
≥ 30 kg
One morning tablet of tezacaftor
100 mg/ivacaftor 150 mg once daily.

No evening dose.
One morning tablet of tezacaftor 100 mg/ivacaftor
150 mg once daily or less frequently.

Dosing intervals should be modified according to clinical response and tolerability.

Table 3: Dosing recommendations for use in patients with hepatic impairment
Age/Weight
Moderate (Child-Pugh Class B)
Severe (Child-Pugh Class C)
No evening dose.
12 years and older
One morning tablet of tezacaftor
100 mg/ivacaftor 150 mg once daily.

No evening dose.
One morning tablet of tezacaftor 100 mg/ivacaftor
150 mg once daily or less frequently.

Dosing intervals should be modified according to clinical response and tolerability.

No evening dose.

Paediatric population

The safety and efficacy of Symkevi in children aged less than 6 years has not yet been established. No data are available (see sections 4.8 and 5.1).

Method of administration

For oral use.

Patients should be instructed to swallow the tablets whole. The tablets should not be chewed, crushed, or broken before swallowing because there are no clinical data currently available to support other methods of administration.

Both Symkevi and ivacaftor tablets should be taken with fat-containing food, such as food recommended in standard nutritional guidelines (see section 5.2).

Food or drink containing grapefruit should be avoided during treatment (see section 4.5).

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Summary of the safety profile

The most common adverse reactions experienced by patients aged 12 years and older who received Symkevi in combination with ivacaftor in phase 3 clinical studies were headache (14% versus 11% on placebo) and nasopharyngitis (12% versus 10% on placebo).

Tabulated list of adverse reactions

Table 4 reflects adverse reactions observed with Symkevi in combination with ivacaftor and with ivacaftor monotherapy in clinical studies. 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).

Table 4: Adverse reactions
MedDRA System Organ
Class
Adverse reactions
Frequency
Infections and infestations
Upper respiratory tract infection,
Nasopharyngitis* very common
Rhinitis 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
Sinus congestion*, Pharyngeal erythema common
Gastrointestinal disorders
Abdominal pain, Diarrhoea very common
Nausea* common
Hepatobiliary disorders
Transaminase elevations very common
Skin and subcutaneous tissue disorders
Rash very common
Reproductive system and breast disorders
Breast mass common
Breast inflammation,
Gynaecomastia, Nipple disorder,
Nipple pain uncommon
Investigations
Bacteria in sputum very common
*Adverse reactions observed during clinical studies with IVA/TEZ in combination with ivacaftor.

The safety data from 1042 adults and 130 children aged 6 to less than 12 years old, treated with Symkevi in combination with ivacaftor for up to an additional 96 weeks in two long-term safety and efficacy rollover studies (study 661-110 and study 661-116 part A, respectively) were consistent with the safety data from the placebo-controlled phase 3 studies.

Description of selected adverse reactions

Transaminase elevations

During the adult placebo-controlled phase 3 studies (up to 24 weeks), the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 × ULN were similar between Symkevi- and placebo-treated patients; 0.2%, 1.0%, and 3.4% in Symkevi-treated patients, and 0.4%, 1.0%, and 3.4% in placebo-treated patients. One patient (0.2%) on therapy and two patients (0.4%) on placebo permanently discontinued treatment for elevated transaminases. No patients treated with Symkevi experienced a transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN.

Paediatric population

The safety of Symkevi in combination with ivacaftor was evaluated in 124 patients between 6 to less than 12 years of age. The tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg dose has not been investigated in clinical studies in children aged 6 to less than 12 years weighing 30 to < 40 kg.

The safety profile is generally consistent among children and adolescents, and is also consistent with adult patients.

During the 24-week, open-label phase 3 study in patients aged 6 to less than 12 years (study 661-113 part B, n=70), the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 1.4%, 4.3%, and 10.0%, respectively. No Symkevi-treated patients experienced a transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN or discontinued Symkevi treatment due to transaminase elevations. One patient interrupted treatment due to elevated transaminases, and subsequently resumed Symkevi treatment successfully (see section 4.4 for management of elevated transaminases).

Other special populations

The safety profile of Symkevi in combination with ivacaftor, including respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal), was generally similar across all subgroups of patients, including analysis by age, gender, and baseline percent predicted FEV1 (ppFEV1).

Reporting of suspected adverse reactions

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.

Tezacaftor/ivacaftor in combination with ivacaftor should not be prescribed in patients with CF who are heterozygous for the F508del mutation and have a second CFTR mutation not listed in section 4.1.

Elevated transaminase and hepatic injury

Cases of liver failure leading to transplantation have been reported within the first 6 months of treatment in patients with and without pre-existing advanced liver disease whilst receiving treatment with other CFTR modulator regimens. Tezacaftor/ivacaftor in combination with ivacaftor should be used with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If tezacaftor/ivacaftor in combination with ivacaftor is 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 tezacaftor/ivacaftor in combination with ivacaftor, as well as with ivacaftor monotherapy.
Therefore, liver function tests are recommended for all patients prior to initiating treatment, every three months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring of liver function tests should be considered.
Interrupt treatment and promptly measure serum transaminases and total bilirubin if a patient develops

signs or symptoms of liver injury. Interrupt dosing, in the event of ALT or AST >5 × the upper limit of normal (ULN), or ALT or AST >3 × ULN with total bilirubin >2 × ULN. Closely monitor the laboratory tests until the abnormalities resolve. Following resolution consider the benefits and risks of resuming treatment (see section 4.8). Patients who resume treatment after interruption should be monitored closely.

Hepatic impairment

The use of tezacaftor/ivacaftor in combination with ivacaftor is not recommended in patients with severe hepatic impairment unless the benefits are expected to outweigh the risks (see sections 4.2 and 5.2).

Depression

Depression (including suicidal ideation and suicide attempt) has been reported in patients treated with tezacaftor/ivacaftor in combination with ivacaftor, 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, unusual changes in behaviour, anxiety, or insomnia and to seek medical advice immediately if these symptoms present.

Renal impairment

Caution is recommended in patients with severe renal impairment or end-stage renal disease (see sections 4.2 and 5.2).

Patients after organ transplantation

Tezacaftor/ivacaftor in combination with ivacaftor 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 ciclosporin or tacrolimus.

Interactions with medicinal products

CYP3A inducers

Exposure to tezacaftor and ivacaftor may be reduced by the concomitant use of CYP3A inducers, potentially resulting in reduced efficacy of tezacaftor/ivacaftor and ivacaftor. Therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.5).

CYP3A inhibitors

The dose of tezacaftor/ivacaftor and ivacaftor should be adjusted when used concomitantly with strong or moderate CYP3A inhibitors (see section 4.5 and Table 2 in section 4.2).

Paediatric population

Cataracts

Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patients treated with ivacaftor-containing regimens. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to treatment cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating treatment with tezacaftor/ivacaftor in combination with ivacaftor (see section 5.3).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Medicinal products affecting the pharmacokinetics of tezacaftor and ivacaftor

CYP3A inducers

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 of Symkevi and ivacaftor. Co-administration of ivacaftor with rifampicin, 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 rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum).

CYP3A inhibitors

Co-administration with itraconazole, a strong CYP3A inhibitor, increased tezacaftor exposure (measured as AUC) by 4-fold and increased ivacaftor AUC by 15.6-fold. The dose of Symkevi should be adjusted when co-administered with strong CYP3A inhibitors (see Table 2 in section 4.2).

Examples of strong CYP3A inhibitors include ketoconazole, itraconazole, posaconazole, and voriconazole, telithromycin and clarithromycin.

Physiologically based pharmacokinetic modeling suggested co-administration with fluconazole, a moderate CYP3A inhibitor, may increase tezacaftor exposure (AUC) by approximately 2-fold.
Co-administration of fluconazole increased ivacaftor AUC by 3-fold. The dose of Symkevi and ivacaftor should be adjusted when co-administered with moderate CYP3A inhibitors (see Table 2 in section 4.2).

Examples of moderate CYP3A inhibitors include fluconazole, erythromycin and verapamil.

Co-administration with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor and tezacaftor; therefore, food or drink containing grapefruit should be avoided during treatment (see section 4.2).

Potential for tezacaftor/ivacaftor to interact with transporters

In vitro studies showed that tezacaftor is a substrate for the uptake transporter OATP1B1, and efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (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 are used with Symkevi.

In vitro studies showed that ivacaftor is not a substrate for OATP1B1, OATP1B3, or P-gp. Ivacaftor 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 ivacaftor and M1-IVA, while any potential changes in M6-IVA exposures are not expected to be clinically relevant.

Ciprofloxacin

Co-administration of ciprofloxacin did not affect the exposure of ivacaftor or tezacaftor. No dose adjustment is required when Symkevi is co-administered with ciprofloxacin.

Medicinal products affected by tezacaftor and ivacaftor

CYP2C9 substrates

Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) is recommended during co-administration of warfarin with Symkevi given in combination with ivacaftor.
Other medicinal products for which exposure may be increased include glimepiride and glipizide;
these medicinal products should be used with caution.

CYP3A, digoxin and other P-gp substrates

CYP3A substrates

Co-administration with (oral) midazolam, a sensitive CYP3A substrate, did not affect midazolam exposure. No dose adjustment of CYP3A substrates is required when co-administered with Symkevi in combination with ivacaftor.

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 Symkevi in combination with ivacaftor 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.

Hormonal contraceptives

Symkevi in combination with ivacaftor has been studied with an estrogen/progesterone oral contraceptive and was found to have no significant effect on the exposures of the hormonal contraceptive. Symkevi and ivacaftor are not expected to modify the efficacy of hormonal contraceptives.

OATP1B1 substrates

Symkevi in combination with ivacaftor has been studied with pitavastatin, an OATP1B1 substrate, and was found to have no clinically relevant effect on the exposure of pitavastatin (1.24-fold increased exposure based on AUC). No dose adjustment of OATP1B1 substrates is required when co-administered with Symkevi.

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of tezacaftor or ivacaftor 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 therapy during pregnancy.

Breast-feeding

Limited data show that tezacaftor and ivacaftor are excreted into human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Tezacaftor

There are no data available on the effect of tezacaftor on fertility in humans. Tezacaftor had no effects on fertility and reproductive performance indices in male and female rats at doses up to 100 mg/kg/day.

Ivacaftor

There are no data available on the effect of ivacaftor on fertility in humans. Ivacaftor had an effect on fertility in rats (see section 5.3).

Symkevi in combination with ivacaftor has minor influence on the ability to drive and use machines.
Dizziness has been reported in patients receiving Symkevi in combination with ivacaftor, as well as ivacaftor monotherapy (see section 4.8). Patients experiencing dizziness should be advised not to drive or use machines until symptoms abate.

There are no known risks due to overdose with Symkevi and there is no specific antidote available in the event of overdose. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX31

Mechanism of action

Tezacaftor is a selective CFTR corrector that binds to the first Membrane Spanning Domain (MSD-1) of CFTR. Tezacaftor facilitates the cellular processing and trafficking of normal or multiple mutant forms of CFTR (including F508del-CFTR) to increase the amount of CFTR protein delivered to the cell surface, resulting in increased chloride transport in vitro.

Ivacaftor is a CFTR potentiator that potentiates the channel-open probability (or gating) of CFTR at the cell surface to increase chloride transport. For ivacaftor to function CFTR protein must be present at the cell surface. Ivacaftor can potentiate the CFTR protein delivered to the cell surface by tezacaftor, leading to a further enhancement of chloride transport than either active substance alone.
The combination targets the abnormal CFTR protein by increasing the quantity and function of CFTR at the cell surface and subsequently increasing airway surface liquid height, and ciliary beat frequency in vitro in human bronchial epithelial (HBE) cells from homozygous F508del CF patients. The exact mechanisms by which tezacaftor improves cellular processing and trafficking of F508del-CFTR and ivacaftor potentiates F508del-CFTR are not known.

Pharmacodynamic effects

Effects on sweat chloride

In study 661-106 (patients homozygous for the F508del mutation), the treatment difference between Symkevi in combination with ivacaftor and placebo in mean absolute change from baseline in sweat chloride through week 24 was -10.1 mmol/L (95% CI: -11.4, -8.8; nominal P<0.0001*).

In study 661-108 (patients heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity), the treatment difference in mean absolute change from baseline in sweat chloride through week 8 was -9.5 mmol/L (95% CI: -11.7, -7.3; nominal P<0.0001*) between Symkevi in combination with ivacaftor and placebo, and -4.5 mmol/L (95% CI: -6.7, -2.3; nominal P<0.0001*) between ivacaftor and placebo.

In study 661-115 (patients aged 6 to less than 12 years who were homozygous or heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity), the within treatment mean absolute change in sweat chloride from baseline at week 8 was -12.3 mmol/L (95% CI: -15.3, -9.3; nominal P<0.0001). In subgroup analyses the mean absolute change was -12.9 mmol/L (95% CI: -16.0, -9.9) for patients with F/F and for patients with F/RF the mean absolute change was -10.9 mmol/L (95% CI: -20.8, -0.9).
*Nominal p-value, based on hierarchical testing procedure.

The pharmacokinetics of tezacaftor and ivacaftor are similar between healthy adult volunteers and patients with CF. Following once daily dosing of tezacaftor and twice-daily dosing of ivacaftor in patients with CF, plasma concentrations of tezacaftor and ivacaftor reach steady-state within 8 days and within 3 to 5 days, respectively, after starting treatment. At steady-state, the accumulation ratio is approximately 2.3 for tezacaftor and 3.0 for ivacaftor. Exposures of tezacaftor (administered alone or in combination with ivacaftor) increase in an approximately dose-proportional manner with increasing doses from 10 mg to 300 mg once daily. Key pharmacokinetic parameters for tezacaftor and ivacaftor at steady-state are shown in Table 8.

Table 8: Mean (SD) pharmacokinetic parameters of tezacaftor and ivacaftor at steady-state in patients with CF

Active substance
Cmax
(mcg/mL) t½ (h)
AUC0-24h or AUC0-12h
(mcg∙h/mL)*
Tezacaftor 100 mg once daily/ivacaftor 150 mg every
12 hours
Tezacaftor