4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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.

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.

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).

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Symkevi 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

Liver function decompensation, including liver failure leading to transplantation and death has been reported in CF patients with pre-existing cirrhosis and portal hypertension whilst receiving treatment with other CFTR modulator regimens. TEZ/IVA in combination with IVA should be used with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If TEZ/IVA 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 Symkevi in combination with ivacaftor, as well as with ivacaftor monotherapy. Therefore, liver function tests 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 of liver function tests should be considered. In the event of significant elevations of transaminases (e.g., patients with 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 resolution of transaminase elevations, the benefits and risks of resuming treatment should be considered (see section 4.8).

Hepatic impairment

The use of Symkevi 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).

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

Symkevi 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 Symkevi and ivacaftor. Therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.5).

CYP3A inhibitors

The dose of Symkevi 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 Symkevi 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'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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

It is unknown whether tezacaftor, ivacaftor, or their metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of tezacaftor and ivacaftor 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 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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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

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 x 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 x ULN associated with elevated total bilirubin >2 x 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 x ULN were 1.4%, 4.3%, and 10.0%, respectively. No Symkevi-treated patients experienced a transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x 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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.