SYMKEVI

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.

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 One morning tablet of tezacaftor 50 mg/ivacaftor 75 mg twice a week, approximately 3 to 4 days Table 2: Dosing recommendations for concomitant use with moderate or strong CYP3A inhibitors Age/Weight Moderate CYP3A inhibitors Strong CYP3A inhibitors day - one tablet of ivacaftor 75 mg on the next day.

Continue alternating tablets each day. No evening dose. 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.

2). Renal impairment No dose adjustment is recommended for patients with mild or moderate renal impairment. 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.

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.

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.

2). 5).

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 Upper respiratory tract infection, Nasopharyngitis* very common Infections and infestations Rhinitis common Nervous system disorders Headache*, Dizziness* very common Ear pain, Ear discomfort, Tinnitus, Tympanic membrane hyperaemia, Vestibular disorder common Ear and labyrinth disorders Ear congestion uncommon Oropharyngeal pain, Nasal congestion very common Respiratory, thoracic and mediastinal disorders Sinus congestion*, Pharyngeal erythema common Abdominal pain, Diarrhoea very common Gastrointestinal disorders Nausea* common Table 4: Adverse reactions MedDRA System Organ Class Adverse reactions Frequency Hepatobiliary disorders Transaminase elevations very common Skin and subcutaneous tissue disorders Rash very common Breast mass common Reproductive system and breast disorders 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.

4% in placebo-treated patients. 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. 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.

4 for management of elevated transaminases). , 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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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. 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.

, 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. 8). 2). 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. 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.

5). 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.

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

1.