Symkevi · 4.4 Special warnings and precautions for use · 1

HOS-098569 · has-adverse-reaction-information · PDF-Seite 9

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). 9  Table 4: Adverse reactions MedDRA System Organ Adverse reactions Frequency Class Upper respiratory tract infection, very common Infections and infestations Nasopharyngitis* Rhinitis common Psychiatric disorders Depression not known Nervous system disorders Headache*, Dizziness* very common Ear pain, Ear discomfort, Tinnitus, Tympanic membrane common Ear and labyrinth disorders hyperaemia, Vestibular disorder Ear congestion uncommon Oropharyngeal pain, Nasal very common Respiratory, thoracic and congestion mediastinal disorders Sinus congestion*, Pharyngeal common erythema Abdominal pain, Diarrhoea very common Gastrointestinal disorders Nausea* common Hepatobiliary disorders Transaminase elevations very common Skin and subcutaneous tissue

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HOS-098565 · has-contraindication-information · PDF-Seite 5

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

HOS-098564 · has-indication-information · PDF-Seite 2

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.

HOS-098567 · has-interaction-information · PDF-Seite 7

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, exposu

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HOS-098568 · has-pregnancy-information · PDF-Seite 9

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).

HOS-098566 · has-warning-information · PDF-Seite 5

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 5 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

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