Kaftrio · 4.4 Special warnings and precautions for use · 2

HOS-099402 · has-adverse-reaction-information · PDF-Seite 44

Summary of the safety profile The most common adverse reactions experienced by patients aged 12 years and older who received IVA/TEZ/ELX in combination with IVA were headache (17.3%), diarrhoea (12.9%), upper respiratory tract infection (11.9%) and aminotransferase increased (10.9%). Serious adverse reactions of rash experienced by patients aged 12 years and older were reported in 1.5% patients treated with IVA/TEZ/ELX in combination with IVA (see section 4.4). Tabulated list of adverse reactions Table 4 reflects adverse reactions observed with IVA/TEZ/ELX in combination with IVA, TEZ/IVA in combination with IVA, and IVA 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. 44  Table 4: Adverse reactions MedDRA System Organ Class Adverse Reactions Frequency Upper respiratory tract infection*, very common Infections and infestations Nasopharyngitis Rhinitis*, Influenza* common Immune system disorders Hypersensitivity not known Metabolism and nutrition Hypoglycaemia* common disorders Psychiatric disorders Depression, Behavioural changes not known Nervous system disorders Headache*, Dizziness* very common Ear pain, Ear discomfort, Tinnitus, Tympanic membrane hyperaemia, common Ear and labyrinth disorders Vestibular disorder Ear congestion uncommon Oropharyngeal pain, Nasal congestion* very common Rhinorrhoea*, Sinus congestion, Respiratory, thoracic and Pharyngeal erythema, Abnormal common

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HOS-099396 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The most common adverse reactions experienced by patients aged 12 years and older who received IVA/TEZ/ELX in combination with IVA were headache (17.3%), diarrhoea (12.9%), upper respiratory tract infection (11.9%) and aminotransferase increased (10.9%). Serious adverse reactions of rash experienced by patients aged 12 years and older were reported in 1.5% patients treated with IVA/TEZ/ELX in combination with IVA (see section 4.4). Tabulated list of adverse reactions Table 4 reflects adverse reactions observed with IVA/TEZ/ELX in combination with IVA, TEZ/IVA in combination with IVA, and IVA 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. 11  Table 4: Adverse reactions MedDRA System Organ Class Adverse Reactions Frequency Upper respiratory tract infection*, very common Infections and infestations Nasopharyngitis Rhinitis*, Influenza* common Immune system disorders Hypersensitivity not known Metabolism and nutrition Hypoglycaemia* common disorders Psychiatric disorders Depression, Behavioural changes not known Nervous system disorders Headache*, Dizziness* very common Ear pain, Ear discomfort, Tinnitus, Tympanic membrane hyperaemia, common Ear and labyrinth disorders Vestibular disorder Ear congestion uncommon Oropharyngeal pain, Nasal congestion* very common Rhinorrhoea*, Sinus congestion, Respiratory, thoracic and Pharyngeal erythema, Abnormal common mediastina

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HOS-099398 · has-contraindication-information · PDF-Seite 39

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

HOS-099392 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

HOS-099391 · has-indication-information · PDF-Seite 2

Kaftrio tablets are indicated in a combination regimen with ivacaftor for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who have at least one non-Class I mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see sections 4.2 and 5.1).

HOS-099397 · has-indication-information · PDF-Seite 35

Kaftrio granules are indicated in a combination regimen with ivacaftor for the treatment of cystic fibrosis (CF) in paediatric patients aged 2 to less than 6 years who have at least one non-Class I mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see sections 4.2 and 5.1).

HOS-099394 · has-interaction-information · PDF-Seite 9

Medicinal products affecting the pharmacokinetics of ELX, TEZ and/or IVA CYP3A inducers ELX, TEZ and IVA are substrates of CYP3A (IVA is a sensitive substrate of CYP3A). Concomitant use of strong CYP3A inducers may result in reduced exposures and thus reduced IVA/TEZ/ELX efficacy. Co-administration of IVA with rifampicin, a strong CYP3A inducer, significantly decreased IVA area under the curve (AUC) by 89%. ELX and TEZ exposures are also expected to decrease during co-administration with strong CYP3A inducers; therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.4). 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 ELX AUC by 2.8-fold and TEZ AUC by 4.0- to 4.5-fold. When co-administered with itraconazole and ketoconazole, IVA AUC increased by 15.6-fold and 8.5-fold, respectively. The dose of IVA/TEZ/ELX and IVA should be reduced when co-administered with strong CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4). Examples of strong CYP3A inhibitors include: • ketoconazole, itraconazole, posaconazole and voriconazole • telithromycin and clarithromycin Simulations indicated that co-administration with moderate CYP3A inhibitors fluconazole, erythromycin and verapamil, may increase ELX and TEZ AUC by approximately 1.9- to 2.3-fold. Co-administration of fluconazole increased IVA AUC by 2.9-fold. The dose of IVA/TEZ/ELX and IVA should be reduced when co-administered with moderate CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4). Examples of moderate CYP3A inhibitors include: • fluconazole • erythromycin Co-administration with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ELX, TEZ and IVA. Food or drink containing grapefruit should be avoided during treatment with IVA/TEZ/ELX and IVA (see section 4.2). Ciprofloxacin ELX/TEZ/IVA was not evaluated for concomitant use with ciprofloxacin. However, ciprofloxacin had no clinically relevant effect on the exposure of TEZ or IVA and is not expected to have a clinically relevant effect on the exposure of ELX. Therefore, no dose adjustment is necessary during concomitant administration of IVA/TEZ/ELX with ciprofloxacin. Potential for interaction with transporters In vitro studies showed th

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HOS-099400 · has-interaction-information · PDF-Seite 41

Medicinal products affecting the pharmacokinetics of ELX, TEZ and/or IVA CYP3A inducers ELX, TEZ and IVA are substrates of CYP3A (IVA is a sensitive substrate of CYP3A). Concomitant use of strong CYP3A inducers may result in reduced exposures and thus reduced IVA/TEZ/ELX efficacy. Co-administration of IVA with rifampicin, a strong CYP3A inducer, significantly decreased IVA area under the curve (AUC) by 89%. ELX and TEZ exposures are also expected to decrease during co-administration with strong CYP3A inducers; therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.4). 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 ELX AUC by 2.8-fold and TEZ AUC by 4.0- to 4.5-fold. When co-administered with itraconazole and ketoconazole, IVA AUC increased by 15.6-fold and 8.5-fold, respectively. The dose of IVA/TEZ/ELX and IVA should be reduced when co- administered with strong CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4). Examples of strong CYP3A inhibitors include: 41 • ketoconazole, itraconazole, posaconazole and voriconazole • telithromycin and clarithromycin Simulations indicated that co-administration with moderate CYP3A inhibitors fluconazole, erythromycin and verapamil, may increase ELX and TEZ AUC by approximately 1.9- to 2.3-fold. Co-administration of fluconazole increased IVA AUC by 2.9-fold. The dose of IVA/TEZ/ELX and IVA should be reduced when co-administered with moderate CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4). Examples of moderate CYP3A inhibitors include: • fluconazole • erythromycin Co-administration with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ELX, TEZ and IVA. Food or drink containing grapefruit should be avoided during treatment with IVA/TEZ/ELX and IVA (see section 4.2). Ciprofloxacin ELX/TEZ/IVA was not evaluated for concomitant use with ciprofloxacin. However, ciprofloxacin had no clinically relevant effect on the exposure of TEZ or IVA and is not expected to have a clinically relevant effect on the exposure of ELX. Therefore, no dose adjustment is necessary during concomitant administration of IVA/TEZ/ELX with ciprofloxacin. Potentia

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HOS-099395 · has-pregnancy-information · PDF-Seite 11

Pregnancy A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of ELX, TEZ, or IVA 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 IVA/TEZ/ELX during pregnancy. Breast-feeding Limited data show that ELX, TEZ, and IVA are excreted in human milk and have been quantified in plasma of breastfed newborns/infants of treated women. There is insufficient information on the effects of IVA/TEZ/ELX in newborns/infants. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from IVA/TEZ/ELX therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data available on the effect of ELX, TEZ and IVA on fertility in humans. TEZ had no effects on fertility and reproductive performance indices in male and female rats at clinically relevant exposures. ELX and IVA had an effect on fertility in rats (see section 5.3).

HOS-099401 · has-pregnancy-information · PDF-Seite 43

Pregnancy A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of ELX, TEZ, or IVA 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 IVA/TEZ/ELX during pregnancy. Breast-feeding Limited data show that ELX, TEZ, and IVA are excreted in human milk and have been quantified in plasma of breastfed newborns/infants of treated women. There is insufficient information on the effects of IVA/TEZ/ELX in newborns/infants. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from IVA/TEZ/ELX therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data available on the effect of ELX, TEZ and IVA on fertility in humans. TEZ had no effects on fertility and reproductive performance indices in male and female rats at clinically relevant exposures. ELX and IVA had an effect on fertility in rats (see section 5.3). 43

HOS-099399 · has-warning-information · PDF-Seite 39

Elevated transaminases 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. Elevated transaminases are common in patients with CF. In clinical studies, elevated transaminases were more frequently observed in patients treated with IVA/TEZ/ELX in combination with IVA compared to placebo. In patients taking IVA/TEZ/ELX in combination with IVA, these elevations have sometimes been associated with concomitant elevations in total bilirubin. Assessments of transaminases (ALT and AST) and total bilirubin are recommended for all patients prior to initiating treatment, every 3 months during the first year of treatment and annually thereafter (see section 4.2). For patients with a history of liver disease or transaminase elevations, more frequent monitoring should be considered. Interrupt treatment and promptly measure serum transaminases and total bilirubin if a patient develops clinical 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. Patients who resume treatment after interruption should be monitored closely. In patients with pre-existing advanced liver disease, IVA/TEZ/ELX in combination with IVA should be used with caution and only if the benefits are expected to outweigh the risks (see sections 4.2, 4.8, and 5.2). Hepatic impairment Treatment of patients with moderate hepatic impairment is not recommended. For patients with moderate hepatic impairment, the use of IVA/TEZ/ELX 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 (see Table 3). Patients with severe hepatic impairment should not be treated with IVA/TEZ/ELX (see sections 4.2, 4.8, and 5.2). Depression Depression (including suicidal ideation and suicide attempt) has been reported in patients treated with IVA/TEZ/ELX, usually occurring within three months of treatment initiation and in patients with a history of psychiatric disorders (see section 4.8). In some cases, symptom improvement was reported after dose reduction or treatment discontinuation. Patients (and caregive

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HOS-099393 · has-warning-information · PDF-Seite 6

Elevated transaminases 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. Elevated transaminases are common in patients with CF. In clinical studies, elevated transaminases were more frequently observed in patients treated with IVA/TEZ/ELX in combination with IVA compared to placebo. In patients taking IVA/TEZ/ELX in combination with IVA, these elevations have sometimes been associated with concomitant elevations in total bilirubin. Assessments of transaminases (ALT and AST) and total bilirubin are recommended for all patients prior to initiating treatment, every 3 months during the first year of treatment and annually thereafter (see section 4.2). For patients with a history of liver disease or transaminase elevations, more frequent monitoring should be considered. Interrupt treatment and promptly measure serum transaminases and total bilirubin if a patient develops clinical 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 6 laboratory tests until the abnormalities resolve. Following resolution, consider the benefits and risks of resuming treatment. Patients who resume treatment after interruption should be monitored closely. In patients with pre-existing advanced liver disease, IVA/TEZ/ELX in combination with IVA should be used with caution and only if the benefits are expected to outweigh the risks (see sections 4.2, 4.8, and 5.2). Hepatic impairment Treatment of patients with moderate hepatic impairment is not recommended. For patients with moderate hepatic impairment, the use of IVA/TEZ/ELX 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 (see Table 3). Patients with severe hepatic impairment should not be treated with IVA/TEZ/ELX (see sections 4.2, 4.8, and 5.2). Depression Depression (including suicidal ideation and suicide attempt) has been reported in patients treated with IVA/TEZ/ELX, usually occurring within three months of treatment initiation and in patients with a history of psychiatric disorders (see section 4.8). In some cases, symptom improvement was reported after dose re

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