Orkambi · 4.4 Special warnings and precautions for use · 1

HOS-216901 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile The most common adverse reactions are dyspnoea (14.0%), diarrhoea (11.0%), and nausea (10.2%). Serious adverse reactions included hepatobiliary events, e.g., transaminase elevations (0.5%), cholestatic hepatitis (0.3%) and hepatic encephalopathy (0.1%). Tabulated list of adverse reactions Table 5 reflects the adverse reactions reported with lumacaftor/ivacaftor and ivacaftor monotherapy from clinical trials, post-authorisation safety studies and spontaneous reporting. 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); and not known (frequency cannot be estimated using the available data). 13 Table 5: Adverse reactions in lumacaftor/ivacaftor-treated patients and in patients treated with ivacaftor alone System organ class Frequency Adverse reactions Infections and infestations very common Nasopharyngitis* common Upper respiratory tract infection, rhinitis Psychiatric disorders not known Depression Vascular disorders uncommon Hypertension Nervous system disorders very common Headache, dizziness* uncommon Hepatic encephalopathy† Ear and labyrinth disorders common Ear pain*, ear discomfort*, tinnitus*, tympanic membrane hyperaemia*, vestibular disorder* uncommon Ear congestion* Respiratory, thoracic and very common Nasal congestion, dyspnoea, productive cough, mediastinal disorders sputum increased common Respiration abnormal, oropharyngeal pain, sinus congestion*, rhinorrhoea, pharyngeal erythema*, bronchospasm Gastrointestinal disorders very common Abdominal pain*, abdominal pain up

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HOS-216907 · has-adverse-reaction-information · PDF-Seite 42

Summary of the safety profile The most common adverse reactions are dyspnoea (14.0%), diarrhoea (11.0%), and nausea (10.2%). Serious adverse reactions included hepatobiliary events, e.g., transaminase elevations (0.5%), cholestatic hepatitis (0.3%) and hepatic encephalopathy (0.1%). Tabulated list of adverse reactions Table 5 reflects the adverse reactions reported with lumacaftor/ivacaftor and ivacaftor monotherapy from clinical trials, post-authorisation safety studies and spontaneous reporting. 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); and not known (frequency cannot be estimated from the available data). Table 5: Adverse reactions in lumacaftor/ivacaftor-treated patients and in patients treated with ivacaftor alone System organ class Frequency Adverse reactions Infections and infestations very common Nasopharyngitis* common Upper respiratory tract infection, rhinitis Psychiatric disorders not known Depression Vascular disorders uncommon Hypertension Nervous system disorders very common Headache, dizziness* uncommon Hepatic encephalopathy† Ear and labyrinth disorders common Ear pain*, ear discomfort*, tinnitus*, tympanic membrane hyperaemia*, vestibular disorder* uncommon Ear congestion* Respiratory, thoracic and very common Nasal congestion, dyspnoea, productive cough, mediastinal disorders sputum increased common Respiration abnormal, oropharyngeal pain, sinus congestion*, rhinorrhoea, pharyngeal erythema*, bronchospasm 42  System organ class Frequency Adverse reactions Gastrointestinal disorders very common Abdominal pain*, abdominal pain upper, diarrhoea, nausea

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HOS-216903 · has-contraindication-information · PDF-Seite 33

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

HOS-216897 · has-contraindication-information · PDF-Seite 4

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

HOS-216896 · has-indication-information · PDF-Seite 2

Orkambi tablets are indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see sections 4.2, 4.4, and 5.1).

HOS-216902 · has-indication-information · PDF-Seite 30

Orkambi granules are indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see sections 4.2, 4.4, and 5.1).

HOS-216905 · has-interaction-information · PDF-Seite 35

Based on exposure and indicated doses, the interaction profile is considered to be the same for all strengths and pharmaceutical forms. Lumacaftor is a strong inducer of CYP3A and ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. There is potential for other medicinal products to affect lumacaftor/ivacaftor when administered concomitantly, and also for lumacaftor/ivacaftor to affect other medicinal products. Potential for other medicinal products to affect lumacaftor/ivacaftor Inhibitors of CYP3A Co-administration of lumacaftor/ivacaftor with itraconazole, a strong CYP3A inhibitor, did not impact the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor when co-administered with a CYP3A inhibitor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours, the approved dose of ivacaftor monotherapy. No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking lumacaftor/ivacaftor. However, when initiating lumacaftor/ivacaftor in patients taking strong CYP3A inhibitors, the dose should be adjusted (see sections 4.2 and 4.4). No dose adjustment is recommended when used with moderate or weak CYP3A inhibitors. Inducers of CYP3A Co-administration of lumacaftor/ivacaftor with rifampicin, a strong CYP3A inducer, had minimal effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. Therefore, co-administration of lumacaftor/ivacaftor is not recommended with strong CYP3A inducers (see sections 4.2 and 4.4). No dose adjustment is recommended when used with moderate or weak CYP3A inducers. Potential for lumacaftor/ivacaftor to affect other medicinal products CYP3A substrates Lumacaftor is a strong inducer of CYP3A. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. The net effect of lumacaftor/ivacaftor therapy is expected to be strong CYP3A induction. Therefore, concomitant use of lumacaftor/ivacaftor with CYP3A substrates may decrease the exposure of these substrates (see section 4.4). 35 P-gp substrates In vitro studies indicated that lumacaftor has the potential to both inhibit and induce P-gp. Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of lumacaftor/ivac

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HOS-216899 · has-interaction-information · PDF-Seite 6

Based on exposure and indicated doses, the interaction profile is considered to be the same for all strengths and pharmaceutical forms. Lumacaftor is a strong inducer of CYP3A and ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. There is potential for other medicinal products to affect lumacaftor/ivacaftor when administered concomitantly, and also for lumacaftor/ivacaftor to affect other medicinal products. Potential for other medicinal products to affect lumacaftor/ivacaftor Inhibitors of CYP3A Co-administration of lumacaftor/ivacaftor with itraconazole, a strong CYP3A inhibitor, did not impact the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor when co-administered with a CYP3A inhibitor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours, the approved dose of ivacaftor monotherapy. No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking lumacaftor/ivacaftor. However, when initiating lumacaftor/ivacaftor in patients taking strong CYP3A inhibitors, the dose should be adjusted (see sections 4.2 and 4.4). No dose adjustment is recommended when used with moderate or weak CYP3A inhibitors. 6 Inducers of CYP3A Co-administration of lumacaftor/ivacaftor with rifampicin, a strong CYP3A inducer, had minimal effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. Therefore, co-administration of lumacaftor/ivacaftor is not recommended with strong CYP3A inducers (see sections 4.2 and 4.4). No dose adjustment is recommended when used with moderate or weak CYP3A inducers. Potential for lumacaftor/ivacaftor to affect other medicinal products CYP3A substrates Lumacaftor is a strong inducer of CYP3A. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. The net effect of lumacaftor/ivacaftor therapy is expected to be strong CYP3A induction. Therefore, concomitant use of lumacaftor/ivacaftor with CYP3A substrates may decrease the exposure of these substrates (see section 4.4). P-gp substrates In vitro studies indicated that lumacaftor has the potential to both inhibit and induce P-gp. Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of lumacaftor/ivacaf

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HOS-216906 · has-pregnancy-information · PDF-Seite 41

Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of lumacaftor/ivacaftor in pregnant women. Animal studies with lumacaftor and ivacaftor do not indicate direct or indirect harmful effects with respect to developmental and reproductive toxicity, whereas effects were noted with ivacaftor only at maternally toxic doses (see section 5.3). As a precautionary 41 measure, it is preferable to avoid the use of lumacaftor/ivacaftor during pregnancy unless the clinical condition of the mother requires treatment with lumacaftor/ivacaftor. Breast-feeding Limited data show that ivacaftor and lumacaftor are excreted into human milk. There is insufficient information on the effects of lumacaftor/ivacaftor in newborns/infants. 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 No human data on the effects of lumacaftor and/or ivacaftor on fertility are available. Lumacaftor had no effects on fertility and reproductive performance indices in male and female rats. Ivacaftor impaired fertility and reproductive performance indices in male and female rats (see section 5.3).

HOS-216900 · has-pregnancy-information · PDF-Seite 13

Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of lumacaftor/ivacaftor in pregnant women. Animal studies with lumacaftor and ivacaftor do not indicate direct or indirect harmful effects with respect to developmental and reproductive toxicity, whereas effects were noted with ivacaftor only at maternally toxic doses (see section 5.3). As a precautionary measure, it is preferable to avoid the use of lumacaftor/ivacaftor during pregnancy unless the clinical condition of the mother requires treatment with lumacaftor/ivacaftor. Breast-feeding Limited data show that ivacaftor and lumacaftor are excreted into human milk. There is insufficient information on the effects of lumacaftor/ivacaftor in newborns/infants. 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 No human data on the effects of lumacaftor and/or ivacaftor on fertility are available. Lumacaftor had no effects on fertility and reproductive performance indices in male and female rats. Ivacaftor impaired fertility and reproductive performance indices in male and female rats (see section 5.3).

HOS-216898 · has-warning-information · PDF-Seite 4

Patients with CF who are heterozygous for the F508del mutation in the CFTR gene Lumacaftor/ivacaftor is not effective in patients with CF who have the F508del mutation on one allele plus a second allele with a mutation predicted to result in a lack of CFTR production or that is not responsive to ivacaftor in vitro (see section 5.1). Patients with CF who have a gating (Class III) mutation in the CFTR gene Lumacaftor/ivacaftor has not been studied in patients with CF who have a gating (Class III) mutation in the CFTR gene on one allele, with or without the F508del mutation on the other allele. Since the exposure of ivacaftor is very significantly reduced when dosed in combination with lumacaftor, lumacaftor/ivacaftor should not be used in these patients. Respiratory adverse reactions Respiratory adverse reactions (e.g., chest discomfort, dyspnoea, bronchospasm, and respiration abnormal) were more common during initiation of lumacaftor/ivacaftor therapy. Serious respiratory events were seen more frequently in patients with percent predicted forced expiratory volume in 1 second (ppFEV1) < 40, and may lead to discontinuation of the medicinal product. Clinical experience in patients with ppFEV1 < 40 is limited and additional monitoring of these patients is recommended during initiation of therapy (see section 4.8). A transient decline in FEV1 has also been observed in some patients following initiation of lumacaftor/ivacaftor. There is no experience of initiating 4 treatment with lumacaftor/ivacaftor in patients having a pulmonary exacerbation and initiating treatment in patients having a pulmonary exacerbation is not advisable. Effect on blood pressure Increased blood pressure has been observed in some patients treated with lumacaftor/ivacaftor. Blood pressure should be monitored periodically in all patients during treatment (see section 4.8). Elevated transaminases and hepatic injury Abnormalities in liver function, including advanced liver disease, can be present in patients with CF. Worsening of liver function in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension receiving lumacaftor/ivacaftor. Cases of liver failure leading to transplantation have been reported within the first 6 months of treatment in patients with and witho

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HOS-216904 · has-warning-information · PDF-Seite 33

Patients with CF who are heterozygous for the F508del mutation in the CFTR gene Lumacaftor/ivacaftor is not effective in patients with CF who have the F508del mutation on one allele plus a second allele with a mutation predicted to result in a lack of CFTR production or that is not responsive to ivacaftor in vitro (see section 5.1). Patients with CF who have a gating (Class III) mutation in the CFTR gene Lumacaftor/ivacaftor has not been studied in patients with CF who have a gating (Class III) mutation in the CFTR gene on one allele, with or without the F508del mutation on the other allele. Since the exposure of ivacaftor is very significantly reduced when dosed in combination with lumacaftor, lumacaftor/ivacaftor should not be used in these patients. Respiratory adverse reactions Respiratory adverse reactions (e.g., chest discomfort, dyspnoea, bronchospasm, and respiration abnormal) were more common during initiation of lumacaftor/ivacaftor therapy. Serious respiratory events were seen more frequently in patients with percent predicted forced expiratory volume in 1 second (ppFEV1) <40, and may lead to discontinuation of the medicinal product. Clinical experience in patients with ppFEV1 <40 is limited and additional monitoring of these patients is recommended during initiation of therapy (see section 4.8). A transient decline in FEV1 has also been observed in some patients following initiation of lumacaftor/ivacaftor. There is no experience of initiating treatment with lumacaftor/ivacaftor in patients having a pulmonary exacerbation and initiating treatment in patients having a pulmonary exacerbation is not advisable. Effect on blood pressure Increased blood pressure has been observed in some patients treated with lumacaftor/ivacaftor. Blood pressure should be monitored periodically in all patients during treatment (see section 4.8). Elevated transaminases and hepatic injury Abnormalities in liver function, including advanced liver disease, can be present in patients with CF. Worsening of liver function in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension receiving lumacaftor/ivacaftor. 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 treated with other CFTR modu

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