Deltyba

HOS-096338 · has-adverse-reaction-information · PDF-Seite 19

Summary of the safety profile 19  The most frequently observed adverse drug reactions in patients treated with delamanid + Optimised Background Regimen (OBR) (i.e. incidence > 10%) are nausea (32.9%), vomiting (29.9%), headache (28.4%), sleep disorders and disturbances (28.2%), dizziness (22.4%), gastritis (15.9%) and decreased appetite (13.1%). Tabulated list of adverse reactions The list of adverse drug reactions and frequencies are based on the results from 2 double-blind placebo controlled clinical trials and on spontaneous reports. The adverse drug reactions are listed by MedDRA System Organ Class and Preferred Term. Within each System Organ Class, adverse reactions are listed under frequency categories of 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 (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table: Adverse drug reactions to delamanid System Organ Frequency Frequency Frequency Frequency not Class very common common uncommon known Endocrine - Hypothyroidisma - - disorders Metabolism and Decreased appetite - - - nutrition disorders Psychiatric Sleep disorders and Psychotic disorderc - - disorders disturbancesb Anxietyd Depressione Hallucinationf Nervous system Dizziness Hypoaesthesia Lethargy - disorders Headacheg Tremor Cardiac disorders - Atrioventricular - - block first degree Ventricular extrasystoles Palpitations Respiratory, - Throat irritation - - thoracic and mediastinal disorders Gastrointestinal Nausea Dyspepsia

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HOS-096332 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile 6  The most frequently observed adverse drug reactions in patients treated with delamanid + Optimised Background Regimen (OBR) (i.e. incidence > 10%) are nausea (32.9%), vomiting (29.9%), headache (28.4%), sleep disorders and disturbances (28.2%), dizziness (22.4%), gastritis (15.9%) and decreased appetite (13.1%). Tabulated list of adverse reactions The list of adverse drug reactions and frequencies are based on the results from 2 double-blind placebo controlled clinical trials and on spontaneous reports. The adverse drug reactions are listed by MedDRA System Organ Class and Preferred Term. Within each System Organ Class, adverse reactions are listed under frequency categories of 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 (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table: Adverse drug reactions to delamanid System Organ Frequency Frequency Frequency Frequency not Class very common common uncommon known Endocrine - Hypothyroidisma - - disorders Metabolism and Decreased appetite - - - nutrition disorders Psychiatric Sleep disorders and Psychotic disorderc - - disorders disturbancesb Anxietyd Depressione Hallucinationf Nervous system Dizziness Hypoaesthesia Lethargy - disorders Headacheg Tremor Cardiac disorders - Atrioventricular - - block first degree Ventricular extrasystoles Palpitations Respiratory, - Throat irritation - - thoracic and mediastinal disorders Gastrointestinal

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HOS-096334 · has-contraindication-information · PDF-Seite 16

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Serum albumin < 2.8 g/dL (see section 4.4 regarding use in patients with serum albumin ≥ 2.8 g/dL). - Coadministration of medicinal products that are strong inducers of CYP3A4 (e.g. carbamazepine).

HOS-096328 · has-contraindication-information · PDF-Seite 3

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Serum albumin < 2.8 g/dL (see section 4.4 regarding use in patients with serum albumin ≥ 2.8 g/dL). - Coadministration of medicinal products that are strong inducers of CYP3A4 (e.g. carbamazepine).

HOS-096327 · has-indication-information · PDF-Seite 2

Deltyba is indicated for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adults, adolescents, children and infants with a body weight of at least 10 kg when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability (see sections 4.2, 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

HOS-096333 · has-indication-information · PDF-Seite 15

Deltyba is indicated for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adults, adolescents, children and infants with a body weight of at least 10 kg when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability (see sections 4.2, 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

HOS-096336 · has-interaction-information · PDF-Seite 18

Effects of other medicinal products on delamanid Cytochrome P450 3A4 inducers Clinical drug-drug interactions studies in healthy subjects indicated a reduced exposure to delamanid, of up to 45% following 15 days of concomitant administration of the strong inducer of cytochrome P450 (CYP) 3A4 (rifampicin 300 mg daily) with delamanid (200 mg daily). No clinically relevant reduction in delamanid exposure was observed with the weak inducer efavirenz when administered at a dose of 600 mg daily for 10 days in combination with delamanid 100 mg twice daily. Anti-HIV medicinal products In clinical drug-drug interaction studies in healthy subjects, delamanid was administered alone (100 mg twice daily) and with tenofovir disoproxil (245 mg daily) or lopinavir/ritonavir (400/100 mg daily) for 14 days and with efavirenz for 10 days (600 mg daily). Delamanid exposure remained unchanged (< 25% difference) with anti-HIV medicinal products tenofovir disoproxil and efavirenz but was slightly increased with the combination anti-HIV medicinal products containing lopinavir/ritonavir. Effects of delamanid on other medicinal products In-vitro studies showed that delamanid did not inhibit CYP450 isozymes. In-vitro studies showed that delamanid and metabolites did not have any effect on the transporters MDR1(p-gp), BCRP, OATP1, OATP3, OCT1, OCT2, OATP1B1, OATP1B3 and BSEP, at concentrations of approximately 5 to 20-fold greater than the Cmax at steady state. However, since the 18 concentrations in the gut can potentially be much greater than these multiples of the Cmax, there is a potential for delamanid to have an effect on these transporters. Anti-tuberculosis medicinal products In a clinical drug-drug interaction study in healthy subjects, delamanid was administered alone (200 mg daily) and with rifampicin/isoniazid/pyrazinamide (300/720/1800 mg daily) or ethambutol (1100 mg daily) for 15 days. Exposure of concomitant anti-TB drugs (rifampicin [R]/ isoniazid [H]/ pyrazinamide [Z]) was not affected. Co-administration with delamanid significantly increased steady state plasma concentrations of ethambutol by approximately 25%, the clinical relevance is unknown. Anti-HIV medicinal products In a clinical drug-drug interaction study in healthy subjects, delamanid was administered alone (100 mg twice daily) and tenofovir disoproxil (245 mg daily), lopinavir/ritonavir (400/100 mg daily) for 14 days and with efavirenz for 10 da

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HOS-096330 · has-interaction-information · PDF-Seite 5

Effects of other medicinal products on delamanid Cytochrome P450 3A4 inducers Clinical drug-drug interactions studies in healthy subjects indicated a reduced exposure to delamanid, of up to 45% following 15 days of concomitant administration of the strong inducer of cytochrome P450 (CYP) 3A4 (rifampicin 300 mg daily) with delamanid (200 mg daily). No clinically relevant reduction in delamanid exposure was observed with the weak inducer efavirenz when administered at a dose of 600 mg daily for 10 days in combination with delamanid 100 mg twice daily. Anti-HIV medicinal products In clinical drug-drug interaction studies in healthy subjects, delamanid was administered alone (100 mg twice daily) and with tenofovir disoproxil (245 mg daily) or lopinavir/ritonavir (400/100 mg daily) for 14 days and with efavirenz for 10 days (600 mg daily). Delamanid exposure remained unchanged (< 25% difference) with anti-HIV medicinal products tenofovir disoproxil and efavirenz but was slightly increased with the combination anti-HIV medicinal products containing lopinavir/ritonavir. Effects of delamanid on other medicinal products In-vitro studies showed that delamanid did not inhibit CYP450 isozymes. 5 In-vitro studies showed that delamanid and metabolites did not have any effect on the transporters MDR1(p-gp), BCRP, OATP1, OATP3, OCT1, OCT2, OATP1B1, OATP1B3 and BSEP, at concentrations of approximately 5 to 20-fold greater than the Cmax at steady state. However, since the concentrations in the gut can potentially be much greater than these multiples of the Cmax, there is a potential for delamanid to have an effect on these transporters. Anti-tuberculosis medicinal products In a clinical drug-drug interaction study in healthy subjects, delamanid was administered alone (200 mg daily) and with rifampicin/isoniazid/pyrazinamide (300/720/1800 mg daily) or ethambutol (1100 mg daily) for 15 days. Exposure of concomitant anti-TB drugs (rifampicin [R]/ isoniazid [H]/ pyrazinamide [Z]) was not affected. Co-administration with delamanid significantly increased steady state plasma concentrations of ethambutol by approximately 25%, the clinical relevance is unknown. Anti-HIV medicinal products In a clinical drug-drug interaction study in healthy subjects, delamanid was administered alone (100 mg twice daily) and tenofovir disoproxil (245 mg daily), lopinavir/ritonavir (400/100 mg daily) for 14 days and with efavirenz for 10 day

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HOS-096331 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no or limited amount of data from the use of delamanid in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Deltyba is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether delamanid/metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of delamanid and/or its metabolites in milk (for details see section 5.3). A risk to the newborns/infants cannot be excluded. It is recommended that women should not breastfeed during treatment with Deltyba. Fertility Deltyba had no effect on male or female fertility in animals (see section 5.3). There are no clinical data on the effects of delamanid on fertility in humans.

HOS-096337 · has-pregnancy-information · PDF-Seite 19

Pregnancy There are no or limited amount of data from the use of delamanid in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Deltyba is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether delamanid/metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of delamanid and/or its metabolites in milk (for details see section 5.3). A risk to the newborns/infants cannot be excluded. It is recommended that women should not breastfeed during treatment with Deltyba. Fertility Deltyba had no effect on male or female fertility in animals (see section 5.3). There are no clinical data on the effects of delamanid on fertility in humans.

HOS-096329 · has-warning-information · PDF-Seite 3

There are no clinical data on the use of delamanid to treat - extra pulmonary tuberculosis (e.g. central nervous system, bone) - infections due to Mycobacterial species other than those of the M. tuberculosis complex - latent infection with M. tuberculosis There are no clinical data on the use of delamanid as part of combination regimens used to treat drug- susceptible M. tuberculosis. Resistance to delamanid Delamanid must only be used in an appropriate combination regimen for MDR-TB treatment as recommended by WHO to prevent development of resistance to delamanid. QT prolongation QT prolongation has been observed in patients treated with delamanid. This prolongation increases slowly over time in the first 6 to 10 weeks of treatment and remains stable thereafter. QTc prolongation is very closely correlated with the major delamanid metabolite DM-6705. Plasma 3 albumin and CYP3A4 regulate the formation and metabolism of DM-6705 respectively (see Special Considerations below). General recommendations It is recommended that electrocardiograms (ECG) should be obtained before initiation of treatment and monthly during the full course of treatment with delamanid. If a QTcF > 500 ms is observed either before the first dose of delamanid or during delamanid treatment, treatment with delamanid should either not be started or should be discontinued. If the QTc interval duration exceeds 450/470 ms for male/female patients during delamanid treatment, these patients should be administered more frequent ECG monitoring. It is also recommended that serum electrolytes, e.g. potassium, are obtained at baseline and corrected if abnormal. Special considerations Cardiac risk factors Treatment with delamanid should not be initiated in patients with the following risk factors unless the possible benefit of delamanid is considered to outweigh the potential risks. Such patients should receive very frequent monitoring of ECG throughout the full delamanid treatment period. - Known congenital prolongation of the QTc-interval or any clinical condition known to prolong the QTc interval or QTc > 500 ms. - History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. - Any predisposing cardiac conditions for arrhythmia such as severe hypertension, left ventricular hypertrophy (including hypertrophic cardiomyopathy) or congestive cardiac failure accompanied by reduc

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HOS-096335 · has-warning-information · PDF-Seite 16

There are no data on treatment with delamanid for more than 24 consecutive weeks (see section 4.2). There are no clinical data on the use of delamanid to treat - extra pulmonary tuberculosis (e.g. central nervous system, bone) - infections due to Mycobacterial species other than those of the M. tuberculosis complex - latent infection with M. tuberculosis There are no clinical data on the use of delamanid as part of combination regimens used to treat drug- susceptible M. tuberculosis. Resistance to delamanid Delamanid must only be used in an appropriate combination regimen for MDR-TB treatment as recommended by WHO to prevent development of resistance to delamanid. QT prolongation 16 QT prolongation has been observed in patients treated with delamanid. This prolongation increases slowly over time in the first 6 to 10 weeks of treatment and remains stable thereafter. QTc prolongation is very closely correlated with the major delamanid metabolite DM-6705. Plasma albumin and CYP3A4 regulate the formation and metabolism of DM-6705 respectively (see Special Considerations below). General recommendations It is recommended that electrocardiograms (ECG) should be obtained before initiation of treatment and monthly during the full course of treatment with delamanid. If a QTcF > 500 ms is observed either before the first dose of delamanid or during delamanid treatment, treatment with delamanid should either not be started or should be discontinued. If the QTc interval duration exceeds 450/470 ms for male/female patients during delamanid treatment, these patients should be administered more frequent ECG monitoring. It is also recommended that serum electrolytes, e.g. potassium, are obtained at baseline and corrected if abnormal. Special considerations Cardiac risk factors Treatment with delamanid should not be initiated in patients with the following risk factors unless the possible benefit of delamanid is considered to outweigh the potential risks. Such patients should receive very frequent monitoring of ECG throughout the full delamanid treatment period. - Known congenital prolongation of the QTc-interval or any clinical condition known to prolong the QTc interval or QTc > 500 ms. - History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. - Any predisposing cardiac conditions for arrhythmia such as severe hypertension, left ventricular hypertrop

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