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資料１－２ 調査結果報告書 (22 ページ)
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| 出典情報 | 薬事・食品衛生審議会 薬事分科会医薬品等安全対策部会安全対策調査会（令和4年度第10回） |
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Patients on stable doses of strong multi pathway CYP / P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitors
Coadministration of ADEMPAS with strong multi pathway CYP and P-gp/BCRP inhibitors such as azole antimycotics (e.g. ketoconazole,
itraconazole) or HIV protease inhibitors (e.g. ritonavir) increases exposure to ADEMPAS (see Sections 4.4 SPECIAL WARNINGS AND
PRECAUTIONS FOR USE and 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS).
When initiating ADEMPAS in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors, consider a starting dose
of 0.5 mg, three times a day to mitigate the risk of hypotension. Monitor for signs and symptoms of hypotension on initiation and on
treatment. Consider a dose reduction for patients on ADEMPAS doses higher than or equal to 1.0 mg if the patient develops signs or
symptoms of hypotension (see Sections 4.2 DOSE AND METHOD OF ADMINISTRATION, 4.4 SPECIAL WARNINGS AND
PRECAUTIONS FOR USE and 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS).
4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Concomitant use with other medicinal products
The concomitant use of ADEMPAS with strong multi-pathway CYP and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP)
inhibitors such as azole antimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir) results in a pronounced
increase in riociguat exposure (see Section 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF
INTERACTIONS - Pharmacokinetic Interactions).
Assess the benefit-risk for each patient individually before prescribing ADEMPAS in patients on stable doses of strong multi pathway
CYP and P-gp/BCRP inhibitors. Consider a starting dose of 0.5 mg ADEMPAS, three times a day to mitigate the risk of hypotension.
Monitor for signs and symptoms of hypotension on initiation and on treatment and consider a dose reduction for patients on ADEMPAS
doses higher than or equal to 1.0 mg if the patient develops signs or symptoms of hypotension (see Section 4.2 DOSE AND METHOD
OF ADMINISTRATION and Section 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF
INTERACTIONS).
In patients on stable doses of ADEMPAS, the initiation of strong multi pathway CYP and P-gp/BCRP inhibitors is not recommended as
no dosage recommendation can be given due to limited data. Alternative treatments should be considered.
4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS
Pharmacokinetic Interactions
Effects of Other Substances on ADEMPAS
Riociguat is cleared mainly via cytochrome P450-mediated (CYP1A1, CYP3A4, CYP2C8, CYP2J2) oxidative metabolism, direct
biliary/faecal excretion of the unchanged drug, and renal excretion of the unchanged drug via glomerular filtration. Based on in vitro
studies, riociguat was found to be a substrate for the membrane transport proteins P-gp/BCRP. Inhibitors or inducers of these enzymes or
transporters may affect riociguat exposure.
Concomitant use with strong multi pathway CYP and P-gp/BCRP inhibitors
Highly active antiretroviral therapy (HAART)
22
Coadministration of ADEMPAS with strong multi pathway CYP and P-gp/BCRP inhibitors such as azole antimycotics (e.g. ketoconazole,
itraconazole) or HIV protease inhibitors (e.g. ritonavir) increases exposure to ADEMPAS (see Sections 4.4 SPECIAL WARNINGS AND
PRECAUTIONS FOR USE and 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS).
When initiating ADEMPAS in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors, consider a starting dose
of 0.5 mg, three times a day to mitigate the risk of hypotension. Monitor for signs and symptoms of hypotension on initiation and on
treatment. Consider a dose reduction for patients on ADEMPAS doses higher than or equal to 1.0 mg if the patient develops signs or
symptoms of hypotension (see Sections 4.2 DOSE AND METHOD OF ADMINISTRATION, 4.4 SPECIAL WARNINGS AND
PRECAUTIONS FOR USE and 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS).
4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Concomitant use with other medicinal products
The concomitant use of ADEMPAS with strong multi-pathway CYP and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP)
inhibitors such as azole antimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir) results in a pronounced
increase in riociguat exposure (see Section 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF
INTERACTIONS - Pharmacokinetic Interactions).
Assess the benefit-risk for each patient individually before prescribing ADEMPAS in patients on stable doses of strong multi pathway
CYP and P-gp/BCRP inhibitors. Consider a starting dose of 0.5 mg ADEMPAS, three times a day to mitigate the risk of hypotension.
Monitor for signs and symptoms of hypotension on initiation and on treatment and consider a dose reduction for patients on ADEMPAS
doses higher than or equal to 1.0 mg if the patient develops signs or symptoms of hypotension (see Section 4.2 DOSE AND METHOD
OF ADMINISTRATION and Section 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF
INTERACTIONS).
In patients on stable doses of ADEMPAS, the initiation of strong multi pathway CYP and P-gp/BCRP inhibitors is not recommended as
no dosage recommendation can be given due to limited data. Alternative treatments should be considered.
4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS
Pharmacokinetic Interactions
Effects of Other Substances on ADEMPAS
Riociguat is cleared mainly via cytochrome P450-mediated (CYP1A1, CYP3A4, CYP2C8, CYP2J2) oxidative metabolism, direct
biliary/faecal excretion of the unchanged drug, and renal excretion of the unchanged drug via glomerular filtration. Based on in vitro
studies, riociguat was found to be a substrate for the membrane transport proteins P-gp/BCRP. Inhibitors or inducers of these enzymes or
transporters may affect riociguat exposure.
Concomitant use with strong multi pathway CYP and P-gp/BCRP inhibitors
Highly active antiretroviral therapy (HAART)
22