TABLE 2.
Evidence review summary of incremental risk considerations.
| Risk consideration | Evidence |
|---|---|
| 1 Unintended misuse | |
| 1.1 Drug-drug interaction with nitrates | • Tadalafil plus nitrates can ↓ blood pressure (BP) Kloner et al. (2003) |
| • No adverse event (AE) with single dose of 5 mg or 10 mg tadalafil H6D-LC-LVAB (2022); H6D-EW-LVCM (2022) | |
| • Mean max ↓4 mmHg with tadalafil 20 mg daily for 1 week H6D-EW-LVDN (2022); H6D-LC-LVBY (2022) | |
| • No increased risk of hypotensive cardiovascular outcome with co-possession Nunes et al. (2021) | |
| • Post-marketing reports identified 34 AE cases out of 84.7 million patients exposed to Cialis, seven major AE cases a | |
| • Nitrate use in Europe is declining Schwabe/Ludwig Hrsg (2021); Kloner et al. (2003); Montalescot et al. (2013); NICE (2011); Crespo-Leiro et al. (2016); NHS Digital (2015) | |
| • Label states not to use Cialis if taking nitrates Lilly (2021) | |
| 1.2 Drug-drug interaction with doxazosin and other alpha blockers | • Tadalafil plus alpha blockers can ↓BP |
| • Use is mainly for benign prostatic hypertrophy in the United Kingdom NICE (2019), and rarely for hypertension in Germany Schwabe/Ludwig Hrsg (2021) | |
| • Tadalafil 20 mg + doxazosin causes ↓BP, but 5 mg does not H6D-EW-LVFG (2023); H6D-EW-LVFT (2023); H6D-EW-LVGT (2023) | |
| • Four double-blind studies found no difference in BP for tadalafil + alfuzosin, silodosin, or tamsulosin Goldfischer et al. (2012); Study PDY5734 (2023); H6D-EW-LVAY (2023); H6D-EW-LVGN (2023) | |
| • Post-marketing reports identified 225 AE cases, 17 serious a | |
| • Label states to discuss use of Cialis with pharmacist or doctor if taking alpha-blockers Lilly (2021) | |
| 1.3 Drug-drug interaction with riociguat | • Tadalafil plus riociguat can ↓BP |
| • Riociguat is licensed for the treatment under specialist care of pulmonary arterial hypertension that affects 15 to 60 people per million in Europe Galiè et al. (2016) | |
| • Label states not to use Cialis if taking riociguat Lilly (2021) | |
| 1.4 Drug-drug interaction with antihypertensives | • Six trials found no clinically significant ↓BP for men with controlled and poorly controlled hypertension on 1–4 antihypertensives H6D-EW-LVAV (2023); H6D-EW-LVDP (2023); H6D-EW-LVBC (2023); H6D-EW-LVDS (2023); H6D-EW-LVAW (2023); H6D-EW-LVDV (2023) |
| • Post-marketing reports identified 339 serious AE cases, 27 due to hypotension and 58 a major adverse cardiovascular event; most had pre-existing cardiovascular risk factors a | |
| 1.5 Drug-drug interaction with alcohol | • Excessive alcohol with tadalafil can cause headaches and dizziness but not lower levels of alcohol H6D-EW-LVAE (2023); H6D-EW-LVDO (2023) |
| 1.6 Use in men with severe renal or hepatic disease | • Post-marketing data does not causally link tadalafil with a decrease in hepatic or renal function a |
| • Daily dosing is not recommended for men with severe renal impairment because of the increased concentration of tadalafil and poor clearance H6D-EW-LVAJ (2023); H6D-EW-LVDT (2023) | |
| 2 Worsened outcomes due to self-management | |
| 2.1 Delayed diagnosis of CVD and other underlying conditions | • 70% of men already have an underlying comorbidity diagnosed before ED Kirby et al. (2011) |
| • Diabetes often remains undiagnosed for many years and PDE5 inhibitors have been shown to be beneficial, lowering all-cause mortality and incident myocardial infarction (MI) Anderson et al. (2016) | |
| 2.2 Failure to read/understand safety information in men unfit to have sex due to CVD | • Use of tadalafil is contraindicated in men with current, significant CVD Lilly (2021) |
| • New adverse cardiac events are not associated with PDE5 inhibitor use for managing ED in men with significant CVD Levine et al. (2012) | |
| 3 Intentional misuse | |
| 3.1 To enhance sexual performance | • 11% of men in a European study reported using PDE5 inhibitors without ED Corona et al. (2018) |
| • 13%–27% of men who do not self-assess as having ED have mild ED Korkes et al. (2008); Harte et al. (2011) | |
| 3.2 Intentional misuse: use with ‘poppers’ | • Limited data exist regarding the use of PDE5 inhibitors with concomitant illicit drugs including recreational nitrates and such use appears low Chu et al. (2003) |
| •There are no post marketing concerns a | |
| 3.3 Use in women | •Tadalafil is not indicated for women, post marketing reports identified 267 cases a |
| 4 Intentional overdose | |
| 4.1 Use at a higher dose/frequency than on the label | • Due to its nonlinear pharmacokinetics at doses >20 mg, tadalafil exposure in case of overdose or CYP3A4 enzyme inhibition remains within safe boundaries EMTEX (2021) |
| 5 Accidental ingestion | |
| 5.1 Accidental ingestion by children | • Post-marketing data report 14 cases, 2 serious with full recovery a |
a
Post-marketing adverse event reports from 84,674,000 patients exposed to Cialis worldwide from 2002 to 2020 (EMTEX, 2021).