**2. Phosphodiesterase-5 (PDE5) inhibitors**

**The class of medication**

236 Advances in Clinical Audiology

PDE5 inhibitors

PEG interferons

hearing loss.

**Type of report Presence** 

Case report (1 subject)

Prospective study (21 subjects)

Analysis of 47 case reports (pharmacovigilance)

Case report (2 subjects)

(before/after) 49 subjects

Prospective study (before/after) 73 subjects

Prospective study (before/after) 21 subjects

Case report (1 subject)

Case report (1 subject)

Case report (6 subjects)

Case report (3 subjects)

Interferons Prospective study

**of tinnitus**

Not stated

Not stated

Not stated

Not stated

Not stated

Yes (4 of 6) **Type of hearing** 

**Measuring method Reversibility** 

Not stated In some cases,

Pure tone audiometry; impedance audiometry; stapedial reflex absent on both sides

Pure tone audiometry

Pure tone audiometry, ABR

Pure tone audiometry

Pure tone audiometry

Pure tone audiometry

Pure tone audiometry, tympanometry (normal)

audiometry, DPOAE

Not stated Yes [36]

Not stated No [37]

No improvement in three cases, some improvement in two cases, no data in one case

**of hearing loss**

No [23]

Yes [24]

[26]

[31]

[38]

yes; in others long-term impairment

In one case, yes [27]

Yes [30]

Yes [31]

Not applicable [35]

Yes (2 cases), no (1 case)

**References**

**loss**

Profound bilateral sensorineural hearing loss

Unilateral sensorineural hearing loss 1 h after injection of

Unilateral or bilateral sensorineural hearing loss

sensorineural hearing loss

sensorineural hearing loss

Unilateral hearing loss

hearing loss

Five subjects developed unilateral and one bilateral sensorineural hearing loss

**Table 1.** Summary of clinical reports describing hearing loss in PDE5- and interferon-treated patients.

Although in the industrialized countries, the hepatitis C and B therapy with pegylated or non-pegylated interferons and ribavirin is being replaced by other pharmacological regimes, one should not ignore the fact that not all countries and hospitals have adopted the new routine and that the interferons are still in use, possibly contributing to drug-related

Yes Unilateral

None found Pure tone

drug

Yes Unilateral

Yes Sensorineural hearing loss

Yes Unilateral

Yes Sensorineural hearing loss

PDE5 inhibitors block the phosphodiesterase-5 in the smooth muscle cells lining the blood vessels in the cardiovascular system. Phosphodiesterase-5 degrades cyclic GMP, regulating smooth muscle tone. The first PDE5 inhibitor–sildenafil–was introduced in the market in 1998 under the name Viagra. PDE5 inhibitors are used for the treatment of erectile dysfunctions and for pulmonary artery hypertension.

In the year 2007, an alarming report was published by Mukherjee and Shivakumar, in which a case of bilateral profound sensorineural hearing loss was described in 44-year-old man who took 50 mg/day of sildenafil for 2 weeks [23]. Based on that report, **FDA issued a warning about possible sudden hearing loss among users of PDE5 inhibitors**.

Over the past 10 years, evidence suggesting negative influence of PDE5 inhibitors on hearing has accumulated. In a clinical study, Okuyucu et al. [24] reported significant but reversible unilateral hearing loss in four of 18 patients taking PDE5 inhibitors. The hearing loss affected the right ear at 10,000 Hz (p = 0.008).

Much larger epidemiological study published 1 year later by McGwin [25] evaluated the relationship between hearing loss and the use of PDE5 inhibitors in a population-based sample. This USA-based study was designed using self-reported hearing impairment and PDE5i use and included over eleven thousand men who were 40 years or older. Results of this study indicated that men with hearing loss are more than twice as likely to use PDE5 inhibitors, when compared with those not reporting hearing loss. However, no causal relationship could be established in that study.

In 2011, Khan et al. [26] published a report based on data provided by pharmacovigilance agencies Europe, the Americas, East Asia and Australasia, and on published reports. The authors identified among PDE5 inhibitor users 47 cases of sensorineural hearing loss, most of them unilateral. Almost 70% of the subjects (mean age 56.6 years, men-to-women ratio 7:1) reported hearing loss within 24 h after ingestion of PDE5 inhibitors.

In 2012, unilateral sudden sensorineural hearing loss affecting two male PDE5 inhibitor users (age 37 and 43) was described by Barreto and Bahmad [27]. Unfortunately, neither the time after the hearing loss has occurred nor the dosage of PDE5 inhibitors was stated. In addition to the hearing loss, both patients were affected by vertigo and tinnitus. After combination therapy consisting of steroids administered orally and intratympanically, one of the patients recovered partially, whereas the other one was left with permanent profound sensorineural hearing loss.

The causal relationship between the PDE5 inhibitors and (sudden) sensorineural hearing loss remains to be confirmed using experimental models. Au and colleagues using the animal model (C57BL/6J mice) and sildenafil (Viagra) were unable to find the differences in hearing thresholds between the drug- and placebo-treated animals [28]. However, other functional studies in mice with the use of osmotic pumps for drug release demonstrated that the inner ear of animals exposed to sildenafil reacted with hydrops [29].

The epidemiological and case report data indicate that PDE5 inhibitors may have general negative impact on hearing. Moreover, PDE5 inhibitors may induce sudden sensorineural hearing loss that in some cases can be successfully treated with corticosteroids; in some other cases, the patients recover without any treatment; and lastly, it can also leave patients with permanent hearing impairment.
