Cialis Back Pain May Be Due To Greater PDE11 Affinity Than Viagra, Levitra

Cialis' greater affinity for PDE11 than other PDE5 inhibitors is the likely explanation for the greater incidence of back pain and myalgia seen with the Lilly/Icos erectile dysfunction agent, FDA speculates in review documents.

Cialis reviewers were concerned that "myalgia and back pain were reported more frequently in subjects receiving Cialis than in subjects receiving other PDE5 inhibitors ( Viagra , Levitra ) at therapeutic doses," the clinical pharmacology review states.

Lilly/Icos maintained that the back pain/myalgia was a class effect shared with Pfizer's Viagra (sildenafil) and Bayer/GlaxoSmithKline's Levitra (vardenafil).

"The sponsor hypothesized that the development of myalgia and back pain is a class effect of PDE5 inhibition secondary to vasocongestion in the lower lumbar and gluteal musculature," pharmacology reviewer Yangmee Shin explained.

Because PDE5 is present in skeletal muscle tissue, Lilly/Icos pointed out that the inhibition of PDE5 in the muscles of the back could result in vasodilation, and pooling of venous blood in the large muscle groups of the gluteal and low back regions could be responsible for back pain/myalgia.

The concurrent review of Levitra also explored the possibility that the adverse event was a class effect (¹ Pharmaceutical Approvals Monthly Dec. 1, 2003, p. 28).

Data Insufficient To Conclude Class Effect

"The information provided is not sufficient to conclude that myalgia and back pain are a class effect of PDE5 inhibitors," Shin concluded in a ² Nov. 13, 2003 memo.

Medical team leader Mark Hirsch, MD, agreed: Although "I have no explanation for the clinical adverse events 'myalgia' and 'back pain,'" he said in a ³ Nov. 20, 2003 memo, "I question the degree to which these events are similar across a drug class."

FDA's Cialis (tadalafil) review team identified several ways in which "Cialis is different from sildenafil and vardenafil," including "a distinct chemical structure and a longer duration of action," which could have been contributing factors for the back pain/myalgia. (See ⁴ (Also see "Cialis Prolonged Activity Widens Nitrate Concern; Risk Management Requested" - Pink Sheet, 15 Apr, 2004.) on impact of longer duration of action)

"Tadalafil is significantly different from other approved PDE5 inhibitors in that it has a longer half-life, lower exposure multiples, possible metabolite activity, produces a different mode of arteritis (involves organs other than the heart), and has higher selectivity and inhibition of PDE11," Acting Supervisory Pharmacologist Suzanne Thornton, PhD, stated.

FDA's April 29, 2002 ⁵ 'approvable' letter cites the possible role of Cialis' metabolite, which has been linked to drug-induced hypersensitivity: "'Myalgia' and 'back pain' tend to occur at the time of the peak concentration of the methylcatechol glucuronide metabolite, which is not specific for PDE5 receptors."

In particular, reviewers noted Cialis' substantially greater affinity for PDE11 than Viagra or Levitra. Cialis has only 5-14 fold greater selectivity for PDE5 than PDE11 "compared to Viagra and Levitra with a >300-fold selectivity," the pharmacology review says.

As PDE11 receptors are mainly located in skeletal muscle, "the inhibition by Cialis and/or its catechol metabolite on PDE11A1 at therapeutic doses could lead to an increase in certain adverse events such as musculoskeletal disorders," Shin suggested.

⁶ Cialis labeling acknowledges the drug's inhibition/selectivity for PDE11 "at concentrations within the therapeutic range," adding that "the physiological role and consequence of PDE11 inhibition in humans have not been defined."

FDAers Disagree About PDE11/Back Pain Link

Hirsch did not concur that PDE11 inhibition was involved in the back pain/myalgia. "In my view, the linkage of back pain and myalgias to inhibition of PDE11A1 remains speculative," his Nov. 20, 2003 memo states.

"The large body of clinical evidence collected in regard to back pain and myalgias reveals no evidence of striated muscle damage."

However, he concluded Lilly/Icos "had not conducted an extensive evaluation of the cause of this adverse event, nor proposed adequate labeling."

The incidence of back pain and myalgia ranged from 8.1% in placebo-controlled Cialis trials to 17.5% in the clinical pharmacology studies; most cases were of mild or moderate severity.

Hirsch said back pain and myalgia were "of concern…even from the earliest IND stages," noting that "vague complaints of 'back pain' and diffuse 'myalgia' were reported when [Cialis] was given in high doses to volunteers."

"This concern is compounded by the fact that the incidence and severity of myalgias and back pain appear to increase with higher dose and higher exposure to tadalafil."

Lilly Needs To Investigate Cause For Back Pain

"The sponsor has not aggressively sought the etiology of these symptoms," Hirsch wrote in an ⁷ April 20, 2002 memo. "There is a need to provide reasonable assurance in humans that these symptoms do not reflect medically significant underlying pathophysiology."

To rule out the presence of medically significant disease processes associated with back pain/myalgia, including vasculitis and other potential effects on the kidney, FDA requested an analysis of adverse event reports.

The approvable letter asks for medical work-up of subjects who reported back pain or myalgia in previously conducted studies and in all ongoing or new studies, "especially studies utilizing higher doses of Cialis."

In addition to the review of back pain/myalgia (BPM) reports, submitted as part of Lilly/Icos' May 27, 2003 "complete response" to the approvable letter, the joint venture conducted a prospectively designed study of 142 patients with single dosing or 7-day multiple dosing "to establish a differential diagnosis of BPM within 48 hours of onset."

New Data Alleviates Concern About Etiology

"None of this data (comparing baseline with 48-hour samples) identified any inflammatory conditions or immune disease-related abnormalities, and there were no differences between patients with or without symptoms," ⁸ medical reviewer Ashok Batra, MD, found.

"Among patients presenting with BPM (including those with renal disease), physical examinations, imaging or laboratory testing failed to detect any significant abnormalities or pathology associated with these events," Batra added.

However, Lilly/Icos was unable to prove its hypothesis that pooling of venous blood associated with PDE5 inhibitors was the cause of the back pain/myalgia.

Additional Study Does Not Support PDE5 Theory

The company conducted another study (LVFA) - looking at renal blood flow and lumbar and venocongestion - to support its theory, but no significant differences in renal blood flow and renal function or tissue inflammation in the lumbar and gluteal regions were detected.

Batra, however, noted that the radiographic techniques used "may not be sufficiently sensitive to detect moderate changes in pooling of venous blood in the low back and gluteal regions."

The Division ultimately did not consider the unknown pathogenesis for the back pain/myalgia to be a sufficient reason for not approving Cialis, consistent with the Levitra review.

Serious Underlying Pathology Is "Unlikely"

"The sponsor has adequately explored the effects of tadalafil on back pain and myalgia," Batra said. "Although the etio-pathogenesis of this adverse event remains unknown, it is unlikely to be associated with serious underlying pathology."

Batra concluded that several aspects of the reported back pain/myalgia "suggest the absence of a serious underlying medical condition." In particular, he pointed out that the adverse events "spontaneously resolv[ed] without sequelae…despite continued dosing."

Labeling says that back pain/myalgia "generally occurred 12-48 hours after dosing and typically resolved within 24 hours."

"In general, pain was reported as mild or moderate in severity…b ut severe back pain was reported infrequently (<5% of all reports)," labeling states. Discontinuation as a consequence of back pain/myalgia is reported as approximately 0.5% of all tadalafil-treated subjects.