Cenforce is quickly and efficiently absorbed in all studied species. However, its systemic bioavailability is reduced due to pre-systemic metabolism in the liver, which aligns with plasma clearance rates across species. The primary metabolite of Cenforce is UK-103,320. In rats, there is a notable gender-based difference in pharmacokinetics, with males metabolizing Cenforce into UK-103,320 more rapidly. The volume of distribution is similar in both rodents and humans but is higher in dogs, likely due to lower plasma protein binding in that species.

In rats, Cenforce follows the expected tissue distribution pattern for a lipophilic weak base, showing an affinity for melanin. However, this is not considered toxicologically significant. Across all tested species, Cenforce is cleared primarily through five oxidative metabolic pathways, with most of the drug excreted in feces within 48 hours. In humans, plasma concentrations of Cenforce increase proportionally across clinical doses. Its metabolism is mainly carried out by cytochrome P3A4 (CYP3A4) and CYP2C9, with CYP3A4 playing a more dominant role at therapeutic doses. While circulating metabolites are present, only UK-103,320 contributes to Cenforce’s therapeutic effects, though to a much lesser extent than the drug itself.

Drug interactions are unlikely to be clinically significant since both Cenforce and UK-103,320 only weakly inhibit key human drug-metabolizing P450 enzymes. Toxicokinetic data suggest a wide safety margin between drug exposure levels in humans and those associated with toxicity in rats and dogs. Table 3 summarizes non-clinical study results.

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Unlike the PDE3 inhibitor milrinone, Cenforce does not exhibit inotropic effects in isolated canine trabeculae or rabbit papillary muscle, even at concentrations up to 10 μM. Preclinical studies indicate that Cenforce acts as a pulmonary vasodilator within its therapeutic concentration range while having only mild systemic vasodilatory effects. This leads to a decrease in pulmonary artery pressure and reduced pulmonary vascular resistance, ultimately alleviating the workload on the right ventricle. Additionally, it helps lower left heart filling pressures, which supports left ventricular function.

Cenforce is not approved for use in pediatric patients under 18 years old. More details on clinical studies related to its use in pediatric pulmonary arterial hypertension (PAH) can be found in the Cenforce (PAH) Risk Management Plan (RMP).

Non-clinical studies have not shown any cardiovascular adverse effects, indicating no significant concerns for human use. However, post-marketing reports have linked Cenforce sildenafil use to serious cardiovascular events such as myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, and hypotension. Most of these cases involved patients with pre-existing cardiovascular risk factors, and many incidents occurred during or soon after sexual activity. Some cases also happened shortly after taking Cenforce without any sexual activity. It remains unclear whether these events were directly caused by the drug or other contributing factors.

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Phosphodiesterase-6 (PDE-6) is present in the retinas of humans, dogs, and rats, and Cenforce inhibits it within the same concentration range. Electroretinogram (ERG) studies in dogs have shown that Cenforce can cause reversible effects on retinal function, proportional to plasma concentrations. However, these effects were only observed at plasma levels higher than those affecting pulmonary vasculature. Toxicology studies in rats and dogs have shown that while Cenforce at pharmacologically active levels can impact the retina, it does not cause structural retinal damage.

An independent peer review of histopathology sections from four long-term toxicity studies in dogs (ranging from one month to one year) and one six-month toxicity study in rats confirmed that Cenforce had no adverse effects on the eye. Importantly, mice, rats, and dogs were exposed to prolonged high plasma concentrations of Cenforce or its active metabolite, UK-103,320—levels known to influence retinal function (as observed in electroretinography studies or isolated retina experiments in dogs). However, even with daily exposure for up to 24 months at concentrations exceeding pharmacologically active levels in the retina, there were no signs of treatment-related retinal or ocular toxicity.

Non-arteritic anterior ischemic optic neuropathy (NAION) has been rarely reported in post-marketing surveillance across all PDE5 inhibitors, including Cenforce.

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In preclinical studies, Cenforce administered intravenously at 0.3 mg/kg increased rat tail bleeding time by about 60%, though the change was not statistically significant. In rabbits, a 1 mg/kg IV dose significantly prolonged bleeding time. While Cenforce enhanced the bleeding time effect of heparin, it did not have a synergistic interaction with either heparin or aspirin. The doses used in these studies were approximately 20 times higher than those required for therapeutic effects on corpus cavernosum pressure in dogs. Cenforce had no impact on clotting time in rats or rabbits.

Clinical data on Cenforce citrate provide more relevant insights into bleeding risks in humans than additional animal studies. In studies evaluating single oral doses above 15 mg, Cenforce was generally found to enhance the anti-aggregatory effects of sodium nitroprusside (SNP) on ADP-induced platelet aggregation in ex vivo platelet samples (Studies 148-201, 148-201A, and 148-206). However, Cenforce did not influence other ex vivo tests, such as ADP-induced aggregation in whole blood or platelet-rich plasma without SNP. These findings confirm that while Cenforce does not directly affect platelet function ex vivo, it can amplify the action of NO donors like SNP. Consistent with its mechanism of action, Cenforce requires an existing nitric oxide presence to exert its pharmacological effect on platelets (Study 148-206). Despite these minor effects on platelet activity in ex vivo models, no significant clinical impact on bleeding time was observed in healthy volunteers (Study 148-206). Furthermore, when Cenforce was co-administered with aspirin, it did not lead to a clinically relevant change in bleeding time (Studies 148-216 and 148-222, as outlined in the Cenforce citrate MAA).

Non-clinical data suggest no relevance to human usage, as there is no evidence that Cenforce affects bleeding time or platelet aggregation when used alone.

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Post-marketing reports have included instances of bleeding events in patients who had taken Cenforce, but a direct causal relationship has not been established. In human studies, Cenforce alone—or in combination with aspirin—showed no effect on bleeding time. However, in vitro research on human platelets indicates that Cenforce can enhance the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor). Additionally, when combined with heparin, Cenforce had an additive effect on bleeding time in anesthetized rabbits, though this interaction has not been studied in humans.

Tables 4 through 7 summarize patient exposure data from 136 completed Cenforce (ED) studies, including placebo-controlled, double-blinded trials, as well as non-placebo-controlled parent and extension studies from the MAH’s clinical trial database. These 136 studies form part of the clinical development program for Cenforce RX; no additional interventional trials were conducted for its OTC application.

It is also worth noting that the clinical trial data in section SVII.3, which characterize key risks, are derived from 75 double-blinded, placebo-controlled clinical trials in men, forming the basis of the safety profile for Cenforce citrate (ED).

Cenforce citrate has also been approved for treating pulmonary arterial hypertension (PAH) in patients classified under World Health Organization (WHO) functional classes II and III. For completeness, data from clinical trials involving both adult and pediatric patients exposed to Cenforce (PAH) is included.

The clinical development program is unlikely to capture all types of adverse reactions, particularly rare ones or those resulting from prolonged or cumulative exposure. Given the short half-life of Cenforce (ED) and its studied dosage regimen (intermittent use as needed), adverse drug reactions (ADRs) with long latency periods are not expected. Estimated exposure data for prescription Cenforce (ED) is provided for informational purposes.

Since its initial approval on February 5, 1998, through June 30, 2019, approximately 88,740,410 patients worldwide have been exposed to Cenforce (ED). The latest cumulative exposure estimate was calculated by adding the previously reported cumulative exposure (February 5, 1998 – February 2, 2018) to the interval exposure from February 3, 2018, through June 30, 2019.

Between February 3, 2018, and June 30, 2019 (the most recent reporting period), an estimated 4,206,561 patients worldwide used Cenforce (ED). In the United States, patient exposure during this period was estimated at 814,223, based on IQVIA’s Total Patient Tracker, which covers approximately 55% of U.S. retail pharmacies and projects data across the entire retail pharmacy sector. Since patient data outside the U.S. is not readily available, non-U.S. patient exposure was estimated using IQVIA’s standard unit data, assuming consistent usage and treatment patterns worldwide.

According to IQVIA Midas data (covering Q1 2018 – Q2 2019), the ratio of non-U.S. (102,885,308 standard units) to U.S. (24,694,345 standard units) usage was applied to the number of U.S. patients to estimate non-U.S. patient exposure. This yielded a total of 3,392,338 non-U.S. patients using Cenforce (ED). When combined with the U.S. estimate (814,223 patients), the worldwide post-marketing exposure was calculated at 4,206,561 patients.

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A review of cumulative post-authorization exposure for the approved Cenforce (ED) prescription product through June 30, 2019, indicates that usage generally aligns with its approved indications. However, there have been instances of use in unapproved populations, including pediatric and female patients.

Cenforce (ED) has not been studied in pediatric patients as part of its clinical program for erectile dysfunction. However, its use in children with PAH was investigated in clinical trials, leading to its approval for pediatric PAH treatment in the European Union in May 2011. Additionally, the MAH conducted several investigational studies on Cenforce for female sexual arousal disorder (FSAD). While these studies confirmed the drug’s safety in women, they did not provide conclusive evidence of its effectiveness in treating FSAD, leading to the termination of the clinical program. (https://fedeltahomecare.com)