昂伟达 盐酸司美那非, Onvarda Simenafil Hydrochloride Tablets, TPN171, 5mg*2 Tablets, China-Originated PDE5 Inhibitor for Male Erectile Dysfunction (ED)

TPN171 is a highly active and highly selective PDE5 inhibitor with a novel chemical structure. Its tablet formulation for the treatment of erectile dysfunction (ED) has been approved and marketed in China (brand name: 昂伟达^®) and Uzbekistan (brand name: Onvita^®). 昂伟达^® has demonstrated significant clinical efficacy and a favorable safety profile, offering broad applicability across diverse patient populations and usage scenarios. It possesses the potential to become a Best-in-Class therapy.

Preclinical studies have shown that TPN171 is a potent PDE5 inhibitor and can significantly enhance penile erectile function in SD rats, Beagle dogs, and rabbits. A Phase III clinical trial demonstrated the marked clinical efficacy of TPN171 tablets. The recommended clinical starting dose is lower than that of other approved PDE5 inhibitors. When taken on demand at doses of 2.5 mg, 5 mg, and 10 mg, the respective rates for successful vaginal penetration were as high as 88.67%, 90.33%, and 92.02% (representing increases of 40.58%, 42.43%, and 43.98%). The respective rates for successful intercourse completion were 70.52%, 72.09%, and 74.65% (increases of 61.91%, 63.70%, and 65.19%). The respective Erectile Function domain scores of the International Index of Erectile Function (IIEF-EF) reached 25.7, 25.6, and 26.1 points (increases of 12.3, 12.3, and 12.7 points), approaching the normal range (≥26 points is considered normal).

TPN171 tablets demonstrate a superior safety profile, with a lower overall incidence of clinical adverse events compared to other approved PDE5 inhibitors. The Phase III clinical trial showed that at doses of 2.5 mg, 5 mg, and 10 mg, TPN171 had a lower incidence of common adverse events such as headache (2.6%, 3.2%, and 3.7%, respectively) and dyspepsia (0%, 0.5%, and 0.5%, respectively). Due to its weaker inhibition of other PDE subtypes (which are associated with side effects), TPN171 has not shown or rarely causes related adverse events. For instance, no visual abnormalities (associated with PDE6 inhibition) or adverse events like back pain and myalgia (associated with PDE11 inhibition) were observed. Additionally, the incidence of flushing (associated with PDE1 inhibition) was lower than that reported for sildenafil.

TPN171 tablets offer rapid onset of action, becoming effective within 30 minutes after oral administration, making them suitable for on-demand use. Their duration of action is well-balanced, with a half-life of 8 to 11 hours, which aligns well with natural daily rhythms. The efficacy of TPN171 is not affected when taken with moderate amounts of alcoholic beverages. Furthermore, TPN171 tablets have broad applicability and can be used by special patient populations, including the elderly, and those with mild to moderate hepatic impairment or mild, moderate, to severe renal impairment.

Medicine Name
Yansuan Simeinafei Pian
Simenafil Hydrochloride Tablets

Composition
Active ingredient: Sildenafil mesylate.
Excipients: Lactose, microcrystalline cellulose, sodium starch glycolate, povidone K30, magnesium stearate, film-coating premix (gastric-soluble type).

Characteristics
Film-coated tablets, white or off-white after removal of the coating.

Indications
For the treatment of erectile dysfunction (ED).

Specifications
Per C₂₄H₃₅N₅O₃·HCl: (1) 2.5mg; (2) 5mg; (3) 10mg.

Dosage and Administration

1. Recommended Dosage and Administration
   For most patients, the recommended starting dose is 5mg taken orally 0.5–4 hours prior to sexual activity. Dosage may be adjusted to 10mg or reduced to 2.5mg based on efficacy and tolerance, with a maximum frequency of once daily. Sexual stimulation is required for efficacy. May be taken with or without food.

2. Special Populations

   • Elderly (≥65 years): No dose adjustment required.
   • Hepatic impairment: Dose reduced by half for mild or moderate impairment (Child-Pugh A or B).

Adverse Reactions
In a 12-week placebo-controlled Phase III trial (n=757), adverse reaction incidence was 36.2% (sildenafil mesylate) vs. 30.9% (placebo). Common (≥2%) adverse reactions exceeding placebo are detailed in Table 1.

Table 1: Adverse Reactions (≥2% incidence and higher than placebo in any dose group)

• Metabolic/Nutritional Disorders: Hyperlipidemia, hyperuricemia.
• Investigations: Elevated ALT, triglycerides, urine occult blood, AST.
• Nervous System Disorders: Dizziness, headache, head discomfort.
• Vascular Disorders: Flushing, heat sensation.
• Gastrointestinal Disorders: Dry mouth.
• Respiratory Disorders: Nasal congestion.
• General Disorders: Fever.

Less frequent (<2%) adverse reactions include hypokalemia, hyponatremia, hyperglycemia, and others as listed.

Contraindications

• Hypersensitivity to any component.
• Concomitant use with nitrates (e.g., organic nitrites/nitrates) or guanylate cyclase stimulators (e.g., riociguat) due to risk of symptomatic hypotension.

Precautions

1. Cardiovascular: Sexual activity poses risk in patients with cardiovascular disease. Avoid in unstable angina, recent MI/stroke, uncontrolled hypertension (≥160/95mmHg), or hypotension (<90/60mmHg). Monitor patients with left ventricular outflow obstruction.
2. Prolonged Erection/Priapism: Cases reported with PDE5 inhibitors. Seek immediate care if erection >4 hours; untreated priapism may cause permanent damage.
3. α-Blockers/Antihypertensives: Concomitant use may potentiate hypotension; start with lowest doses and monitor.
4. Bleeding/Ophthalmic Effects: Avoid in bleeding disorders; monitor for NAION or sudden vision loss.
5. Hearing Loss: Discontinue if sudden hearing loss occurs.
6. Driving/Operating Machinery: May cause dizziness/visual disturbances; caution advised.

Pregnancy/Lactation: Not indicated for women.
Pediatric Use: Not indicated for children.
Geriatric Use: Start with lower doses in elderly with comorbidities.

Drug Interactions

• CYP3A4 Inhibitors (e.g., itraconazole): Increase sildenafil mesylate exposure; start with 2.5mg.
• CYP3A4 Inducers (e.g., rifampin): Reduce sildenafil mesylate efficacy; avoid or resume after inducer discontinuation.
• Alcohol: Mild vasodilatory effects; no significant pharmacokinetic interaction.

Overdose: No specific data; manage supportively.

Pharmacology
Sildenafil mesylate inhibits PDE5, enhancing cGMP-mediated vasodilation in penile tissue to promote erection.

Toxicology
Negative in Ames test, chromosomal aberration, and micronucleus assays. Reproductive toxicity studies show NOAELs at 300mg/kg/day (fertility) and 30mg/kg/day (embryofetal development). No carcinogenic potential in 104-week rat or 26-week transgenic mouse studies.

Pharmacokinetics

• Absorption: Linear kinetics (5–30mg); Tₘₐₓ 0.5–1.3h; food delays absorption but not AUC.
• Distribution: Plasma protein binding ~94%; Vd ~213–268L.
• Metabolism: Primarily CYP3A4-mediated; 9 metabolites identified.
• Excretion: Fecal (48.6%) and urinary (46.6%) routes; half-life 8.02–10.88h.
• Special Populations: Hepatic impairment increases exposure; renal impairment (GFR 15–29mL/min) increases AUC.

Storage
Store sealed at ≤30°C; keep out of reach of children.

Expiration
24 months.