4 CONTRAINDICATIONS

There were 357 patients tadalafil 2.5 mg who were enrolled in the double-blind, uncontrolled extension study (PHIRST-2) and 293 patients completed the 52-week trial.

13.2 Animal Toxicology and/or Pharmacology

Tadalafil is a selective PDE5-inhibitor that can be administered once daily. Its beneficial effects in adults with PAH, consisting of improved exercise capacity, haemodynamics and time to clinical worsening, have been demonstrated in a recent pivotal RCT (PHIRST-1). Patients were at least 12 years old, however the median age was 54 ± 15 years. Tadalafil was well tolerated, side-effects reported were headache, myalgia and flushing.53 No specific data concerning tadalafil in children with PAH are available. Tadalafil, a carboline derivative with vasodilatory activity, selectively inhibits cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

STORAGE & DOSAGE:

During sexual stimulation, nitric oxide (NO) produced and released from nerves and endothelial cells, stimulates soluble guanylate cyclase and initiates the production of the messenger cGMP in the corpus cavernosum smooth muscles. PDE5 is important in regulating intracellular concentrations of cGMP by catalyzing its hydrolysis and inactivating cGMP. The inhibition of PDE5 by tadalafil increases the cGMP level in the corpus cavernosum. As a result, prolonged smooth muscle relaxation occurs together with vasodilation of the corpus cavernosum, leading to penile erection (Carrier, 2003). Tadalafil has no effect in the absence of sexual stimulation.

Length of treatment

In addition, tadalafil is also used to treat benign prostatic hyperplasia (BPH) and pulmonary arterial hypertension (Croxtall and Lyseng-Williamson, 2010). Tadalafil preserves the concentration of cGMP, thus promoting vasodilation in corpus cavernosum and pulmonary vasculature. Tadalafil is rapidly absorbed after oral administration. Compared with other PDE5 inhibitors used in treating 10mg tadalafil erectile dysfunction, tadalafil has the longest duration of action, making it the only once-daily agent of all PDE5 inhibitors. Tadalafil is a phosphodiesterase-5 (PDE-5) inhibitor that was approved by the US Food and Drug Administration (FDA) in 2009 for the treatment of pulmonary arterial hypertension (PAH). The 6MWD in the group assigned to 20 mg of tadalafil in the long-term extension trial was 406 ± 67 m achieved after 16 weeks of therapy and 415 ± 80 m after 52 weeks. The 6MWD in the group assigned to 40 mg of tadalafil was 413 ± 81 m after 16 weeks of therapy and 410 ± 78 m after 52 weeks.

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Deterioration in WHO functional class occurred in 9% of patients in the 20-mg group and 6% of patients taking 40 mg of tadalafil. Few studies have examined the use of tadalafil to treat PAH in children, although patients as young as 12 and 13 years of age have been included in published trials of tadalafil in PAH. In general, tadalafil has been well tolerated in patients with PAH. The most common adverse effects are headache, flushing, and myalgias including back pain.

Possible Alternatives to Tadalafil

In 2004, Ghofrani and colleagues71 compared the acute vasodilator effects of 3 PDE5 inhibitors in 60 consecutive patients as part of their initial evaluation of pulmonary hypertension. Compared with sildenafil and vardenafil, tadalafil produced similar decreases in mPAP and PVR and increases in CI. The peak vasodilator effect occurred after approximately 45 minutes for vardenafil (10 or 20 mg), 60 minutes for sildenafil (50 mg), and 75 to 90 minutes for tadalafil (20–60 mg). In the same year, the first of a few small open-label trials and case reports described the clinical benefits of extended treatment with tadalafil in PAH.72,73 In 2007, 2 small open-label trials in India reported improvement in symptoms and pulmonary hemodynamics in patients with PAH treated with tadalafil.74,75 A large, multicenter, randomized controlled trial of tadalafil called the PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study began to enrolled patients with idiopathic or associated PAH in 2005.76 This pivotal trial randomized 405 patients to placebo, 2.5, 10, 20, or 40 mg of tadalafil once daily. Most patients had idiopathic or heritable PAH.

It’s in your system for a while and clears slowly

Approximately one-quarter had PAH associated with connective tissue disease, and slightly more than half the patients were taking bosentan at the time of enrollment. Randomization was stratified for baseline 6MWD, type of PAH, and background treatment with bosentan. The primary end point was change from baseline to 16 weeks in 6MWD and was significantly greater for the 10-mg, 20-mg, and 40-mg tadalafil groups than for placebo (P = .047, P = .028, and P<.001), but the prespecified significance level of P<.01 was reached only in the group that received 40 mg of tadalafil (Fig. Time to clinical worsening defined as death, heart or lung transplantation, atrial septostomy, hospitalization for worsening PAH, initiation of a new therapy for PAH, or increase in WHO functional class was longer and the incidence of clinical worsening was less in patient who received 40 mg of tadalafil versus placebo. In a subgroup of 93 patients who underwent right heart catheterization at baseline and after 16 weeks of study drug, mPAP and PVR decreased significantly in patients who received 20 mg (n = 17) or 40 mg (n = 18) of tadalafil. Serious adverse events were reported in 13% of patients in the PHIRST trial, but were judged by the investigators to be drug related in only 3.0%.

• Tadalafil 40mg may require dose adjustments based on response.
• The medication can interact with blood thinners regarding bleeding risk.
• Regular health check-ups are recommended while using Tadalafil 40mg.
• Do not take Tadalafil 40mg if you are using recreational drugs.
• Women should not use Tadalafil 40mg, as safety in women is unestablished.
• Always inform your healthcare provider about all medications you are taking.

In a post hoc analysis of elderly patients who were treated with 40 mg of tadalafil77 the incidence of adverse events was no different in patients greater than 65 years of age compared with those who were less than 65 years old.

16.1 How Supplied

CI was also significantly increased in the group treated with 40 mg of tadalafil. The improvement in 6MWD was sustained for 10 months in a subgroup of patients who were enrolled in a long-term extension study of 20 or 40 mg of tadalafil. Of the 213 patients who had completed at least 10 months of tadalafil therapy at the time of publication, the mean change in 6MWD was 37 m at 16 weeks and 38 m after 44 weeks. Based on the results of this pivotal clinical trial, tadalafil was approved by the FDA in May, 2009, at a dosage of 40 mg once daily for the treatment of WHO group 1 PAH. Additional data from the long-term extension study were published separately in 2012. Rare cases of vascular thrombosis have been reported following the use of PDE5 inhibitors, including a case of acute pulmonary embolism associated with tadalafil use in a patient with protein C deficiency.78 Of particular concern is the possible relationship between PDE5 inhibitors and nonarteritic ischemic optic neuropathy (NAION).

Contraindication	Explanation	Alternative Actions
Nitrates use	Can cause severe hypotension	Consult doctor for alternatives
Severe liver impairment	Reduced drug clearance	Adjust dose or avoid
Recent stroke or heart attack	Risk of adverse cardiovascular events	Monitor closely
Hypotension	Blood pressure too low	Treat underlying causes

Although the number of cases has been too low to directly link the use of PDE5 inhibitors with NAION, several reports have raised the possibility of this association with sildenafil37,38 and with tadalafil79–82 when taken for ED.

• Tadalafil 40mg is less common but used in specific therapeutic contexts.
• The medication may cause side effects such as muscle pain or back pain.
• Consult a healthcare professional for proper diagnosis and dosage.
• It is important to disclose all medications and supplements you take.
• Avoid using Tadalafil 40mg if you are pregnant or breastfeeding.
• Report any adverse reactions to your healthcare provider promptly.

Tadalafil is absorbed rapidly, reaching peak plasma concentrations approximately 2 hours after ingestion and is metabolized primarily in the liver via cytochrome P450 (CYP) 3A4 to an inactive catechol metabolite.

Use Case	Intended Effect	Typical Dosage	Onset Time	Duration of Action
Erectile Dysfunction	Improve erectile response	40mg as needed	30-60 min	Up to 36 hours
Pulmonary Hypertension	Relieve symptoms, reduce BP in lungs	40mg daily or as prescribed	15-30 min	6-8 hours
Benign Prostatic Hyperplasia	Improve urinary flow	40mg daily	30 min	Up to 24 hours

Following extensive methylation and glucuronidation, the catechol metabolites are excreted primarily in the feces and urine (61% and 36%, respectively).

3. Competitive Pricing for Distributors & Importers

The purpose of this review is to evaluate the pharmacology, pharmacokinetic properties, clinical efficacy, adverse effects, drug interactions, and dosage and administration of tadalafil in patients with PAH. A literature search of MEDLINE and International Pharmaceutical Abstracts (1960 through September 5, 2010) was conducted with the search terms tadalafil, pulmonary arterial hypertension, and phosphodiesterase-5 inhibitor. Data found from orignial research and case series published in English were screened for relevancy to pharmacology, pharmacokinetics, clinical efficacy and safety, and tolerability. Relevant articles from the bibliographies of the identified published articles were also obtained. Unpublished data and posters were obtained from the manufacturer of tadalafil and the FDA Web site.

It increases your chances of side effects

By selectively inhibiting PDE-5, tadalafil causes nitric oxide–mediated vasodilation in the pulmonary vasculature. Tadalafil has a greater affinity (10,000-fold) for PDE-5 compared with the other PDE inhibitors and has a t½ of 17.5 hours. In a controlled clinical study in patients with PAH, patients receiving tadalafil in a total daily dose of 40 mg had significant improvements in their 6-minute walk distance (33 m from baseline) and time to clinical worsening compared with those receiving placebo (both, P < 0.05). Tadalafil had adverse effects similar to placebo, with headache being the most commonly reported (42%). In the small number of studies available, tadalafil was effective and well tolerated when used to treat patients with PAH.

Tadalafil for Diabetes-Related Sexual Dysfunction

Compared with placebo, tadalafil was associated with significant improvements in exercise capacity and reduced time to tadalafil for premature ejaculation clinical worsening (68% relative risk reduction; P = 0.038). There is limited evidence comparing tadalafil with sildenafil and vardenafil, and the studies are limited by short treatment durations. Tadalafil is a beta-carboline–based PDE5 inhibitor that was designed to inhibit PDE activity and to have high specificity for PDE5. The selectivity of tadalafil for PDE5 is reported to be 9000-fold to 10,000-fold greater than for PDE1 to PDE4 and PDE7 to PDE1069and package insert and to be nearly 800-fold greater for PDE5 than for PDE6.69 The clinical efficacy of tadalafil as a PDE5 inhibitor has been well shown in studies of ED and seems to be at least as effective as other PDE5 inhibitors.70 Following successful reports of sildenafil for the treatment of PAH, several preliminary studies reported similar efficacy for this indication with tadalafil. The longer half-life of tadalafil, which allowed once-daily dosing, also made it an attractive alternative to sildenafil for the long-term treatment of PAH. Plasma elimination has a mean half-life of 17.5 hours in healthy volunteers, but may be greater than 30 hours in patients with PAH.

• Tadalafil 40mg is sometimes used in clinical trials for other conditions.
• Using this high dose increases the risk of side effects; caution is advised.
• Tadalafil 40mg should only be used under medical supervision.
• Be aware of potential vision changes or sudden loss when using this medication.
• The medication is generally well-tolerated when used responsibly.
• Overdose symptoms may include severe hypotension and priapism.