Each tablet contains 20 mg tadalafil. Excipients: Each coated tablet contains 245 mg lactose monohydrate.

Film-coated tablet (tablet). Orange and almond shaped tablets, marked "4467" on one side.

ADCIRCA is indicated in adults for the treatment of pulmonary arterial hypertension (PAH) classified as WHO functional class II and III, to improve exercise capacity.

Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease.

Method of administration:

ADCIRCA is available as 20 mg film-coated tablets for oral use.

Posology:

Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.

The recommended dose is 40 mg (2 x 20 mg) taken once daily with or without food.

Use in elderly patients:

Dose adjustments are not required in elderly patients.

Use in patients with renal impairment:

In patients with mild to moderate renal impairment a starting dose of 20 mg once per day is recommended. The dose may be increased to 40 mg once per day, based on individual efficacy and tolerability. In patients with severe renal impairment the use of ADCIRCA is not recommended.

Use in patients with hepatic impairment:

Due to limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B), following single doses of 10 mg, a starting dose of 20 mg once per day may be considered. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing of tadalafil is not recommended.

Paediatric population:

The safety and efficacy of ADCIRCA in individuals below 18 years of age has not yet been established. No data are available.

Hypersensitivity to the active substance or to any of the excipients.

Acute myocardial infarction within the last 90 days.

Severe hypotension (<90/50 mm Hg).

- In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of ADCIRCA to patients who are using any form of organic nitrate is contraindicated.

ADCIRCA is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.

The following groups of patients with cardiovascular disease were not included in PAH clinical trials:

- Patients with clinically significant aortic and mitral valve disease

- Patients with pericardial constriction

- Patients with restrictive or congestive cardiomyopathy

- Patients with significant left ventricular dysfunction

- Patients with life-threatening arrhythmias

- Patients with symptomatic coronary artery disease

- Patients with uncontrolled hypertension.

Since there are no clinical data on the safety of tadalafil in these patients, the use of tadalafil is not recommended.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. Should signs of pulmonary oedema occur when tadalafil is administered, the possibility of associated PVOD should be considered.

As with other PDE5 inhibitors, tadalafil has systemic vasodilatory properties that may result in transient decreases in blood pressure. Physicians should carefully consider whether their patients with certain underlying conditions, such as severe left ventricular outflow obstruction, fluid depletion, autonomic hypotension or patients with resting hypotension, could be adversely affected by such vasodilatory effects.

Visual defects and cases of NAION have been reported in connection with the intake of ADCIRCA and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, to consult a physician immediately. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.

Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, ADCIRCA is not recommended in patients with severe renal impairment.

Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing of ADCIRCA is not recommended.

Priapism has been reported in men treated with PDE5 inhibitors. Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

ADCIRCA should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).

In patients who are taking alpha₁ blockers, concomitant administration of ADCIRCA may lead to symptomatic hypotension in some patients. Therefore, the combination of tadalafil and doxazosin is not recommended.

For patients chronically taking potent inducers of CYP3A4, such as rifampicin, the use of tadalafil is not recommended.

For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the use of tadalafil is not recommended.

The safety and efficacy of combinations of ADCIRCA and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Inform patients not to take ADCIRCA with these medications.

The efficacy and safety of tadalafil co-administered with prostacyclin or its analogues has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration.

The efficacy of tadalafil in patients already on bosentan therapy has not been conclusively demonstrated.

ADCIRCA contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Effects of other substances on tadalafil

Cytochrome P450 Inhibitors

Azole Antifungals (e.g.,ketoconazole)

Ketoconazole (200 mg daily), increased tadalafil (10 mg) single-dose exposure (AUC) 2-fold and C_max by 15%, relative to the AUC and C_max values for tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) single-dose exposure (AUC) 4-fold and C_max by 22%.

Protease inhibitors (e.g., ritonavir)

Ritonavir (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) single-dose exposure (AUC) 2-fold with no change in C_max. Ritonavir (500 mg or 600 mg twice daily) increased tadalafil (20 mg) single-dose exposure (AUC) by 32% and decreased C_max by 30%.

Cytochrome P450 Inducers

Endothelin-1 receptor antagonists (e.g., bosentan)

Bosentan (125 mg twice daily), a substrate of CYP2C9 and CYP3A4 and a moderate inducer of CYP3A4, CYP2C9 and possibly CYP2C19, reduced tadalafil (40 mg once per day) systemic exposure by 42% and C_max by 27% following multiple dose co-administration. The efficacy of tadalafil in patients already on bosentan therapy has not been conclusively demonstrated. Tadalafil did not affect the exposure (AUC and C_max) of bosentan or its metabolites.

The safety and efficacy of combinations of ADCIRCA and other endothelin-1 receptor antagonists have not been studied.

Antimicrobial agents (e.g., rifampicin)

A CYP3A4 inducer, rifampicin (600 mg daily), reduced tadalafil AUC by 88 % and C_max by 46%, relative to the AUC and C_max values for tadalafil alone (10 mg).

Effects of tadalafil on other medicinal products

Nitrates

In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. This interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Therefore, administration of ADCIRCA to patients who are using any form of organic nitrate is contraindicated.

Anti-hypertensives (including Calcium channel blockers)

The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore this combination is not recommended.

In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with alfuzosin or tamsulosin.

In clinical pharmacology studies, the potential for tadalafil (10 and 20 mg) to augment the hypotensive effects of antihypertensive agents was examined. Major classes of antihypertensive agents were studied either as monotherapy or as part of combination therapy. In patients taking multiple antihypertensive agents whose hypertension was not well controlled, greater reductions in blood pressure were observed compared to subjects whose blood pressure was well controlled, where the reduction was minimal and similar to that in healthy subjects. In patients receiving concomitant antihypertensive medicines, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of doxazosin - see above) is, in general, minor and not likely to be clinically relevant.

Alcohol

Alcohol concentrations were not affected by co-administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations were seen after co-administration with alcohol. Tadalafil (20 mg) did not augment the mean blood pressure decrease produced by alcohol (0.7 g/kg or approximately 180 ml of 40% alcohol [vodka] in an 80-kg male) but in some subjects, postural dizziness and orthostatic hypotension were observed. The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg).

CYP1A2 substrates (e.g., theophylline)

When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase inhibitor) there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small (3.5 bpm) increase in heart rate.

CYP2C9 substrates (e.g., R-warfarin)

Tadalafil (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.

Aspirin

Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.

P-glycoprotein substrates (e.g., digoxin)

Tadalafil (40 mg once per day) had no clinically significant effect on the pharmacokinetics of digoxin.

Oral Contraceptive Pill

At steady-state, tadalafil (40 mg once per day) increased ethinylestradiol exposure (AUC) by 26% and C_max by 70% relative to oral contraceptive administered with placebo. There was no statistically significant effect of tadalafil on levonorgestrel which suggests the effect of ethinylestradiol is due to inhibition of gut sulphation by tadalafil. The clinical relevance of this finding is uncertain.

Terbutaline

A similar increase in AUC and C_max seen with ethinylestradiol may be expected with oral administration of terbutaline, probably due to inhibition of gut sulphation by tadalafil. The clinical relevance of this finding is uncertain.

a. Summary of the safety profile

The most commonly reported adverse reactions, occurring in 10% of subjects in the tadalafil 40-mg treatment arm, were headache, nausea, back pain, dyspepsia, flushing, myalgia, nasopharingitis and pain in extremity. The adverse reactions reported were transient, and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age.

b. Tabulated summary of adverse reactions

In the pivotal placebo-controlled study of ADCIRCA for the treatment of PAH, a total of 323 patients were treated with ADCIRCA at doses ranging from 2.5 mg to 40 mg once daily and 82 patients were treated with placebo. The duration of treatment was 16 weeks. The overall frequency of discontinuation due to adverse events was low (ADCIRCA 11%, placebo 16%). Three hundred and fifty seven (357) subjects who completed the pivotal study entered a long-term extension study. Doses studied were 20 mg and 40 mg once daily.

The table below lists the adverse reactions reported during the placebo-controlled clinical trial in patients with PAH treated with ADCIRCA. Also included in the table are some adverse events/reactions which have been reported in clinical trials and/or post marketing with tadalafil in the treatment of male erectile dysfunction. These events have either been assigned a frequency of “Not known”, as the frequency in PAH patients cannot be estimated from the available data or assigned a frequency based on the clinical trial data from the pivotal placebo-controlled study of ADCIRCA.

Adverse reactions

Frequency estimate: Very common (1/10), Common (1/100 to <1/10), Uncommon (1/1000 to <1/100), Rare (1/10,000 to <1/1000), Very Rare (<1/10,000) and Not known (cannot be estimated from the available data).

¹ Events not reported in registration trials and cannot be estimated from the available data. The adverse reactions have been included in the table as a result of postmarketing or clinical trial data from the use of tadalafil in the treatment of erectile dysfunction.

² Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors.

³ Actual MedDRA terms included are abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and stomach discomfort.

⁴ Clinical non-MedDRA term to include reports of abnormal/excessive menstrual bleeding conditions such as menorrhagia, metrorrhagia, menometrorrhagia, or vaginal haemorrhage.

⁵ The adverse reactions have been included in the table as a result of postmarketing or clinical trial data from the use of tadalafil in the treatment of erectile dysfunction; and in addition, the frequency estimates are based on only 1 or 2 patients experiencing the adverse reaction in the pivotal placebo-controlled study of ADCIRCA.

⁶ Sudden decrease or loss of hearing has been reported in a small number of postmarketing and clinical trial cases with the use of all PDE5 inhibitors, including tadalafil.

⁷ See section c)

c. Description of selected adverse reactions

Headache was the most commonly reported adverse reaction. Headache may occur at the beginning of therapy; and decreases over time even if treatment is continued.

Eli Lilly and Company Limited

POM – Prescription Only Medicine

15 November 2010