Eli Lilly and Company Limited

4.         Clinical particulars

4.2       Posology and method of administration

Deleted (strikethrough):

In responder patients to on-demand regimen who anticipate a frequent use of CIALIS (i.e., at least twice weekly) a once daily regimen with the lowest doses of CIALIS might be considered suitable, based on patient choice and the physician’s judgement.

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Tadalafil at doses of 2.5, 5, and 10 mg taken once a day was initially has been evaluated in 3 clinical studies involving 853 patients of various ages (range 21-82 years) and ethnicities, with erectile dysfunction of various severities (mild, moderate, severe) and etiologies. Most patients in all three studies were responders to previous on-demand treatment with PDE5 inhibitors. In the two primary efficacy studies of general populations, the mean per-subject proportion of successful intercourse attempts were 57 and 67% on CIALIS 5mg, 50% on CIALIS 2.5mg as compared to 31 and 37% with placebo. In the study in patients with erectile dysfunction secondary to diabetes, the mean per-subject proportion of successful attempts were 41 and 46% on CIALIS 5mg and 2.5mg, respectively, as compared to 28% with placebo. Most patients in these three studies were responders to previous on-demand treatment with PDE5 inhibitors. In a subsequent study, 217 patients who were treatment-naive to PDE5 inhibitors were randomized to CIALIS 5mg once a day vs. placebo.  The mean per-subject proportion of successful sexual intercourse attempts was 68% for CIALIS patients compared to 52% for patients on placebo.

10.          DATE OF REVISION OF THE TEXT

date of revision:

                21 February 2011

*This SPC has been re-formatted in its entirety due to QRD changes.

4.         Clinical particulars

4.1       Therapeutic indications

Added (bold):

Treatment of erectile dysfunction in adult males.

4.2       Posology and method of administration

Added (bold) deleted (strikethrough):

Method of administration

For oral use. CIALIS is available as 2.5, 5, 10, and 20 mg film-coated tablets for oral use.

4.4       Special warnings and precautions for use

Added (bold) deleted (strikethrough):

The safety and efficacy of combinations of CIALIS and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. The patients should be informed not to take CIALIS with such combinations. Therefore, the use of such combinations is not recommended.

4.6       Pregnancy and lactation

Added (bold) deleted (strikethrough):

There are limited data from the use of tadalafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of CIALIS during pregnancy.

Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A risk to the suckling child cannot be excluded. CIALIS should not be used during breast feeding. For tadalafil no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

4.8       Undesirable effects

Added (bold) deleted (strikethrough):

b.                                Tabulated summary of adverse reactions

The table below lists the adverse reactions reported induring erectile dysfunction placebo-controlled clinical trials for registrationin patients treated with CIALIS on demand and daily dosing with doses within the currently approved dosing range for CIALIS.  Adverse reactions are also included that have been reported from postmarketing surveillance in patients taking CIALIS on demand.

Note: Table re-formatted in entirety- see SPC

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Added (bold):

Pharmacotherapeutic group: Drugs used in erectile dysfunction, ATC Code: G04BE08.

10.          DATE OF REVISION OF THE TEXT

date of revision:

                06 September 2010

6.             PHARMACEUTICAL PARTICULARS

6.5          Nature and contents of container

Added (bold):

Aluminium/PVC/PE/ PCTFE blisters in cartons of 2, 4, 8, 10, 12, 14 and 28 film-coated tablets.

8.             MARKETING AUTHORISATION NUMBERS

Added:

EU/1/02/237/009                                CIALIS 20mg x 10 film-coated tablets.

10.          DATE OF REVISION OF THE TEXT

date of revision:

18 March 2010

Changes

4.             Clinical particulars

4.8          Undesirable effects

Added (bold):

10.          DATE OF REVISION OF THE TEXT

date of revision:

9 February 2010

4.         Clinical particulars

4.4       Special warnings and precautions for use

Deleted (strikethrough) Added (bold):

In patients who are taking alpha₁ blockers, such as doxazosin, concomitant administration of CIALIS may lead to symptomatic hypotension in some patients (see section 4.5). Therefore, the combination of tadalafil and alpha blockers

doxazosin is not recommended.

4.5       Interaction with other medicinal products and other forms of interaction

Deleted (strikethrough) Added (bold):

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 (see section 4.4).

In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with alfuzosin or tamsulosin. However, caution should be exercised when using tadalafil in patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at minimal dosage and progressively adjusted.

In subjects receiving concomitant tadalafil (20 mg) and doxazosin (8 mg daily), an alpha (1)adrenergic receptor blocker, there was an augmentation of the blood‑pressure‑lowering effect of doxazosin. This effect was still present at 12 hours postdose and had generally disappeared at 24 hours. The number of subjects with potentially clinically significant standing‑blood‑pressure decreases was greater for the combination. Some subjects experienced dizziness but no cases of syncope were reported. Lower doses of doxazosin have not been studied. Therefore, the combination of tadalafil and alpha blockers is not recommended. In a single study in 18 healthy volunteers, tadalafil (10 mg and 20 mg) had no clinically significant effect on blood pressure changes due to tamsulosin, a selective alpha (1A)-adrenergic receptor blocking agent. It is not known how this extrapolates to other alpha (1A)-adrenergic receptor blocking agents.

10.          DATE OF REVISION OF THE TEXT

date of revision:

03 September 2008

Addition:

This SPC has been revised in its entirety adding CIALIS OAD – 2.5mg/5mg text throughout – there are no other content changes.

10.          DATE OF REVISION OF THE TEXT

date of revision:

17 March 2008

4.             Clinical particulars

Section 4.8 Changed in its entirety

4.8          Undesirable effects

The most commonly reported adverse reactions were headache and dyspepsia.  The adverse reactions reported were transient, and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age..

The table below lists the adverse reactions reported during placebo-controlled clinical trials for registration in patients treated with CIALIS on demand and daily dosing.  Adverse reactions are also included that have been reported from postmarketing surveillance in patients taking CIALIS on demand.

Adverse Reactions

Frequency estimate: Very common (³1/10), Common (³1/100 to <1/10), Uncommon (³1/1000 to <1/100), Rare (³1/10,000 to <1/1000), Very Rare (<1/10,000) and Not known (events not reported in registration trials cannot be estimated from postmarketing spontaneous reports).

¹ Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors (see section 4.4).

² 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.

A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in patients treated with tadalafil once a day as compared with placebo. Most of these ECG abnormalities were not associated with adverse reactions.

10.          DATE OF REVISION OF THE TEXT

New date of revision:

17 March 2008

7.             MARKETING AUTHORISATION HOLDER

Eli Lilly Nederland B.V.

Grootslag 1-5, NL-3991 RA, Houten
The Netherlands

9.             DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first Authorisation: 12 November 2002

Date of last renewal:   12 November 2007

10.          DATE OF REVISION OF THE TEXT

New date of revision:

18 October 2007

2.             QUALITATIVE AND QUANTITATIVE COMPOSITION

Added:

10mg: Each coated tablet contains 179mg lactose monohydrate.

20mg: Each coated tablet contains 245mg lactose monohydrate

3.             PHARMACEUTICAL form

Added text in bold:

Film-coated tablet (tablet).

The 10mg tablets are light yellow and almond shaped, marked ‘C 10’ on one side.

The 20mg tablets are yellow and almond shaped, marked ‘C 20’ on one side.

4.             CLINICAL PARTICULARS

4.2          Posology and method of administration

Text added following the approval of 2.5 and 5mg tablet strengths.

CIALIS is 2.5, 5, 10 and 20mg film-coated tablets.

Added text in bold:

Use in Adult Men

In general, the recommended dose is 10mg taken prior to anticipated sexual activity and with or without food.  In those patients in whom tadalafil 10mg does not produce an adequate effect, 20mg might be tried.  It may be taken at least 30 minutes prior to sexual activity.

The maximum dose frequency is once per day.

Added new dosing instructions following approval of 2.5 and 5mg tablet strengths.

In responder patients to on-demand regimen who anticipate a frequent use of CIALIS (ie., at least twice weekly) a once daily regimen with the lowest doses of CIALIS might be considered suitable, based on patient choice and the physician’s judgement.

In these patients, the recommended dose is 5mg taken once a day at approximately the same time of day.  The dose may be decreased to 2.5mg once a day based on individual tolerability.

The appropriateness of continued use of the daily regimen should be reassessed periodically.

Added:

Use in Elderly Men

Once-a-day dosing of tadalafil is not recommended in patients with severe renal impairment. (See sections 4.4 and 5.2.)

Use in Men With Impaired Hepatic Function

Once-a-day dosing has not been evaluated in patients with hepatic impairment; therefore if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician (See section 5.2.)

4.3          Contra-indications

Moved the following text from the end off the section to the top of the section.

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

4.4          Special warnings and precautions for use

Added text in bold:

There is limited clinical data on the safety of single-dose administration of CIALIS in patients with severe hepatic insufficiency.

Deletions in strikethrough text:

The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment.  It is not known if CIALIS is effective in patients with spinal cord injuries and patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy.

Slightly reworded and moved sentence to the bottom of the section:

CIALIS 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.

4.5          Interaction with other medicinal products and other forms of interaction

Replaced medicinal products to substances in the following heading:

Effects of other substances on tadalafil

Reworded paragraph (changes in bold):

A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil alone (10mg).  This reduced exposure can be anticipated to decrease the efficacy of tadalafil; the magnitude of decreased efficacy is unknown.  Other inducers of CYP3A4, such as phenobarbital, phenytoin, and carbamazepine, may also decrease plasma concentrations of tadalafil.

Added text in bold:

Thus, in a patient prescribed any dose of CIALIS (2.5mg - 20mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of Cialis before nitrate administration is considered.

Moved the following text to bottom of the section:

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolised by CYP450 isoforms.  Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9, and CYP2C19.

Tadalafil (10 and 20mg) 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.

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

Changed the word ‘medication’ to ‘medicines’ in several places within section.

4.6          Pregnancy and lactation

Reworded section to read:

CIALIS is not indicated for use by women.

For tadalafil, no clinical data on exposed pregnancies are available.  Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

4.7          Effects on ability to drive and use machines

Cialis is expected to have no or negligible influence on the ability to drive and/or use machines.  No specific studies have been performed to evaluate a potential effect.

Changed to:

No studies on the effect of the ability to drive and use machines have been performed.

4.8          Undesirable effects

                Reformatted entire section:

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness within the clinical trial adverse reaction tables.

Postmarketing adverse reactions reported for Cialis is now presented in table format with frequency classifications.

5.             PHARMACOLOGICAL PROPERTIES

5.3          Preclinical safety data

Added text in bold:

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.

6.             PHARMACEUTICAL PARTICULARS

6.4          Special precautions for storage

Added text in bold:

Store in the original package in order to protect from moisture.

6.5          Nature and contents of container

Changes in bold text:

Aluminium/PVC/PE/ PCTFE blisters in cartons of 4 film-coated tablets.

Aluminium/PVC/PE/ PCTFE blisters in cartons of 2, 4, 8 and 12 film-coated tablets.

9.             DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Changes in bold text:

Date of first Authorisation: 12 November 2002

Date of last renewal: 12 November 2007

10.          DATE OF REVISION OF THE TEXT

New date of revision:

October 2007

4.             CLINICAL PARTICULARS

4.2          Posology and method of administration

Added:

Tadalafil 10 and 20mg is intended for use prior to anticipated sexual activity and is not recommended for continuous daily use.

Deleted:

Continuous daily use of the medication is strongly discouraged because the long-term safety after prolonged daily dosing has not been established and also because the effect of tadalafil usually lasts for longer than one day.  See section 4.4, last paragraph, and section 5.1.

4.4          Special warnings and precautions for use

Deleted:

In dogs given tadalafil daily for 6 to 12 months at doses of 25mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7-18.6] than seen in humans at a 20mg single dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs.  Results from two 6-month studies in volunteers suggest that this effect is unlikely in humans (see section 5.1).  The effects of longer-term daily dosing have not been established.  Therefore, daily use of the medication is strongly discouraged.

4.8          Undesirable effects

Added:

Nervous system: Migraine.

Respiratory system: Epistaxis.

5.             PHARMACOLOGICAL PROPERTIES

5.1          Pharmacodynamic properties

Two studies were conducted in men to assess the potential effect of Cialis 10mg and 20mg administered daily for 6 months on spermatogenesis.  The results of these studies demonstrate no difference from placebo with respect to the proportion of men showing a 50% or greater decrease in sperm concentration.  In addition, in comparison with placebo, there were no adverse effects observed with respect to mean change in sperm count, sperm morphology, or sperm motility at either dose.  However, in the study of 10mg Cialis taken daily for 6 months, results showed a decrease in mean sperm concentration relative to placebo.  This effect was not seen in the study where the higher dose, 20mg, Cialis was taken daily for 6 months.  In addition, there was no effect on mean concentrations of testosterone, luteinizing hormone, or follicle stimulating hormone with either 10 or 20mg of Cialis compared to placebo.  The effects of longer-term daily dosing have not been established.  See also sections 4.4 and 5.3.

Changed to:

Three studies were conducted in men to assess the potential effect on spermatogenesis of Cialis 10mg (one 6-month study) and 20mg (one 6-month and one 9-month study) administered daily.  In two of these studies decreases were observed in sperm count and concentration related to tadalafil treatment of unlikely clinical relevance.  These effects were not associated with changes in other parameters, such as motility, morphology, and FSH.

5.3          Preclinical safety data

Rephrased in bold (previously “Preclinical …”):

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential, and toxicity to reproduction.

6.             PHARMACEUTICAL PARTICULARS

6.4          Special precautions for storage

Added:

Do not store above 30°C.

10.          DATE OF REVISION OF THE TEXT

New date of revision:

28 July 2006

4.             CLINICAL PARTICULARS

4.3                Contra-indications

Added:

Cialis is contra-indicated 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 (see section 4.4).

4.4          Special warnings and precautions for use

Deleted:

The use of PDE5 inhibitors is not recommended in patients with a previous episode of non-arteritic anterior ischaemic optic neuropathy (NAION).

Added:

Visual defects and cases of non-arteritic anterior ischaemic optic neuropathy have been reported in connection with the intake of Cialis and other PDE5 inhibitors.  The patient should be advised that in case of sudden visual defect, he should stop taking Cialis and consult a physician immediately (see section 4.3).

4.8          Undesirable effects

Deleted:

Eye disorders: Non-arteritic anterior ischaemic optic neuropathy (NAION), blurred vision, visual field defect, retinal vascular occlusion.

Added:

Eye disorders: Blurred vision, visual field defect, retinal vascular occlusion.  Non-arteritic anterior ischaemic optic neuropathy (NAION) has been reported at an unknown frequency.

8.             MARKETING AUTHORISATION NUMBERS

EU/1/02/237/001:        4 x 10mg tablets

EU/1/02/237/003:        4 x 20mg tablets

EU/1/02/237/004:        8 x 20mg tablets

Changed to:

EU/1/02/237/001-005

10.          DATE OF REVISION OF THE TEXT

New date of revision:

12 June 2006