Data Sheet
CIALIS™
2.5mg, 5 mg, 10 mg and 20 mg film-coated tablets.
Presentation
2.5 mg: Each light orange-yellow, film coated, almond shaped tablet contains 2.5mg tadalafil and is marked with "C 2 ½" on one side.
5 mg: Each light yellow, almond shaped, film coated tablet contains 5 mg tadalafil and is marked with "C 5" on one side.
10 mg: Each light yellow, almond-shaped, film-coated tablet contains 10 mg
tadalafil and is marked with 'C10' on one side.
20 mg: Each yellow, almond-shaped, film-coated tablet contains 20 mg tadalafil
and is marked with 'C20' on one side.
Uses
Actions
Pharmacotherapeutic group: medicines used in erectile dysfunction.
Tadalafil is a potent, selective, reversible inhibitor of cyclic guanosine
monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual
stimulation causes the local release of nitric oxide, inhibition of PDE5 by
tadalafil produces increased levels of cGMP in the corpus cavernosum. This
results in smooth muscle relaxation and inflow of blood into the penile
tissues, thereby producing an erection. Tadalafil has no effect in the absence
of sexual stimulation.
Pharmacodynamics
Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also >9,000-fold more potent for PDE5 than for PDE8, 9 and 10 and 14-fold more potent for PDE5 than for PDE11. The tissue distribution and physiological effects of the inhibition of PDE8 through PDE11 have not been elucidated.
CIALIS administered to healthy subjects produced no significant difference
compared to placebo in supine systolic and diastolic blood pressure (mean
maximal decrease of 1.6/0.8 mm Hg, respectively), in standing systolic and
diastolic blood pressure (mean maximal decrease of 0.2/4.6 mm Hg,
respectively), and no significant change in heart rate.
Larger effects were recorded among subjects receiving concomitant nitrates
(see CONTRAINDICATIONS).
In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. In addition, no effects were observed on visual acuity, electroretinograms, intraocular pressure, or pupillometry. Across all clinical studies, reports of changes in colour vision were rare (<0.1%).
Studies on Spermatogenesis - Three studies were conducted in men to assess the potential effect on spermatogenesis of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In all 3 studies there were no statistically significant differences between the placebo and tadalafil groups for mean total sperm counts. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinising hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo.
Pharmacokinetics
Absorption
Tadalafil is rapidly absorbed after oral administration and the mean
maximum observed plasma concentration (Cmax) is achieved at a
median time of 2 hours after dosing. Absolute bioavailability of tadalafil
following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food,
thus CIALIS may be taken with or without food. The time of dosing (morning
versus evening) had no clinically relevant effects on the rate and extent of
absorption.
Distribution
The mean volume of distribution is approximately 63 litres, indicating that
tadalafil is distributed into tissues. At therapeutic concentrations, 94% of
tadalafil in plasma is bound to proteins. Protein binding is not affected by
impaired renal function.
Samples collected from healthy human subjects approximately 5 hours after
dosing indicated that <0.0005% of the total dose of tadalafil is distributed
to semen.
Biotransformation
Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.
Elimination
The mean oral clearance for tadalafil is 2.5 L/hour and the mean half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Linearity/Non-Linearity
Tadalafil pharmacokinetics in healthy subjects are linear with respect to
time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases
proportionally with dose. Steady-state plasma concentrations are attained
within 5 days of once-daily dosing.
Pharmacokinetics determined with a population approach in patients with
erectile dysfunction are similar to pharmacokinetics in subjects without
erectile dysfunction.
Elderly
Healthy elderly subjects (65 years or over), had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) relative to healthy subjects aged 19 to 45 years. This effect of age is not clinically significant and does not warrant a dose adjustment.
Renal Impairment
In subjects with renal insufficiency, including those on haemodialysis, tadalafil exposure (AUC) was higher than in healthy subjects. Therefore, the recommended starting dose of tadalafil in patients with mild or moderate renal impairment is 10 mg. For patients with severe renal impairment 10 mg is the maximum recommended dose (see DOSAGE AND ADMINISTRATION).
Hepatic Impairment
Tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A and B) is comparable to exposure in healthy subjects. No controlled data are available in patients with severe hepatic impairment (Child-Pugh Class C) (see WARNINGS AND PRECAUTIONS). Once-a-day administration has not been evaluated in patients with hepatic insufficiency. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.
Patients with Diabetes
Tadalafil exposure (AUC) in patients with diabetes was approximately 19% lower than the AUC value for healthy subjects. This difference in exposure does not warrant a dose adjustment.
Clinical Trials
On-Demand Dosing for the Treatment of Erectile Dysfunction:
Tadalafil, when taken on-demand up to once daily, is effective in improving erectile function in men with erectile dysfunction (ED). In clinical studies assessing patients' ability to engage in successful and satisfying sexual activity, tadalafil demonstrated highly statistically significant improvement compared to placebo. Additionally, partners of patients on tadalafil had statistically significantly greater satisfaction with sexual activity compared to partners of patients on placebo.
Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3250 patients. Tadalafil 10 mg and/or 20 mg, taken on-demand up to once daily, was compared to placebo in 6 primary efficacy studies (5 in general ED population, 1 in patients with diabetes). Seven hundred and twenty four (724) patients received tadalafil 10 mg or 20 mg and 379 patients received placebo in these randomised, double-blinded, parallel-group studies. Patients were free to choose the time interval between dose administration and the time of sexual attempts. Food and alcohol intake were not restricted. The studies were designed in this manner in order to allow for convenience and dosing flexibility for the patient and partner.
Several assessment instruments were used to evaluate the effect of tadalafil on erectile function. Global Assessment Questions (GAQ) were asked to determine whether the treatment improved patients' erections. During clinical studies, patients and partners completed sexual encounter profile (SEP) diaries assessing erectile function and sexual satisfaction of each sexual attempt. The International Index of Erectile Function (IIEF), a recall questionnaire, was also completed by patients. The IIEF provides global measures of erectile function and sexual satisfaction, as well as severity of ED.
In all primary efficacy studies, tadalafil demonstrated consistent and statistically significant improvement compared to placebo in all primary and secondary endpoints evaluated. In each primary efficacy study, a significant treatment effect was declared only if there was a statistically significant improvement on all three co-primary measures: 1) the IIEF Erectile Function domain; 2) SEP Question 2 (assessing the ability to penetrate the partner's vagina); and 3) SEP Question 3 (assessing the ability to maintain the erection). The treatment effect did not diminish over time. Overall, tadalafil consistently showed efficacy in a broad and representative population that included patients with ED of various severities (mild, moderate, severe), aetiologies (including patients with diabetes), ages (21 to 86 years), ethnicities and durations of ED. In the five primary efficacy studies of general populations, 81% of patients reported that tadalafil 20 mg improved their erections compared to 35% of patients on placebo. Also, patients with ED in all severity categories reported improved erections while taking tadalafil 20 mg (86%, 83% and 72% mild, moderate and severe, respectively) compared to patients on placebo 45%, 42% and 19% for mild, moderate and severe, respectively). Tadalafil showed statistically significant improvement in patients' ability to achieve an erection sufficient for sexual intercourse and maintain the erection for successful intercourse as measured by the SEP diaries. In the primary efficacy studies, 75% of intercourse attempts were successful in patients taking tadalafil 20 mg compared to 32% of patients on placebo. This finding was confirmed by partner SEP responses. Tadalafil also demonstrated statistically significant improvement in erectile function as measured by the IIEF Erectile Function domain. Additionally, in the primary efficacy studies, approximately 60% of patients taking tadalafil 20 mg achieved normal erectile function during treatment. Patients with ED in all severity categories improved into the normal range (defined by IIEF).
Patient Confidence and Sexual Satisfaction
The IIEF also measures patients' confidence that they can attain and keep an erection sufficient for sexual intercourse. Tadalafil statistically significantly improved patient confidence. Analysis of the Intercourse Satisfaction and Overall Satisfaction domains of the IIEF showed that tadalafil treatment provided statistically significant enhancement of sexual satisfaction measured by both domains. Additionally, tadalafil improved the proportion of sexual encounters that were satisfying for both the patient and the partner.
Efficacy in ED Patients with Diabetes Mellitus
Tadalafil is effective in treating ED in patients with diabetes. Patients with diabetes (n=451) were included in all primary efficacy studies, one of which specifically assessed tadalafil only in ED patients with Type 1 or Type 2 diabetes. Tadalafil produced statistically significant improvement in erectile function and sexual satisfaction. In these studies, 68% of patients with diabetes taking tadalafil 20 mg reported improved erections.
Period of Responsiveness
Two clinical studies were conducted in 571 patients in an at-home setting to define the period of responsiveness to tadalafil. One of the two studies specifically assessed the improvement of erectile function at 24 and 36 hours following tadalafil administration. In this study, approximately 60% of sexual attempts at both 24 and 36 hours were successful for patients on tadalafil 20 mg compared to approximately 30% of sexual attempts for patients on placebo.
Therefore, tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.
Once-a-Day Dosing for the Treatment of Erectile Dysfunction:
Tadalafil at doses of 2.5, 5, and 10 mg taken once a day 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. In the two primary efficacy studies of general populations, 76 and 85% of patients reported that tadalafil 5 mg taken once a day improved their erections as compared to 29 and 30% with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections while taking tadalafil once a day. In the primary efficacy studies, 62 and 69% of intercourse attempts in the general population studies were successful in tadalafil 5 mg-treated patients as compared to 34 and 39% with placebo. Tadalafil 5 mg significantly improves erectile function over the 24-hour period between the doses.
Indications
Treatment of erectile dysfunction.
In order for CIALIS to be effective, sexual stimulation is required.
Dosage and Administration
CIALIS tablets are for oral use.
CIALIS can be taken with or without food.
On-Demand Dosing:
Use in Adult Men
The maximum recommended dose of CIALIS is 20 mg, taken prior to anticipated sexual activity. The maximum recommended dosing frequency is once per day. CIALIS may be taken between 30 minutes and 36 hours prior to anticipated sexual activity. Patients may initiate sexual activity at varying time points relative to dosing in order to determine their own optimal window of responsiveness. The dose may be lowered to 10 mg based on individual response and tolerability. CIALIS may be taken without regard to food. CIALIS 10 and 20 mg is intended for use prior to anticipated sexual activity and is not for continuous daily use.
Use in Men with Renal Impairment
The recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and without regard to food for patients with mild or moderate renal impairment. Based on efficacy and tolerability the dose may be increased up to 20 mg. For patients with severe renal impairment 10 mg is the maximum recommended dose.
A single dose study in 8 men suffering from End Stage Renal Disease who were stable on haemodialysis showed 3-4 fold increase in AUC and 2-2.5 fold increase in Cmax in tadalafil levels, The half-life of the drug is also prolonged.
Use in Men with Hepatic Impairment
The recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity with or without food for patients with mild to moderate hepatic impairment (Child-Pugh Class A or B). There are no available data about the administration of doses higher than 10 mg of tadalafil to patients with hepatic impairment. There is limited clinical data on the safety of CIALIS in patients with severe hepatic impairment (Child-Pugh Class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. (Refer to Pharmacokinetics in Special Populations - Hepatic Impairment)
Once-a-Day Dosing:
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 dose 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 must not exceed 5mg daily. The dose may be decreased to 2.5mg once a day based on individual tolerability.
There is insufficient evidence on the maximum duration of treatment. The appropriateness of continued use of the once-a-day regimen should be reassessed periodically.
Use in Men with Renal Impairment:
Dosage adjustments are not required in patients with mild or moderate renal impairment. Once-a-day dosing of tadalafil is not recommended in patients with severe renal impairment.
Use in Men with Hepatic Impairment
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 (refer to Pharmacokinetics in Special Populations - Hepatic Impairment).
Use in Men with Diabetes
The presence of diabetes does not require a dose reduction.
Use in Elderly Men
Dosage adjustments are not required in elderly patients. Dosage recommendations described in "Use in Adult Men" apply to elderly men.
Use in Children
CIALIS should not be used in individuals below 18 years of age.
Contraindications
Nitrates and tadalafil must not be used concomitantly. Co-administration of tadalafil with nitric oxide donors, organic nitrates or organic nitrites in any form either regularly or intermittently is contraindicated. Drugs which must not be used concomitantly include, but are not limited to, glyceryl trinitrate (injection, tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite, nicorandil, or organic nitrates in any form. In clinical studies, tadalafil (10 mg) 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.
CIALIS should not be used in patients with a known hypersensitivity to tadalafil or to any of the excipients.
Tadalafil 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 (see WARNINGS and PRECAUTIONS and ADVERSE EFFECTS - Adverse events identified from spontaneous post marketing surveillance).
Warnings and Precautions
Sexual activity carries a potential cardiac risk for patients with pre-existing cardiovascular disease. Therefore, treatments for erectile dysfunction, including CIALIS, should not be used in men with cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease. Patients who experience cardiovascular symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and should report the episode to their physician. The following groups of patients with cardiovascular disease were not included in clinical trials:
- patients with a myocardial infarction within the last 90 days
- patients with unstable angina or angina occurring during sexual intercourse
- patients with New York Heart Association Class 2 or greater heart failure in the last 6 months
- patients with uncontrolled arrhythmias, hypotension (< 90/50 mm Hg), or uncontrolled hypertension
- patients with a stroke within the last 6 months.
Caution should be exercised when prescribing CIALIS to patients with severe hepatic insufficiency (Child-Pugh Class C) or to those taking CYP3A4 inhibitors or inducers or HIV protease inhibitors.
Once-a-day administration has not been evaluated extensively in patients with hepatic insufficiency. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.
In a clinical pharmacology study, administration of tadalafil 10 mg to patients with moderate renal failure (creatine clearance =31 to 50mL/min) was determined to be safe but appeared to be less well tolerated in terms of back pain than in patients with mild renal failure (creatine clearance =51 to 80 mL/min) and in healthy subjects.
In a single dose, pharmacodynamic study of 8 patients with End Stage Renal Disease who were stable on haemodialysis, the reported adverse effects included headache, dizziness, and somnolence.
Tadalafil should be prescribed with caution for patients with creatine clearance < 50 mL/min.
Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, once-a-day dosing of tadalafil is not recommended in patients with severe renal impairment.
For dosage recommendations in patients with renal impairment see Dosage and Administration section.
Priapism has been reported with PDE5 inhibitors, including tadalafil. 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. CIALIS should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease).
The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment.
The safety and efficacy of combinations of CIALIS and other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
Physicians should advise patients to stop taking PDE5 inhibitors, including CIALIS, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including CIALIS. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see ADVERSE EFFECTS).
Caution should be exercised when prescribing CIALIS to patients who are taking alpha1 blockers, such as doxazosin, as simultaneous administration may lead to symptomatic hypotension in some patients.
As with other PDE5 inhibitors, tadalafil has systemic vasodilatory properties
that may result in transient decreases in blood pressure. Prior to prescribing
CIALIS, physicians should carefully consider whether their patients with
underlying cardiovascular disease could be affected adversely by such
vasodilatory effects.
Physicians should advise patients to stop use of all PDE5 inhibitors, including CIALIS, and seek medical attention in the event of a sudden loss of vision in one or both eyes (see CONTRAINDICATIONS). Such an event may be a sign of non-arteritic anterior ischaemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see ADVERSE EFFECTS - Adverse events identified from spontaneous post marketing surveillance)
Specific studies examining potential withdrawal effects from daily use have not been conducted. Rebound effects on blood pressure have not been observed after follow-up assessments at 2 weeks and 4 weeks following cessation of up to 1 year of chronic daily treatment of CIALIS. Blood pressure was not specifically monitored leading up to or between the 2 and 4 weeks post-treatment assessments. Based upon the limited clinical data examining withdrawal effects, it is recommended that physicians continue monitoring the cardiovascular status, including blood pressure changes, of their patients after discontinuation of CIALIS.
Carcinogenicity, Mutagenesis, Impairment of Fertility
Preclinical data reveal no special hazard for humans based on conventional
studies of safety pharmacology, genotoxicity, carcinogenic potential, and
toxicity to reproduction.
There was no impairment of fertility in male and female rats. In dogs given
tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day and above, there
were alterations to the seminiferous tubular epithelium that resulted in a
decrease in spermatogenesis in some dogs. (see Pharmacodynamics).
Pregnancy
CIALIS is not indicated for use in women.
There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in
rats or mice that received up to 1000 mg/kg/day. In a rat pre- and postnatal
development study, the no observed effect dose was 30 mg/kg/day. In the
pregnant rat, the AUC for calculated free drug at this dose was approximately
18 times the human AUC at a 20 mg dose. There are no studies of tadalafil in
pregnant women.
Effects on Ability to Drive and Use Machines
Although the frequency of reports of dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of how they react to CIALIS, before driving or operating machinery.
Adverse Effects
Adverse events identified from clinical trials
On-Demand Dosing:
CIALIS was administered to over 4000 subjects (aged 19 to 86 years) during
clinical trials worldwide. Over 230 patients were treated for longer than one
year and over 720 patients were treated for over 6 months. In controlled phase
2/3 clinical trials, the discontinuation rate due to adverse effects in CIALIS-treated
patients (1.7%) was not significantly different from placebo-treated patients
(1.1%). In these studies, the adverse effects reported with CIALIS were
generally mild or moderate, transient, and decreased with continued dosing.
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 (events not reported in registration trials cannot be estimated from postmarketing spontaneous reports).
Table 1: Adverse Events Reported by ≥ 2% of Patients Treated with Tadalafil 10-20 mg and More Frequent on Drug than Placebo in Phase 3 Studies
| Tadalafil (N=724) |
Placebo (N=379) |
||
| Event | (%) | (%) | |
| Nervous System | Headache | 15 | 6 |
| Digestive System | Dyspepsia Diarrhoea |
12 2 |
2 1 |
| Body as a Whole | Infection | 8 | 7 |
| Musculoskeletal System | Back Pain Muscle Ache |
7 6 |
4 2 |
| Respiratory System | Nasal Congestion Pharyngitis |
4 3 |
3 2 |
| Cardiovascular System | Flushing | 4 | 2 |
Nervous System -. Common: dizziness.
Special Senses - Uncommon: conjunctival hyperaemia; sensations described as eye pain; swelling of eyelids.
Eye Disorders - Rare: changes in colour vision.
Ear and labyrinth disorders - Uncommon: sudden decrease or loss of hearing(a)
(a)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. In some of the cases, medical conditions and other factors were reported that may have also played a role in the ear and labyrinth adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of tadalafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors.
Once-a-Day Dosing:
Table 2: Adverse events reported by patients treated with Tadalafil 2.5-5 mg and more frequent on drug than placebo in phase 3 studies
| Event | Tadalafil (N=500) |
Placebo (N=248) |
| (%) | (%) | |
| Nasal congestion | 1.8 | 0 |
| Dyspepsia | 4.0 | 1.6 |
| Back pain Myalgia |
3.0 2.2 |
1.2 1.2 |
| Flushing | 2.0 | 0.8 |
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.
Adverse events identified from spontaneous post marketing surveillance
Body as a whole
Uncommon; hypersensitivity reactions including rash and urticaria
Rare; facial oedema
Frequency not known; Stevens-Johnson syndrome, and exfoliative dermatitis
Cardiac Disorders(b)
Uncommon; palpitations, tachycardia, chest pain
Rare; myocardial infarction
Frequency not known; unstable angina pectoris, ventricular arrhythmia, sudden cardiac death
(b) Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to determine whether these events are related directly to these factors, to tadalafil, to sexual activity, or to a combination of these or other factors.
Vascular Disorders
Uncommon; hypotension (more commonly reported when tadalafil is given to patients who are already taking antihypertensive agents), hypertension
Gastrointestinal
Common; abdominal pain
Uncommon; gastroesophageal reflux
Skin and subcutaneous tissue
Uncommon; hyperhidrosis (sweating)
Special senses
Uncommon; blurred vision
Rare; visual field defect
Frequency not known: non-arteritic anterior ischemic optic neuropathy (NAION), retinal vascular occlusion.
Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including CIALIS. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
Urogenital System
Rare; prolonged erection
Frequency not known; priapism, spontaneous penile erection
Nervous System
Very common; headache
Common; dizziness
Rare; stroke(b), migraine, syncope, transient ischemic attacks(b)
(b) Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to determine whether these events are related directly to these factors, to tadalafil, to sexual activity, or to a combination of these or other factors.
Respiratory System
Uncommon; epistaxis
Ear and labyrinth disorders
Very rare; sudden decrease or loss of hearing(a)
(a)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. In some of the cases, medical conditions and other factors were reported that may have also played a role in the ear and labyrinth adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of tadalafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors.
Interactions
CIALIS is not expected to cause clinically significant inhibition or induction of the clearance of medicines 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 is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (400 mg daily), increased tadalafil single-dose AUC by 312% and Cmax by 22%, and ketoconazole (200 mg daily), increased tadalafil single-dose AUC by 107% and Cmax by 15% relative to the AUC and Cmax values for tadalafil alone.
Ritonavir (200 mg twice daily), an inhibitor of CYP3A4, 2C9, 2C19, and 2D6, increased tadalafil single-dose AUC by 124% with no change in Cmax. Although specific interactions have not been studied, other HIV protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole and grapefruit juice would likely increase tadalafil exposure.
A selective CYP3A4 inducer, (rifampicin, 600 mg daily), reduced tadalafil single-dose AUC by 88% and Cmax by 46%, relative to the AUC and Cmax values for tadalafil 10mg alone. This reduced exposure can be anticipated to decrease the efficacy of once-a-day-dosed tadalafil; the magnitude of decreased efficacy is unknown. It can be expected that concomitant administration of other CYP3A4 inducers such as phenobarbital, phenytoin and carbamazepine would also decrease plasma concentrations of tadalafil.
Simultaneous administration of an antacid (magnesium hydroxide/aluminium hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil (10 mg).
An increase in gastric pH resulting from administration of nizatidine, an H2 antagonist, had no significant effect on tadalafil (10 mg) pharmacokinetics.
In clinical studies, tadalafil (10 mg) was shown to augment the hypotensive effects of nitrates. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is contraindicated (see CONTRAINDICATIONS).
In a crossover study, 12 healthy volunteers received a single dose of warfarin 25 mg after taking tadalafil 10mg or placebo once daily for 6 days. Tadalafil reduced the exposure (AUC) to R- and S- warfarin by 11% and 13 % respectively but did not alter the effect of warfarin on prothrombin time. (PT). The clinical implications of these findings are unclear. The possibility of and increase or decrease in PT and / or international normalised ratio (INR) should be considered when patients begin taking or cease taking tadalafil.
Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a similar increase may be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain
Tadalafil (10 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.
Tadalafil has systemic vasodilatory properties and may augment the blood pressure lowering effects of antihypertensive agents. Additionally, in patients taking multiple antihypertensive agents whose hypertension was not well controlled, greater reductions in blood pressure were observed. These reductions were not associated with hypotensive symptoms in the vast majority of patients. Appropriate clinical advice should be given to patients when they are treated with antihypertensive medications and CIALIS.
When initiating daily treatment with tadalafil, appropriate clinical considerations should be given to a possible dose adjustment of the antihypertensive therapy.
In two clinical pharmacology studies, no significant decreases in blood pressure were observed when tadalafil was co-administered to healthy subjects taking the selective alpha1A-adrenergic blocker, tamsulosin.
In three clinical pharmacology studies, when tadalafil was co-administered to healthy subjects taking doxazosin (4-8 mg daily), an alpha1-adrenergic blocker, there was an augmentation of the blood-pressure-lowering effect of doxazosin. The number of patients with potentially clinically significant standing-blood-pressure decreases was greater for the combination. In these clinical pharmacology studies there were symptoms associated with the decrease in blood pressure including syncope.
Caution is advised when PDE5 inhibitors are coadministered with nonselective alpha (α1)-blockers. PDE5 inhibitors, including CIALIS, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated.
In some patients, concomitant use of these two drug classes can lower blood pressure significantly, which may lead to symptomatic hypotension (e.g., fainting). Consideration should be given to the following;
- Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate haemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
- In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended dose.
- In those patients already taking an optimised dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.
- Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.
Tadalafil did not affect alcohol concentrations, and alcohol did not affect
tadalafil concentrations. At high doses of alcohol (0.7 g/kg), the addition of
tadalafil did not induce statistically significant mean blood pressure
decreases. In some subjects, postural dizziness and orthostatic hypotension
were observed. When tadalafil was administered with lower doses of alcohol
(0.6 g/kg), hypotension was not observed and dizziness occurred with similar
frequency to alcohol alone.
Due to the known interaction between tadalafil and nitrates or other nitric oxide donors on nitrogen monoxide/cGMP metabolism, patients must be expressly informed that they should never use recreational drugs called "poppers" or "amyl", typically taken through inhalation. These drugs represent various alkyl nitrites including amyl nitrite, butyl nitrite and isobutyl nitrite.
Tadalafil (10 mg) had no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline, a CYP1A2 substrate. The only pharmadynamic effect was a small (3.5 bpm) increase in heart rate.
Overdosage
Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses. In cases of overdose, standard supportive measures should be adopted as required. Haemodialysis contributes negligibly to tadalafil elimination.
In case of overdose, immediately contact the Poisons Information Centre (in Australia, call 13 11 26; in New Zealand call 0800 764 766) for advice.
Pharmaceutical Precautions
Precautions for Storage
Store below 25°C. Store in the original package.
Shelf Life
3 years.
Instructions for Use and Handling
No special requirements.
Medicine Classification
Prescription Medicine
Package Quantities
*CIALIS 2.5mg tablets are blister packed and are presented in cartons containing 28 tablets.
CIALIS 5 mg tablets are blister packed and are presented in cartons containing 28 tablets.
CIALIS 10 mg tablets are blister packed and are presented in cartons
containing 2*, 4 or 8* tablets.
CIALIS 20 mg tablets are blister packed and are presented in cartons
containing 2*, 4 or 8 tablets.
* not currently available in New Zealand
Further Information
Excipients
Tablet core: lactose monohydrate, croscarmellose sodium,
hydroxypropylcellulose, microcrystalline cellulose, sodium laurylsulphate,
magnesium stearate.
Film-coating: lactose monohydrate, hypromellose, triacetin, titanium dioxide
(E171), talc.
CIALIS 20 mg and 10 mg tablets also contain iron oxide yellow CI77492.
CIALIS 5 mg tablets also contain Opadry II complete film coating system Y-30-12863-A Yellow.
CIALIS 2.5mg tablets also contain Opadry II complete film coating system 32K12891 Yellow
Name and Address
Eli Lilly and Company (NZ) Limited
Level 3, Axon House,
414-422 Khyber Pass Road
Newmarket
PO Box 109 197
Newmarket, Auckland
NEW ZEALAND
Telephone (09) 523 9300
Date of Preparation
08 September 2008