Forzest, Generic Cialis Patient Information Sheet

For the use only of a Urologist/ Psychiatrist (endocrinologist, Dermatologist Venerologist)

FORZEST

(Tadalafil Tablets)

COMPOSITION FORZEST TABLETS 10 mg)

Each film coated tablet contains Tadalafil l0 mg

FORZESTTABLETS 20mg

Each film coated tablet contains Tadalafil 20 mg

DESCRIPTION

FORZEST Tablets contain tadalafil. a selective. reversible inhibitor of cyclic guanosine monophosphate [cGMP]-specific phosphodiesterase type 5 (PDE5) It is chemically designated as (6fl,12afl)-6-(1.3-benzodioxol-5-yt)-2-rnemyl-2.3.6,7 12,12a-hexahydropyrazino[1',2, t.6]pyrido(3,4-b)indole-1.4-dione The molecular formula of tadalafil is C22H19N3O4

PHARMACOLOGY

Tadalafil is a 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 revels of cGMP m 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

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, king, and cerebellum The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases Tadalafil is > 10.000-loW more potent for POE5 than for POE1, PDf 2 and POE4. enzymes which are found in the heart twain blood vessels, liver, 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 POE6. an enzyme which is found in the retin a and is responsible for photo transduction Tadalafil is also > 10.000-fold more potent for PDE 5 than for PDE7 through PDE10

Two clinical studies were conducted in 571 patients in an at-home setting to define the period of responsiveness to tadalafil Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 24 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 Sexual Encounter Profile (SEP) diary data collected in clinical studies supports this period of responsiveness and a statistically significant greater proportion of successful intercourse attempts associated with tadalafil treatment compared to placebo treatment up to and through the 12- to 14-hour interval following administration In these studies patients were free to choose the time interval between dose administration and the time of sexual attempts

Tadalafil administered lo healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0. 8 mmHg. respectively), in standing systolic and diastolic blood pressure (mean maximal decease of 0 2/4/6 mmHg. respectively), and no significant change in heart rate When tadalafil and certain oral anti hypertensive medications (including angiotesin II receptor blockers) were assessed in drug interaction studies, tadalafil did not result in clinically significant augmentation of the antihypertensive effects of those medications see Drug Interactions. However, appropriate clinical advice should be given to patients regarding the possibility of a decrease in blood pressure when they are treated with antihypertensive medications The administration of tadalafil to patients who are using any form of organic nitrate is contraindicated

In a study lo assess the effects ol tadalafil on vision, no impairment of colour discrimination (Hue/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 Across all clinical studies, reports of changes in colour vision were rare

(<0.1%).

Two studies were conducted in men to assess the potential effect of tadalafil 10 mg and 20 mg 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 10 mg tadalafil 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. 20 mg. tadalafil 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 20 mg ol tadalafil compared lo placebo The effects of longer-term daily dosing have not been established (see PRECAUTIONS, General and CarcinogenicityMutagenicity Impairment of Fertility) Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3.250 patients, including patients with erectile dysfunction of various severities (mild. moderate, severe), aetiologies, ages (range 21 -86 years), and ethnicities Most patients reported erectile dysfunction of at least 1 year m duration In the primary efficacy studies of general populations. 81 % of patients reported that tadalafil improved their erections as compared to 35% with placebo Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking tadalafil (86%. 63% and 72% for mild, moderate and severe, respectively, as compared to 45%, 42% and 19% with placebo) In the primary efficacy studies. 75% of Intercourse attempts were successful in tadalafll-treaied patients as compared to 32% with placebo

Pharmacokinetics

Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration Cmax is achieved al a median time of 2 hours after dosing Absolute bioavailiability of tadalafil following oral dosing has not been determined The rate and extent of absorption of tadalafil are not influenced by food, thus tadalafil 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

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

Less than 0 0005% of the administered dose appeared in the semen of healthy subjects

Tadalafil is predominantly metabolized by the cytochrome P450 (CYP) 3A4 isoform The major circulating

metabolite is the metnylcatechol 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

The mean oral clearance for tadalafil is 2 5 I/h and the mean half-life is 17 5 hours in healthy subjects Tadalafil

is excreted predominantly as inactive metabolites mainly in the feces (approximately 61% of the dose) and to

a lesser extent in the urine (approximately 36% of the dose)

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 Pharmacokinetics in Special Populations

Geriatric 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

Hepatic Impairment In clinical studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was comparable to exposure m healthy subjects when a dose of 10 mg was administered There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C) Therefore, for patients with mild or moderate hepatic impairment, the maximum dose should not exceed 10 mg. and use m patients with severe hepatic impairment is not recommended

Renal Insufficiency In clinical studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80 mL /min) or moderate {creatinine clearance 31 to 50 mL/min) renal insufficiency In subjects with end-stage renal disease on hemodialysis, there was a two-told increase in Cmax and 2 7- to 4.1 fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects wrth renal impairment, compared to those with normal renal function Hemodialysis (per formed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination In a clinical pharmacology study (N=28} at a dose of 10 mg. back pain was reported as a limiting adverse event in male patients with moderate renal impairment At a dose of 5 mg, the incidence and seventy of back pain was not significantly different than in the general population In patients on hemodialysis taking 10- or 20-mg tadalafil. there were no reported cases of back pain The dose of tadalafil should be limited to 5 mg not more than once daily in patients with severe renal insufficiency or end-stage renal disease A starting dose of 5 mg not more than once daily is recommended tor patients with moderate renal insufficiency, the maximum recommended dose is 10 mg not more than once in every 48 hours No dose adjustment is required in patients with mm renal insufficiency Patients with diabetes Tadalafil exposure (AUC) in patients with diabetes was approximately 19% tower than the AUC value for healthy subjects This difference in exposure does not warrant a dose adjustment.

INDICATIONS

FORZEST (tadalafil) tablets are indicated for the treatment of erectile dysfunction

DOSAGE AND ADMINISTRATION

In order for tadalafil to be effective, sexual stimulation is required Tadalafil is not indicated for use by women

For oral use

Use in adult men The recommended dose is 10 mg taken prior to anticipated sexual activity and without regard to food In those patients in whom FORZEST 10 mg does not produce an adequate effect 20 mg might be tried Tadalafil may improve erectile function up to 36 hours following dosing The maximum recommended dosing frequency is once per day

Dally use of the medication is strongly discouraged because the long-term safety after prolonged daily dosing has not been established see PRECAUTIONS. General

Use in elderly men Dosage adjustments are not required in elderly patients

Use in men with impaired renal function No dose adjustment is required in patients with mild renal insufficiency For patients with moderate (creatinine clearance 31 to 50 mL /min) renal insufficiency a starting dose of 5 mg not more than once daily is recommended, and the maximum dose should be limited to 10 mg not more than once in every 48 hours For patients with severe (creatinine clearance <30 ml/min) renal insufficiency on hemodialysis, the maximum recommended dose is 5 mg (see PRECAUTIONS andPharmacokinetics)

Use in men with impaired hepatic function for patients with mild or moderate degrees of hepatic impairment (Child-Pugh Class A or B), the dose of FORZEST should not exceed 10 mg once daily In patients with severe hepatic impairment (Child-Pugh Class C), the use of FORZEST is not recommended. see PRECAUTIONS and Pharmacokinetic

Use in men with diabetes Dosage adjustments are not required in diabetic patients

Use in children and adolescents FORZEST should not be used in individuals below 18 years of age

PRECAUTIONS

General

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.

Tadalafil should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anaemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulations cavernosal fibrosis or Peyronie's disease)

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FORZEST DESK

RANBAXY LABORATORIES LIMITED

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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 tadalafil is effective in patients with spinal cord injuries and patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy.

The safety and efficacy of combinations of tadalafil and other treatments for erectile dysfunction nave not been studied Therefore the use of such combinations is not recommended

In dogs given tadalafil daily tor 6 to 12 months at doses of 25 mg/kg, day (resuming in at least a 3 - fold greater exposure (range 3.7-18.6) than seen in humans at a 20 mg 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 PHARMACOLOGY The effects of longer-term daily dosing have not been established. Therefore, dairy use of the medication is strongly discouraged

Effects on ability to drive and use machines Tadalafil is expected lo have no or negligible Influence on the ability to drive and/or use machines. No specific studies have been performed to evaluate a potential affect Although the frequency of reports of dullness in placebo and Tadalafil arms in clinical wea was simitar, patients should be aware of now they react to Tadalafil before driving or operating machinery

Warnings

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of then patients. since there is a degree of cardiac risk associated with sexual activity Tadalafil has vasodilator properties, resulting m mild and transient decreases in blood pressure and as such potentiates the hypotensive effect of nitrates (see PHARMACOLOGY and Contraindications

Serious cardiovascular events, including myocardial infarction, unstable angina pectoris, ventricular arrhythmia, strokes, and transient ischaemic attacks occurred during clinical studies of tadalafil. In addition, hypertension and hypotension (including postural hypotension) were also seen infrequently in clinical trials Most of the patients in whom these events have been observed had pre-existing cardiovascular risk factors However, it is not possible to definitively determine whether these events are related directly to these risk factors

There is limited clinical data on the safety of tadalafil in the following groups, if prescribed, a careful individual benefit risk evaluation should be undertaken by the prescribing physician.

Tadalafil should be limited to 5 mg not more than once daily in patients with severe renal insufficiency or end-stage renal disease The starting dose of tadalafil in patients with a moderate degree of renal insufficiency should be 5 mg not more than once daily, and the maximum dose should be limited to 10 mg not more than once in every 48 hours. No dose adjustment is required in patients with mild renal insufficiency In patients with mid or moderate hepatic impairment, the dose of tadalafil should not exceed 10 mg Because or insufficient information in patients with severe hepatic impairment, use of tadalafil in this group is not recommended

Priapism was not reported in clinical trials with tadalafil However, priapism has been reported with another PDE5 inhibitor 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

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 FORZEST to patients who are using any form of organic nitrate is contraindicated.

Agents for the treatment of erectile dysfunction, including FORZEST. 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

The following groups of patients with cardiovascular disease were not included in clinical trials and the use of Tadalafil Is therefore contraindicated:

• Patients with 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 fast 6 months

- Patients with uncontrolled arrhythmias, hypotension (< 90 /50mmHg). or uncontrolled hypertension

• Patients with a stroke within the last 6 months

FORZEST should not be used in patients with hypersensitivity to tadalafil or to any of the excipients

Pregnancy

Tadalafil is not indicated for use by women There are no studies of tadalafil in pregnant women There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1000 mg/kg/day

Drug Interactions

Many of the interaction studies were conducted with 10 mg tadalafil. as indicated below With regard to those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out

Effects of other medicinal products on tadalafil: Tadalafil Is principally metabolized by CYP3A4 A selective inhibitor of CYP3A4. ketoconazole. increased tadalafil AUG by 107%. Relative to the AUG values for tadalafil alone (10 mg dose) Although specific interactions have not been studied, some protease inhibitors, such as ritonavir and saquinavir and other CYP3A4 inhibitors such as erythromycin, clarithromycin, itraconazole and grapefruit juice, should be co-administered with caution as they would be expected lo increase plasma concentrations of tadalafil Consequently the incidence of the undesirable effects might be increased The role of transporters (for example, p-glycoprotein) in the disposition of tadalafil is not known There is thus the potential of drug interactions mediated by inhibition of transporters

A CYP3A4 inducer, rifampicin. reduced tadalafil AUG by 88% relative to the AUC values for tadalafil alone (10 mg dose) It can be expected that concomitant administration of other CYP3A4 inducers, such as phenobarbital. phenytoin and carbamazepine will also decrease plasma concentrations ol tadalafil

Effects of tadalafil on other medicinal products. in clinical studies, tadalafil (10 mg ) was shown to augment the hypotensive effects of nitrates Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated (see Contraindications

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by CYP450 isoforms Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4.CYP1A2.CYP2D6 CYP2E1 andCYP2C9

Tadalafil (10 mg) had no clinically significant effect on exposure (AUC) to S-warafin or R-warafin (CYP2C9 substrate). nor did tadalafil affect changes in prothrombin time induced by warfarin. Tadalafil (10 mg ) did not potentiate the increase In bleeding time caused by acetylsalicylic acid In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of antihypertensive agents was examined Major classes of antihypertensive agents were studied, including calcium channel blockers (amlodipine) angiotensin converting enzyme (ACE) inhibitors (enalapril) beta-adrenergic receptor blockers (metoprol) thiazide diuretics (bendrofluazide), and angiotensin II receptor blockers (various types and doses, alone or m combination with thiazides calcium channel blockers, beta-blockers. and/or alpha blockers) Tadalafil (10 mg, except for studies with angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had no clinically significant interaction with any of these classes Tadalafil (10 and 20 mg) had no clinically significant effect on blood pressure changes due to Tamsulosin. an alpha-adrenergic receptor blocking agent. In patients receiving concomitant antihypertensive medications, tadalafil 20 mg may induce a blood pressure decrease, which is, in general, minor and not likely to be clinically relevant Analysis of Phase 3 clinical Dial data showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medications However appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medications

Alcohol concentrations (mean maximum blood concentration 0.06%) were not affected by co administration with tadalafil (10 mg) The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg) nor was the effect of alcohol on blood pressure augmented by tadalafil (20 mg) In addition no changes in tadalafil concentrations were seen 3 hours after co- administration with alcohol

Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol a smear increase may be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain

When tadalafil 10 mg was administered with theophylline (a non selective phosphodiesterase inhibitor) in a clinical pharmacology study there was no pharmacokinetic interaction The only pharmacodynamic edict was a small (3.5 bpm) increase in heart rate Although this effect is minor and was of no clinical significance in this study, it should be considered when co- administered these medications Specific interaction studies with anti diabetic agents were not conducted

Carcinogenicity; Mutagenicity/ Impairment of Fertility

Preclinical data reveal no special hazard tor humans based on conventional studies of safety pharmacology, genotoxicity. Carcinogenic potential, and toxicity to reproduction.

There was no evidence of teratogenicity, embryotoxicity or foetotoxicrty in rats or mice that received up to 1.000 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 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 (resulting in at least a 3-fold greater exposure (range 3.7-18.6) than seen in humans given a single 20 mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs (see PRECAUTIOUS. General and PHARMACOLOGY )

Adverse Reactions

The most commonly reported adverse reactions are headache and dyspepsia

Very common adverse reactions ( >1/10) Headache 14.5%. dyspepsia (12.3%)

Common adverse reactions (> 1/100. < 1/10): Dizziness (2 3%). flushing (4.1%), nasal congestion (4.3%), back pain (6.5%). myalgia (5.7%)

Swelling of eyelids, sensations described as eye pain and conjunctival hyperaemia are uncommon adverse reactions

The adverse events reported with tadalafil were transient, and generally mild or moderate Adverse-event data are limited In patients over 75 years of age

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

STORAGE

Store below 25C protected from moisture

SUPPLY

FORZEST TABLETS 20 mg Blister strip of 4's & carton of 4's

FORZEST TABLETS 10mg Blister strip ot 4's & carton of 4s

KEEP All MEDICINES OUT Of REACH Of CHILDREN.

REFERENCES

1 ABPI Compendium of Data Sheets and Summaries of Product Characteristics; CIAUS. Eli Lilly and Company Limited, 2003

2 US Prescribing, information for Cialis. Lilly ICOSLLC USA. November2003.

Information compiled in February 2004

MADE IN INDIA

RANBAXY

Laboratories

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FORZEST