Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: RELIGRA 25, 50 & 100 mg

Dosage form and strength: Film-coated Tablet and 25 mg, 50 mg & 100 mg

PROFESSIONAL INFORMATION FOR RELIGRA 25, 50 & 100 mg

SCHEDULING STATUS

S4

1 NAME OF THE MEDICINE

RELIGRA 25 mg

RELIGRA 50 mg

RELIGRA 100 mg

2 QUALITATIVE AND QUANTITAVE COMPOSITION

RELIGRA 25 mg: Each film coated tablet contains 35,12 mg of sildenafil citrate equivalent to

25 mg of sildenafil.

RELIGRA 50 mg: Each film coated tablet contains 70,24 mg of sildenafil citrate equivalent to

50 mg of sildenafil.

RELIGRA 100 mg: Each film coated tablet contains 140,48 mg of sildenafil citrate equivalent to

100 mg of sildenafil.

RELIGRA is sugar free.

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

RELIGRA 25 mg: Blue coloured round, biconvex, film coated tablets, debossed with 124 on one

side and J on the other side.

RELIGRA 50 mg: Blue coloured round, biconvex, scored film coated tablets, debossed with 125

on one side and J on the other side with score line.

RELIGRA 100 mg: Blue coloured round, biconvex, scored film coated tablets, debossed with 126

on one side and J on the other side with score line.

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Product proprietary name: RELIGRA 25, 50 & 100 mg

Dosage form and strength: Film-coated Tablet and 25 mg, 50 mg & 100 mg

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

RELIGRA is indicated only for the treatment of erectile dysfunction.

THIS PRODUCT IS NOT AN APHRODISIAC.

4.2 Posology and method of administration

Posology

Use in adults:

The recommended dose is 50 mg, taken as needed approximately one hour before sexual activity.

Based on efficacy and toleration, the dose may be increased to 100 mg or decreased to 25 mg.

The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is

once per day.

The following factors are associated with increased plasma levels of RELIGRA:

Age > 65 (40 % increase in AUC), hepatic impairment (e.g. cirrhosis, 80 %), severe renal

impairment (creatinine clearance < 30 mL/min, 100 %), and concomitant use of potent cytochrome

P450 3A4 inhibitors (erythromycin 182 %, saquinavir 210 %, ketoconazole, itraconazole, 200 %,

ritonavir 1 000 %).

Special populations

Use in patients with mild to moderately impaired renal function:

A starting dose of 25 mg should not be exceeded.

Use in patients with mild to moderately impaired hepatic function:

Since RELIGRA clearance is reduced in patients with hepatic impairment (e.g. cirrhosis), a starting

dose of 25 mg should not be exceeded.

Use in elderly patients:

Healthy elderly volunteers (65 years or over) had a reduced clearance of

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RELIGRA. A starting dose of 25 mg should be considered in patients older than

65 years of age.

Use in patients using potent CYP 3A4 inhibitors:

Given the extent of the interaction with patients receiving concomitant therapy with

cytochrome P450 3A4 inhibitors (e.g. ritonavir, erythromycin, saquinavir,

ketoconazole, itraconazole), RELIGRA should not be used concomitantly with these medicines

(see section 4.3).

RELIGRA was shown to potentiate the hypotensive effects of nitrates and its administration in

patients who use nitric oxide donors or nitrates in any form is therefore contraindicated

Use in children:

RELIGRA is not indicated for use in children.

Method of administration

RELIGRA tablets are for oral administration.

4.3 Contraindications

Hypersensitivity to sildenafil or to any of the excipients (see section 6.1).

•

Consistent with its known effects on the nitric oxide/cGMP pathway (see

section 5.1), RELIGRA was shown to potentiate the hypotensive effects

of acute and chronic nitrates, and its administration to patients who are

concurrently using nitric oxide donors, organic nitrates or organic nitrites

in any form either regularly or intermittently is therefore contraindicated.

The co-administration of PDE5 inhibitors, including sildenafil, with

guanylate cyclase stimulators, such as riociguat, is contraindicated as it

may potentially lead to symptomatic hypotension (see section 4.5).

•

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•

Concomitant use of RELIGRA with potent cytochrome P450 3A4

inhibitors e.g. ritonavir, erythromycin, saquinavir, ketoconazole and

itraconazole is contraindicated.

•

Medicines for the treatment of erectile dysfunction, including RELIGRA, should not be

used in men for whom sexual activity is inadvisable (e.g. patients with severe

cardiovascular disorders such as unstable angina or severe cardiac failure).

RELIGRA 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 section 4.4).

The use of RELIGRA is contraindicated in patients with severe hepatic impairment and

patients with severe impairment of renal function (creatinine clearance < 30 ml/min) not on

haemodialysis or continuous ambulatory peritoneal dialysis.

•

The safety of sildenafil has not been studied in the following sub-groups of patients and its

use is therefore contraindicated: hypotension (blood pressure < 90/50 mmHg), recent

history of stroke or myocardial infarction and known hereditary degenerative retinal

disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders

of retinal phosphodiesterases)

4.4 Special warnings and precautions for use

A thorough medical history and physical examination should be undertaken to diagnose erectile

dysfunction, determine potential underlying causes and identify appropriate treatment.

Cardiovascular risk factors

There is a potential for cardiac risk of sexual activity in patients with pre-

existing cardiovascular disease. Therefore, treatments for erectile

dysfunction, including RELIGRA, should not be generally used in men for

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Product proprietary name: RELIGRA 25, 50 & 100 mg

Dosage form and strength: Film-coated Tablet and 25 mg, 50 mg & 100 mg

whom sexual activity is inadvisable because of their underlying

cardiovascular status.

RELIGRA has systemic vasodilatory properties that resulted in transient decreases in supine

blood pressure in healthy volunteers. Clinical practitioners should carefully consider whether their

patients with underlying cardiovascular disease could be affected adversely by such vasodilatory

effects, especially in combination with sexual activity. Patients with increased susceptibility to

vasodilators include those with left ventricular outflow obstruction (e.g. aortic stenosis,

hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system

atrophy manifesting as severely impaired autonomic control of blood pressure.

RELIGRA potentiates the hypotensive effect of nitrates (see section 4.3).

Serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac

death, ventricular dysrhythmia, cerebrovascular haemorrhage, transient ischaemic attack,

hypertension and hypotension have been reported post-marketing in temporal association with the

use of RELIGRA. Most, but not all, of these patients had preexisting cardiovascular risk factors.

Many events were reported to occur during or shortly after sexual intercourse and a few were

reported to occur shortly after the use of RELIGRA without sexual activity. It is not possible to

determine whether these events are related directly to these factors or to other factors.

Priapism

Medicines for the treatment of erectile dysfunction, including RELIGRA, 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). ^{(1, 2}

)

Prolonged erections and priapism have been reported with sildenafil in post-marketing experience.

In the event of an erection that persists longer than 4 hours, the patient should seek immediate

medical assistance. If priapism is not treated immediately, penile tissue damage and permanent

loss of potency could result.

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Product proprietary name: RELIGRA 25, 50 & 100 mg

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Concomitant use with other PDE5 inhibitors or other treatments for erectile dysfunction

The safety and efficacy of combinations of sildenafil with other PDE5 inhibitors, or other

pulmonary arterial hypertension(PAH) treatments containing sildenafil (REVATIO), or other

treatments for erectile dysfunction have not been studied.

Therefore, the use of such combinations is not recommended.

Effects on vision

Cases of visual defects have been reported spontaneously in connection with the intake of

sildenafil and other PDE5 inhibitors (see section 4.8). Cases of non- arteritic anterior ischaemic

optic neuropathy, a rare condition, have been reported spontaneously and in an observational

study in connection with the intake of sildenafil and other PDE5 inhibitors (see section 4.8).

Patients should be advised that in the event of any sudden visual defect, they should stop taking

RELIGRA and consult a clinical practitioner immediately (see section 4.3).

Concomitant use with ritonavir

Co-administration of RELIGRA with ritonavir is contraindicated (see section 4.5).

Concomitant use with alpha-blockers

Caution is advised when sildenafil is administered to patients taking an alpha-

blocker, as the co-administration may lead to symptomatic hypotension in a few

susceptible individuals (see section 4.5). This is most likely to occur within 4 hours post sildenafil

dosing. In order to minimise the potential for developing postural hypotension, patients should be

hemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Initiation of

sildenafil at a dose of 25 mg should be considered (see section 4.2). In addition, clinical

practitioners should advise patients what to do in the event of postural hypotensive symptoms.

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Product proprietary name: RELIGRA 25, 50 & 100 mg

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Effect on bleeding

Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of

sodium nitroprusside in vitro. There is no safety information on the administration of sildenafil to

patients with bleeding disorders or active peptic ulceration. Therefore, RELIGRA should be

administered with caution to these patients.

Hearing loss

A sudden unilateral or bilateral decrease of loss of hearing (sensorineural deafness) with or

without associated vestibular symptoms has been reported with the use of PDE5 inhibitors,

including RELIGRA. There is insufficient information regarding the reversibility of the hearing loss

and the role of underlying risk factors for hearing loss in individual subjects.

Women

RELIGRA is not indicated for use by women

4.5 Interaction with other medicines and other forms of interaction

Effects of other medicines on sildenafil

In vitro studies:

Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major

route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil

clearance and inducers of these isoenzymes may increase sildenafil clearance.

In vivo studies:

Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil

clearance when co-administered with CYP3A4 inhibitors (such as

ketoconazole, erythromycin and cimetidine). Although no increased incidence of adverse events in

these patients, when sildenafil is administered concomitantly with CYP3A4 inhibitors, a starting

dose of 25 mg should be considered.

Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent

Initial:…………

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Product proprietary name: RELIGRA 25, 50 & 100 mg

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P450 inhibitor, at steady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in

a 300 % (4-fold) increase in sildenafil C_maxand a 1 000 % (11-fold) increase in sildenafil plasma

AUC. At 24 hours, the plasma levels of sildenafil were still approximately 200 ng/mL, compared to

approximately 5 ng/mL when sildenafil was administered alone. This is consistent with ritonavir’s

marked effects on a broad range of P450 substrates. Sildenafil had no effect on ritonavir

pharmacokinetics. Based on these pharmacokinetic results co-administration of sildenafil with

ritonavir is contraindicated (see section 4.3)

Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at

steady state (1 200 mg three times daily) with sildenafil (100 mg single dose) resulted in a 140 %

increase in sildenafil C_maxand a 210 % increase in sildenafil AUC. Sildenafil had no effect on

saquinavir pharmacokinetics (see section 4.2).

Stronger CYP3A4 inhibitors such as ketoconazole and itraconazole would be

expected to have greater effects.

When a single 100 mg dose of sildenafil was administered with erythromycin, a

moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there as a 182 %

increase in sildenafil systemic exposure (AUC). In normal healthy male volunteers, there was no

evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, C_max, t_max, elimination

rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite.

Cimetidine (800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, caused a 56

% increase in plasma sildenafil concentrations when co- administered with sildenafil (50 mg) to

healthy volunteers.

Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest

increases in plasma levels of sildenafil.

Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the

bioavailability of sildenafil.

Although specific interaction studies were not conducted for all medicines, population

pharmacokinetic analysis showed no effect of concomitant treatment on sildenafil

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Product proprietary name: RELIGRA 25, 50 & 100 mg

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pharmacokinetics when grouped as CYP2C9 inhibitors (such as tolbutamide, warfarin,

phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic

antidepressants), thiazide and related diuretics, loop and potassium sparing diuretics, angiotensin

converting enzyme inhibitors, calcium channel blockers, beta-adrenoreceptor antagonists or

inducers of CYP450 234 metabolism (such as rifampicin, barbiturates).

In a study of healthy male volunteers, co-administration of the endothelin antagonist, bosentan,

(an inducer of CYP3A4 [moderate], CYP2C9 and possibly of CYP2C19) at steady state (125 mg

twice a day) with sildenafil at steady state (80 mg three times a day) resulted in 62,6 % and 55,4

% decrease in sildenafil AUC and C_max, respectively. Therefore, concomitant administration of

strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma

concentrations of sildenafil

Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent

Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate

component it has the potential to result in a serious interaction with sildenafil.

Effects of sildenafil on other medicines

In vitro studies:

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6,

2E1 and 3A4 (IC50 >150 μM). Given sildenafil peak plasma concentrations of approximately 1 μM

after recommended doses, it is unlikely that RELIGRA will alter the clearance of substrates of

these isoenzymes. There are no data on the interaction of sildenafil and non-specific

phosphodiesterase inhibitors such as theophylline or dipyridamole.

In vivo studies:

Consistent with its known effects on the nitric oxide/cGMP pathway (see section

5.1), sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-

administration with nitric oxide donors or nitrates in any form is therefore contraindicated (see

section 4.3).

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Product proprietary name: RELIGRA 25, 50 & 100 mg

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Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5

inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment

the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of

the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors,

including sildenafil, is contraindicated (see section 4.3).

Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to

symptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4

hours post sildenafil dosing (see sections 4.2 and 4.4). In three specific interaction studies, the

alpha-blocker doxazosin (4 mg and 8 mg)

and sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign

prostatic hyperplasia (BPH) stabilized on doxazosin therapy

In these study populations, mean additional reductions of supine blood pressure of 7/7 mmHg, 9/5

mmHg and 8/4 mmHg, and mean additional reductions of standing blood pressure of 6/6 mmHg,

11/4 mmHg and 4/5 mmHg, respectively, were observed. When RELIGRA and doxazosin were

administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent

reports of patients who experienced symptomatic postural hypotension. These reports included

dizziness and light-headedness, but not syncope.

No significant interactions were shown when sildenafil (50 mg) was co-administered

with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.

Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by

acetyl salicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with

mean maximum blood alcohol levels of 80 mg/dL.

Pooling of the following classes of antihypertensive medication; diuretics, beta-

blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive medicines (vasodilator and

centrally-acting), adrenergic neurone blockers, calcium channel blockers and alpha-adrenoceptor

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blockers, showed no difference in the side effect profile in patients taking sildenafil compared to

placebo treatment.

In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in

hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8

mmHg. The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg.

These additional blood pressure reductions were of a similar magnitude to those seen when

sildenafil was administered alone to healthy volunteers. ⁽²⁾

Sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors,

saquinavir and ritonavir, both of which are CYP3A4 substrates.

In healthy male volunteers, sildenafil at steady state (80 mg three times a day) resulted in a 49,8

% increase in bosentan AUC and a 42 % increase in bosentan C_max(125 mg twice a day)

4.6 Fertility, pregnancy and lactation

RELIGRA is not indicated for use by women.

There are no adequate and well-controlled studies in pregnant or breast-feeding

women.

No relevant adverse effects were found in reproduction studies in rats and rabbits following oral

administration of sildenafil.

There was no effect on sperm motility or morphology after single 100 mg oral doses

of sildenafil in healthy volunteers.

4.7 Effects on ability to drive and use machines

RELIGRA may have a minor influence on the ability to drive and use machines.

As dizziness and altered vision were reported with in clinical trials with sildenafil, patients should

be aware how they react to RELIGRA before driving or operating machinery.

4.8 Undesirable effects

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MedDRA System Organ

Class

Frequency

Adverse Reactions

Rhinitis

Infections and infestations

Less frequent

Immune system disorders

Nervous system disorders

Hypersensitivity

Frequent

Headache, dizziness

Less frequent

Somnolence, hypoaesthesia,

cerebrovascular accident,

transient ischaemic attack,

syncope

Frequency

unknown

Frequent

Seizure, seizure recurrence

Eye disorders

Visual colour distortions, visual

disturbance, blurred vision

Lacrimation disorders, eye pain,

photophobia, photopsia, ocular

hyperaemia, visual brightness,

conjunctivitis, retinal

Less frequent

haemorrhage, arteriosclerotic

retinopathy, retinal disorder,

glaucoma, visual field defect,

diplopia, visual acuity reduced,

myopia, asthenopia, vitreous

floaters, iris disorder, mydriasis,

halo vision, eye oedema, eye

swelling, eye disorder,

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conjunctival hyperaemia, eye

irritation, abnormal sensation in

eye, eyelid oedema, scleral

discoloration

Frequency

unknown

Non-arteritic anterior ischaemic

optic neuropathy (NAION),

retinal vascular occlusion

Vertigo, tinnitus, deafness

Tachycardia, palpitations,

myocardial infarction, atrial

fibrillation, unstable angina

Sudden cardiac death,

ventricular dysrhythmia

Flushing, hot flush

Ear and labyrinth disorders Less frequent:

Cardiac disorders

Less frequent

Frequency

unknown

Vascular disorders

Frequent

Less frequent:

Frequent

Hypertension, hypotension,

Nasal congestion

Respiratory, thoracic and

mediastinal disorders

Less frequent

Epistaxis, sinus congestion,

throat tightness, nasal oedema,

nasal dryness

Gastrointestinal disorders

Frequent

Nausea, Dyspepsia

Less frequent

Gastro oesophageal reflux

disease, vomiting, abdominal

pain upper, dry mouth, oral

hypoesthesia

Skin and subcutaneous

tissue disorders

Less frequent

Rash

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Frequency

unknown

Stevens-Johnson Syndrome

(SJS), Toxic Epidermal

Necrolysis (TEN)

Musculoskeletal and

connective tissue

disorders

Less frequent

Myalgia, pain in extremity

Renal and urinary

disorders

Less frequent

Haematuria

Reproductive system and

breast disorders

Penile haemorrhage,

haematospermia,

increased erection

Priapism

Frequency

unknown

General disorders and

administration site

conditions

Less frequent

Chest pain, fatigue, feeling hot,

irritability

Investigations

Less frequent

Increased heart rate

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is

important. It allows continued monitoring of the benefit/risk balance of the medicine.

Health care providers are asked to report any suspected adverse reactions via the “6.04 Adverse

Drug Reactions Reporting Form”, found online under SAHPRA’s publications:

https://www.sahpra.org.za/Publications/Index/8

4.9 Overdose

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In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those

seen at lower doses, but the incidence rates and severities were increased. Doses of 200 mg did

not result in increased efficacy but the incidence of adverse reactions (headache, flushing,

dizziness, dyspepsia, nasal congestion, altered vision) was increased.

Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to

In cases of overdose, standard supportive measures should be adopted as required.

Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to

plasma protein and not eliminated in the urine.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals; Drugs used in erectile dysfunction. ATC

Code: G04B E03

Pharmacological classification: A 7.1.5 Vasodilators – peripheral

Sildenafil restores impaired erectile function by increasing blood flow to the penis, in

response to sexual stimulation. ⁽¹⁾

Sildenafil is a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is

responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant

effect on isolated human corpus cavernosum but enhances the relaxant effect of NO on this

tissue. When the NO/cGMP pathway is activated, during sexual stimulation, inhibition of PDE5 by

sildenafil results in increased corpus cavernosum levels of cGMP, producing smooth muscle

relaxation in the corpus cavernosum allowing the inflow of blood.

5.2 Pharmacokinetic properties

Absorption:

Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to

120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral

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bioavailability is approximately 40 % (range 25 – 63 %). The oral pharmacokinetics of sildenafil is

proportional over the recommended dose range (25 – 100 mg).

When sildenafil is taken with a high fat meal, the rate of absorption is reduced with a mean delay

in T_maxof 60 minutes and a mean reduction in C_maxof 29 %.

Distribution:

The mean steady state volume of distribution (V_ss) for sildenafil is 105 L, indicating distribution into

the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96 %

bound to plasma proteins. Protein binding is independent to total medicine concentrations. In healthy

volunteers receiving sildenafil (100 mg single dose), less than 0,0002 % (average 188 ng) of the

administered dose was present in ejaculate 90 minutes after dosing.

Biotransformation:

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route)

hepatic microsomal isoenzymes. The major circulating metabolite results from N- demethylation of

sildenafil. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency

for PDE5 approximately 50 % that of the parent compound. Plasma concentrations of this

metabolite are approximately 40 % of those seen for sildenafil. The N-desmethyl metabolite is

further metabolised, with a terminal half-life of approximately 4 hours.

Elimination:

The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half-life of 3 – 5

hours. After either oral or intravenous administration, sildenafil is excreted as metabolites

predominantly in the faeces (approximately 80 % of

administered oral dose) and to a lesser extent in the urine (approximately 13 % of administered

oral dose).

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Special patient groups:

Elderly:

Healthy elderly patients (65 years or over) had a reduced clearance of sildenafil, with free plasma

concentrations approximately 40 % greater than those seen in healthy younger volunteers (18 –

45 years).

Renal insufficiency:

In volunteers with mild (CLcr (creatinine clearance) = 50 – 80 ml/min) and moderate (CLcr = 30 –

49 ml/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) were

not altered. In volunteers with severe (CLcr ≤ 30 ml/min) renal impairment, sildenafil clearance

was reduced, resulting in increases in AUC (100 %) and C_max(88 %) compared to age-matched

volunteers with no renal impairment.

Hepatic insufficiency:

In volunteers with hepatic cirrhosis (Child-Pugh A and B) sildenafil clearance was reduced,

resulting in increases in AUC (84 %) and C_max(47 %) compared to age-matched volunteers with

no hepatic impairment.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

•

Calcium hydrogen phosphate anhydrous

Cellulose microcrystalline

Croscarmellose sodium

Magnesium stearate

Film coating – Opadry II blue 85F505164 (consists of polyvinyl alcohol-part hydrolyzed,

titanium dioxide, macrogol/PEG, talc, FD&C blue #2/indigo carmine aluminium lake, FD&C

blue #2/indigo carmine AL 3 % - 5 %) and purified water

Initial:…………

July 2024

Page 17 of 19

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: RELIGRA 25, 50 & 100 mg

Dosage form and strength: Film-coated Tablet and 25 mg, 50 mg & 100 mg

•

Clear coating – Opadry clear 02K19253 (consists of HPMC 2910/Hypromellose 5 cP and

triacetin) and purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

24 months

6.4 Special precautions for storage

•

Store at or below 25 ^oC.

Store the tablets in the blister until required for use.

This medicine does not require any special storage conditions.

6.5 Nature and contents of container

RELIGRA film coated tablets are packed in blister strips of clear transparent PVC forming film and

plain aluminium lidding foil, containing 4 film coated tablets per blister.

(Or)

Blister strips of clear transparent PVC/PVdC forming film and plain aluminium lidding foil,

containing 4 film coated tablets per blister.

Pack size: 4 film coated tablets per blister. 1 or 3 or 6 blisters packed in a box.

Blister packs are enclosed in an outer carton box.

6.6 Special precautions for disposal and other handling

No special requirements

Initial:…………

July 2024

Page 18 of 19

Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: RELIGRA 25, 50 & 100 mg

Dosage form and strength: Film-coated Tablet and 25 mg, 50 mg & 100 mg

7 HOLDER OF CERTIFICATE OF REGISTRATION:

Hetero Drugs South Africa (Pty) Ltd,

Waterfall Corporate

Campus, Building No.2,

First Floor, 74 Waterfall Drive,

Midrand, 2066

8 REGISTRATION NUMBERS

RELIGRA 25 mg: 47/7.1.5/1295

RELIGRA 50 mg: 47/7.1.5/12956

RELIGRA 100 mg: 47/7.1.5/12957

9 DATE OF FIRST AUTHORISATION

06 April 2022

10 DATE OF REVISION OF THE TEXT

03 July 2024

Initial:…………

July 2024

Page 19 of 19