Rectogesic 0.4% rectal ointment

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Glyceryl trinitrate
Available from:
CST Pharma Ltd
ATC code:
C05AE01
INN (International Name):
Glyceryl trinitrate
Dosage:
4mg/1gram
Pharmaceutical form:
Rectal ointment
Administration route:
Rectal
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 01070400; GTIN: 5055946803739

PAR Rectogesic 0.4% Rectal Ointment

UK/H/0823/001/MR

Public Assessment Report

Mutual Recognition Procedure

Rectogesic 0.4% Rectal Ointment

UK/H/0823/001/MR

UK licence no: PL 16508/0037

PROSTRAKAN LIMITED

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PAR Rectogesic 0.4% Rectal Ointment

UK/H/0823/001/MR

TABLE OF CONTENTS

Module 1: Information about initial procedure

Page 3

Module 2: Summary of Product Characteristics

Page 4

Module 3: Product Information Leaflets

Page 22

Module 4: Labelling

Page 24

Module 5: Scientific Discussion

Page 28

1 Introduction

2 Quality aspects

3 Non-clinical aspects

4 Clinical aspects

5 Overall conclusions

Module 6

Steps take after initial procedure

Not applicable

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Module 1

Product Name

Rectogesic 0.4% Rectal Ointment

Type of Application

Bibliographic, Article 10.1(a)(ii)

Active Substance

Glyceryl trinitrate

Form

Rectal Ointment

Strength

0.4% w/w

MA Holder

Prostrakan Limited, 3 Galabank Business Park, Queen Street,

Galashields, TD1 1QH, UK

RMS

CMS

Austria, Belgium, Czech Republic, Denmark, Finland, France,

Germany, Greece, Hungary, Ireland, Italy, Luxembourg, The

Netherlands, Norway, Poland, Portugal, Slovak Republic, Spain

and Sweden

Procedure Number

UK/H/0823/001/MR

Timetable

Day 90 – 21

March 2006

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Module 2

Summary of Product Characteristics

1.

NAME OF THE MEDICINAL PRODUCT

Rectogesic 4 mg/g Rectal Ointment.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Glyceryl trinitrate: 4 mg/g.

One gram of rectal ointment contains 40 mg Glyceryl trinitrate in propylene glycol corresponding to 4

mg Glyceryl trinitrate (GTN). The delivered dose from 375 mg of this formulation is approximately 1.5

mg GTN.

The ointment also contains 36 mg Propylene Glycol, and 140 mg Lanolin, per gram rectal ointment.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Rectal ointment.

Off-white smooth opaque ointment formulation.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Rectogesic 4 mg/g Rectal Ointment is indicated for relief of pain associated with chronic anal fissure.

In the clinical development of the drug, a modest effect has been shown on improvements in average

daily pain intensity (see Section 5.1).

4.2

Posology and method of administration

Route of administration: rectal use

Adults

A finger covering, such as cling film or a finger cot, may be placed on the finger to be used to

apply the ointment. (Finger cots to be obtained separately from local pharmacy or surgical

supplies retailer or cling film from local store.) The finger is placed along side a 2.5cm dosing

line which is provided on the outside carton in which Rectogesic is supplied, and a strip of

ointment the length of the line is expressed onto the end of the finger by gently squeezing the

tube. The amount of ointment expressed is approximately 375 mg (1.5 mg GTN). The covered

finger is then gently inserted into the anal canal to the distal interphalangeal joint of the finger

and applied circumferentially to the anal canal.

The dose delivered from the 4 mg/g ointment is 1.5 mg glyceryl trinitrate. The dose is to be

applied intra-anally every twelve hours. Treatment may be continued until the pain abates, up

to a maximum of 8 weeks.

Rectogesic should be used following conservative treatment failure for acute symptoms of anal

fissure.

Elderly

No specific information concerning the usage of Rectogesic in the elderly is available

Patients with Hepatic or Renal Impairment

No specific information concerning the usage of Rectogesic in patients with hepatic or renal

impairment is available

Children and Adolescents:

Rectogesic is not recommended for use in children and adolescents below 18 years of age due

to a lack of data on safety and efficacy.

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4.3

Contraindications

Hypersensitivity to the active substance “glyceryl trinitrate” or to any of the excipients or

idiosyncratic reactions to other organic nitrates.

Concomitant treatment with sildenafil citrate, tadalafil, vardenafil, and with nitric oxide (NO)

donors, such as other long-acting GTN products, isosorbide dinitrate and amyl or butyl-nitrite.

Postural hypotension, hypotension or uncorrected hypovolaemia as the use of glyceryl trinitrate

in such states could produce severe hypotension or shock.

Increased intracranial pressure (e.g. head trauma or cerebral haemorrhage) or inadequate

cerebral circulation.

Migraine or recurrent headache.

Aortic or mitral stenosis.

Hypertrophic obstructive cardiomyopathy.

Constrictive pericarditis or pericardial tamponade.

Marked anaemia.

Closed-angle glaucoma.

4.4

Special warnings and precautions for use

The risk/benefit ratio of Rectogesic has to be established on an individual basis. In some

patients, following treatment with Rectogesic, severe headache can occur. In some cases reevaluation

of the correct dosing is suggested. In patients where the risk benefit ratio is deemed

to be negative, treatment with Rectogesic should be withdrawn under the guidance of a

physician and other therapeutic or surgical interventions should be initiated.

Rectogesic should be used with caution in patients who have severe hepatic or renal disease.

Excessive hypotension, especially for prolonged periods of time, must be avoided because of

possible deleterious effects on the brain, heart, liver and kidney from poor perfusion and the

attendant risk of ischaemia, thrombosis and altered function of these organs. Patients should be

advised to change position slowly when changing from lying or sitting to upright to minimize

postural hypotension. This advice is particularly important for those patients with low blood

volume and under diuretic treatment. Paradoxical bradycardia and increased angina pectoris

may accompany glyceryl trinitrate-induced hypotension. The elderly may be more susceptible

to the development of postural hypotension, particularly on sudden rising. No specific

information concerning the usage of Rectogesic in the elderly is available.

Alcohol may enhance the hypotensive effects of glyceryl trinitrate.

If the physician elects to use glyceryl trinitrate ointment for patients with acute myocardial

infarction or congestive heart failure, careful clinical and haemodynamic monitoring must be

used to avoid the potential hazards of hypotension and tachycardia.

If bleeding associated with haemorrhoids increases, treatment should be stopped.

This formulation contains propylene glycol and lanolin which may cause skin irritations and skin

reactions (e.g. contact dermatitis).

If anal pain persists, differential diagnosis may be required to exclude other causes of the pain.

Glyceryl trinitrate can interfere with the measurement of catecholamines and vanilmandelic acid in urine

as it increases the excretion of these substances.

Concomitant treatment with a number of other medicinal products should be handled with

caution. Please refer to section 4.5 for specific information.

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4.5

Interaction with other medicinal products and other forms of interaction

Concomitant treatment with other vasodilators, calcium channel blockers, ACE inhibitors, beta blockers,

diuretics, anti-hypertensives, tricyclic anti-depressants and major tranquillisers, as well as the

consumption of alcohol, may potentiate the blood pressure lowering effects of Rectogesic. Therefore,

concomitant treatment with these medications should be carefully considered before treatment with

Rectogesic is initiated.

The hypotensive effect of nitrates are potentiated by concurrent administration of phosphodiesterase

inhibitors, e.g. sildenafil, tadalafil, vardenafil and theophylline. (see Section 4.3).

Rectogesic is contraindicated for concomitant treatment with, nitric oxide (NO) donors such as

isosorbide dinitrate and amyl or butyl-nitrite (see Section 4.3).

Acetyl cysteine may potentiate the vasodilatory effects of glyceryl trinitrate.

Concomitant treatment with heparin leads to a decrease in heparin efficacy. Close monitoring of blood

coagulation parameters is necessary and the dose of heparin has to be adapted accordingly. After

withdrawal of Rectogesic there may be an abrupt increase in PTT. In this case reduction of heparin

dosage may be necessary.

Concurrent administration of glyceryl trinitrate may cause a reduction of the thrombolytic activity of

alteplase.

Co-administration of Rectogesic with dihydroergotamine may increase the bioavailability of

dihydroergotamine and lead to coronary vasoconstriction. The possibility that the ingestion of

acetylsalicylic acid and non-steroidal anti-inflammatory drugs might diminish the therapeutic response to

Rectogesic cannot be excluded.

4.6

Pregnancy and lactation

Pregnancy:

There are no adequate data from the use of glyceryl trinitrate in pregnant women. Animal

studies are inconclusive with respect to effects on pregnancy embryonal/foetal parturition and postnatal

development (see Section 5.3). Rectogesic should not be used during pregnancy.

Lactation:

It is not known whether glyceryl trinitrate is excreted in human milk. Due to the potential

harmful effects on the breast fed child (see Section 5.3), the use of Rectogesic is not recommended

during breast feeding.

4.7

Effect on ability to drive and use machinery

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

Rectogesic may cause dizziness, light-headedness, blurred vision, headache or tiredness in some patients,

especially on first use. Patients should be cautioned about driving or operating machinery while using

Rectogesic.

4.8

Undesirable effects

In patients treated with Rectogesic 4 mg/g Rectal Ointment, the most common treatment related adverse

reaction was dose-related headache which occurred with an incidence of 57%.

Adverse reactions from clinical studies are displayed by system organ class in the table below. Within

the system organ class, the adverse reactions are listed by frequency using the following groupings: very

common (> 1/10), common (>1/100 <1/10), uncommon (>1/1000 <1/100).

System Organ Class

Frequency

Adverse Reaction

Nervous system disorder

Very common

Headache

Common

Dizziness

Gastrointestinal disorders

Common

Nausea

Uncommon

Diarrhoea, anal discomfort,

vomiting, rectal bleeding, rectal

disorder

Skin and subcutaneous tissue

disorders

Uncommon

Pruritus, anal burning and

itching

Cardiovascular system

disorders

Uncommon

Tachycardia

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Adverse reactions to glyceryl trinitrate 2% ointment (used in the prophylaxis of angina pectoris) are

generally dose-related and almost all of these reactions are the result of vasodilator activity. Headache,

which may be severe, is the most commonly reported side effect. In the Phase III clinical trials with

Rectogesic 4 mg/g Rectal Ointment the incidence of mild, moderate and severe headache was 18%, 25%

and 20%. Patients with a previous history of migraine or recurrent headache were at a higher risk of

developing headache during treatment (see Section 4.3). Headache may be recurrent with each daily

dose, especially at higher doses. Headache can be treated with mild analgesics e.g. paracetamol and in

general is reversible on discontinuation of treatment.

Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur.

Hypotension occurs infrequently, but in some patients may be severe enough to warrant discontinuation

of therapy. Syncope, crescendo angina and rebound hypertension have been reported but are uncommon.

Allergic reactions to glyceryl trinitrate are uncommon, and the great majority of those reported have been

cases of contact dermatitis or fixed drug eruptions occurring in patients receiving glyceryl trinitrate in

ointments or patches. There have been a few reports of genuine anaphylactoid reactions and these

reactions can probably occur in patients receiving glyceryl trinitrate by any route. Extremely rarely,

ordinary doses of organic nitrates have caused methaemoglobinaemia in normal–seeming patients. Flush

has been observed as a rare adverse reaction for other products containing glyceryl trinitrate.

4.9

Overdose

Accidental overdose of Rectogesic may result in hypotension and reflex tachycardia. No specific

antagonist of the vasodilator effects of nitroglycerin is known, and no intervention has been subjected to

controlled study as a therapy for nitroglycerin overdose. Because the hypotension associated with

nitroglycerin overdose is the result of venodilation and arterial hypovolaemia, prudent therapy in this

situation should be directed toward increasing central fluid volume. Passive elevation of the patient’s

legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.

In exceptional cases of severe hypotension or shock, resuscitation measures may be needed.

Excessive dosage may also give rise to methaemoglobinaemia. This should be treated with methylene

blue infusion.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: pending

ATC Code: pending

The principal pharmacologic action of glyceryl trinitrate is mediated via the release of nitric oxide. When

glyceryl trinitrate ointment is applied by the intra-anal route, the internal anal sphincter becomes relaxed.

Hypertonicity of the internal but not the external anal sphincter is a predisposing factor in the formation

of anal fissures. The blood vessels to the anoderm course through the internal anal sphincter (IAS).

Therefore hypertonicity of the IAS may thereby decrease blood flow and cause ischaemia to this region.

Distension of the rectum results in the anorector inhibitory reflex and relaxation of the internal anal

sphincter. The nerves mediating this reflex lie in the wall of the gut. Release of the neurotransmitter NO

from nerves of this type play a significant role in the physiology of the internal anal sphincter.

Specifically, NO mediates the anorector inhibitory reflex in man, relaxing the IAS.

The link between IAS hypertonicity and spasm and the presence of an anal fissure has been established.

Patients with chronic anal fissure have a significantly higher mean maximum resting anal pressure than

controls and anodermal blood flow in chronic anal fissure patients was significantly lower than in

controls. In patients whose fissures healed following a sphincterotomy, a reduction in anal pressure and

improvement in anodermal blood flow was demonstrated, providing further evidence for the ischaemic

nature of anal fissure. Topical application of a NO donor (glyceryl trinitrate) relaxes the anal sphincter,

resulting in a reduction of anal pressure and an improvement in anoderm blood flow.

Effect on pain

In three Phase III clinical trials Rectogesic 4 mg/g Rectal Ointment has been shown to improve the

average daily pain intensity associated with chronic anal fissure compared with placebo, measured using

a 100mm visual analogue scale. In the first study, Rectogesic 4 mg/g Rectal Ointment decreased average

daily pain intensity over 21 days by 13.3mm (baseline 39.2mm) compared to 4.3mm (baseline 25.7mm)

for placebo (p<0.0063) and over 56 days by 18.8mm compared to 6.9mm (p<0.0001), respectively. This

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corresponds to a treatment effect (difference between the percentage change for Rectogesic and placebo)

of 17.2% over 21 days and 21.1% over 56 days. In the second study, Rectogesic 4 mg/g Rectal Ointment

decreased average daily pain intensity over 21 days by 11.1mm (baseline 33.4mm) compared to 7.7mm

(baseline 34.0mm) for placebo (p<0.0388) and over 56 days by 17.2mm compared to 13.8mm

(p<0.0039), respectively. This corresponds to a treatment effect of 10.6% over 21 days and 10.9% over

56 days. In the third study, Rectogesic 4 mg/g Rectal Ointment decreased average daily pain intensity

over 21 days by 28.1mm (baseline 55.0mm) compared to 24.9mm (baseline 54.1mm) for placebo

(p<0.0489) and over 56 days by 35.2mm compared to 33.8mm (p<0.0447), respectively. This

corresponds to a treatment effect of 5.1% over 21 days and 1.5% over 56 days.

Effect on healing

In all three studies, healing of anal fissures in patients treated with Rectogesic 4 mg/g Rectal Ointment

was not statistically different from placebo. Rectogesic is not indicated for healing of chronic anal

fissure.

5.2

Pharmacokinetic properties

The volume of distribution of glyceryl trinitrate is about 3 L/kg and is cleared from this volume at

extremely rapid rates, with a resulting serum half-life of about 3 minutes. The observed clearance rates

(close to 1 L/kg/min) greatly exceed hepatic blood flow. The known sites of extrahepatic metabolism

include red blood cells and vascular walls. The initial products in the metabolism of glyceryl trinitrate

are inorganic nitrate and the 1,2 and 1,3-dinitroglycerols. The dinitrates are less effective vasodilators

than glyceryl trinitrate, but they are longer lived in the serum. Their contribution to the relaxation of the

internal anal sphincter is unknown. The dinitrates are further metabolised to non-vasoactive mononitrates

and ultimately to glycerol and carbon dioxide. In six healthy subjects, the average bioavailability of

glyceryl trinitrate applied to the anal canal as a 0.2% ointment was approximately 50% of the 0.75 mg

dose.

5.3

Pre-clinical safety data

Repeat Dose Toxicity

No systemic toxicity studies have been conducted with Rectogesic. Published data suggest that high oral

doses of glyceryl trinitrate may have toxic effects (methaemoglobinaemia, testicular atrophy and

aspermatogenesis) in long term treatment. However, these findings represent no special hazards for

humans under the conditions of therapeutic use.

Mutagenicity and carcinogenicity

Data from preclinical studies with GTN indicate genotoxic effects in the repair deficient S. typhimurium

strain TA1535 only and carcinogenic effects. However, an increased carcinogenic risk under the

conditions of therapeutic use is considered very unlikely.

Reproductive Toxicity

Reproductive toxicity studies, in rats and rabbits with intravenous, intraperitoneal, and dermal

administration of glyceryl trinitrate did not show any adverse effects on fertility or embryonic

development at dosages which did not induce parental toxicity. No teratogenicity had been observed. In

rats foetotoxic effects (decreased birth weights) were seen at dosages above 1 mg/kg/d (i.p.) and 28

mg/kg/d (dermal) after in utero exposure during foetal development.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Propylene glycol

Lanolin

Sorbitan sesquioleate

Hard paraffin

White soft paraffin

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years

After first opening : 8 weeks

6.4

Special precautions for storage

Do not store above 25°C.

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Do not freeze.

Keep the tube tightly closed.

6.5

Nature and contents of container

30 g

Aluminium tubes with white polyethylene non-piercing screw caps

6.6

Special Precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

Prostrakan Limited,

3 Galabank Business Park,

Queen Street,

Galashields,

TD1 1QH,

8.

MARKETING AUTHORISATION NUMBER

PL 16508/0037

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

August 2004

10.

DATE OF (PARTIAL) REVISION OF THE TEXT

21/12/2006

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Module 3

Product Information Leaflet

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