4.1. Therapeutic indications

Rectogesic 4 mg/g Rectal Ointment is indicated in adults 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 (over 65 years):

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.

4.3. Contraindications

Hypersensitivity to the active substance “glyceryl trinitrate” or to any of the excipients listed in section 6.1 or to other organic nitrates.

Concomitant treatment with phosphodiesterase type 5 (PDE5) inhibitors e.g sildenafil citrate, tadalafil, vardenafil and other organic nitrates 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 re-evaluation 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 cardiac disorders e.g. 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.

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 organic nitrates are potentiated by concurrent administration of phosphodiesterase type 5 (PDE5) inhibitors, e.g. sildenafil, tadalafil and vardenafil (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 of intravenous glyceryl trinitrate with intravenous 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 intravenous glyceryl trinitrate and alteplase 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 alter the therapeutic response to Rectogesic cannot be excluded.

4.6. Fertility, pregnancy and lactation

Fertility: There are no data available on the effect of Rectogesic on fertility in humans. Studies in rats suggest no particular hazard under recommended conditions of use (see Section 5.3).

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. Effects on ability to drive and use machines

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

Adverse reactions to glyceryl trinitrate 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 is reversible on discontinuation of treatment.

Rare cases of orthostatic hypotension-type events associated with symptoms of vertigo and dizziness were reported in clinical trials. There was no discernible dose-related trend in the incidence of these events.

The orthostatic hypotension-type event was of mild intensity in the majority of these patients, and there were no severe orthostatic hypotension-type events reported during the Phase III clinical studies.

Dizziness and vertigo contributed to the discontinuation of glyceryl trinitrate in a few cases.

Post-marketing Experience

Because these reactions are received from spontaneous reporting, the frequency is not known (cannot be estimated from the available data).

Nervous system disorders: Lightheadedness, syncope

Vascular disorders: Hypotension, orthostatic hypotension

Immune system disorders: Hypersensitivity, anaphylactoid reaction

General disorders and administration site conditions: Application site irritation, application site rash, application site pain

Lightheadedness and hypotension (including orthostatic hypotension) in some patients may be severe enough to warrant discontinuation of therapy.

Class effects

Extremely rarely, ordinary doses of organic nitrates have caused methaemoglobinaemia in normal–seeming patients. Flushing, unstable angina and withdrawal hypertension may also occur.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Accidental overdose of Rectogesic may result in hypotension and reflex tachycardia. No specific antagonist of the vasodilator effects of glyceryl trinitrate is known, and no intervention has been subjected to controlled study as a therapy for glyceryl trinitrate overdose. Because the hypotension associated with glyceryl trinitrate 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.