Aphthaseal

Aphthaseal HEXACETONIDE is indicated for intraarticular, intrasynovial or periarticular use in adults and adolescents for the symptomatic treatment of subacute and chronic inflammatory joint diseases including:

- Rheumatoid arthritis

- Juvenile Idiopathic Arthritis (JIA)

- Osteoarthritis and post-traumatic arthritis

- Synovitis, tendinitis, bursitis and epicondylitis

Aphthaseal HEXACETONIDE may also be used for the intraarticular use in children aged 3 - 12 years with Juvenile Idiopathic Arthritis (see Posology below).

Aphthaseal Allergy or Triamcinolone Nasal Spray is indicated for the treatment of the symptoms of seasonal allergic rhinitis.

Posology

Intraarticular injection (dosage for adults and adolescents) for all indications

The dose 2-20 mg is determined individually according to the size of the joint and the amount of articular fluid. Large joints (e.g. hip, knee, shoulder) generally require 10-20 mg (0.5-1 ml), medium-sized joints 5-10 mg (0.25-0.5 ml), and smaller joints 2-6 mg (0.1-0.3 ml). If there is a lot of articular fluid, it can be aspirated prior to administration of the drug. The next dose and the number of injections depend on the progress of the clinical condition. Because Aphthaseal HEXACETONIDE is long-acting, administration of injections into individual joints more frequently than at 3-4 week intervals is not recommended. Accumulation of the drug at the injection site must be avoided, because it may cause atrophy.

Dosage for intraarticular use in children aged 3 - 12 years with Juvenile Idiopathic Arthritis

The dosage regime for Aphthaseal hexacetonide intraarticular injection for JIA in children is 1 mg/kg for large joints (knees, hips, and shoulders) and 0.5 mg/kg for smaller joints (ankles, wrists, and elbows). For the hands and feet, 1-2 mg/joint for metacarpophalangeal/metatarsophalangeal (MCP/MTP) joints, and 0.6-1 mg/joint for proximal interphalangeal (PIP) joints may be used.

Periarticular injection (dosage for adults and adolescents only)

Bursitis/Epicondylitis: Generally 10-20 mg (0.5-1 ml) depending on the size of the bursa and the severity of the disease. In the majority of cases a single treatment is sufficient.

Synovitis/Tendinitis: Generally 10-20 mg (0.5-1 ml). The need for additional injections should be determined on the basis of response to treatment.

Method of administration

Asepsis must be observed in the use of this product. The vial should be shaken carefully before use to ensure suspension. The injection site should be sterilised using the same technique as with lumbar puncture.

At each treatment session, an injection may be given into two joints at the most. Do not administer in unstable joints.

This formulation is intended for intraarticular, periarticular and intrasynovial use, and must not be used for intravenous, intraocular, epidural or intrathecal use.

Precautions to be taken before handling or administering the medicinal product

Patients aged 18 years and over: The recommended dose is 220 micrograms as 2 sprays in each nostril once daily. Once symptoms are controlled patients can be maintained on 110 micrograms (1 spray in each nostril once daily). The minimum effective dose should be used to ensure continued control of symptoms.

Children: not recommended for children or adolescents under 18 years of age.

Medical advice should be sought if symptoms worsen or persist after 14 days treatment.

It is important to shake the bottle gently before each use.

Each actuation delivers 55 micrograms triamcinolone acetonide from the nasal actuator to the patient (estimated from in vitro testing) after an initial priming of 5 sprays until a fine mist is achieved. Aphthaseal Allergy Nasal Spray will remain adequately primed for 2 weeks. If the product is unused for more than 2 weeks, then it can be adequately re-primed with one spray. The nozzle should be pointed away from you while you are doing this.

After using the spray: Wipe the nozzle carefully with a clean tissue or handkerchief, and replace the cap.

If the spray does not work and it may be blocked, clean it as follows. NEVER try to unblock it or enlarge the tiny spray hole with a pin or other sharp object because this will destroy the spray mechanism.

The nasal spray should be cleaned at least once a week or more often if it gets blocked.

TO CLEAN THE SPRAY

1. Remove the cap and the spray nozzle only* (pull off).

2. Soak the cap and spray nozzle in warm water for a few minutes, and then rinse under cold running tap water.

3. Shake or tap off the excess water and allow to air-dry.

4. Re-fit the spray nozzle.

5. Prime the unit as necessary until a fine mist is produced and use as normal.

* Part as indicated on diagram below,

Also, the bottle should be discarded after 30 actuations or within one month of starting treatment. Do not transfer any remaining suspension to another bottle.

This medicinal product must not be administered to infants born recently or prematurely because it contains benzyl alcohol. It may provoke toxic and anaphylactoid reactions in children under 3 years of age, and so should not be used in infants and children up to 3 years of age.

Aphthaseal HEXACETONIDE is contraindicated in the case of:

- active tuberculosis

- herpes simplex keratitis,

- acute psychoses,

systemic mycoses and parasitoses (strongyloid infections).

Hypersensitivity to any of the ingredients of this preparation or an infection in the nose contraindicates its use.

This product contains a potent glucocorticoid and so should be used with caution in patients suffering from the following conditions:

- cardiac insufficiency, acute coronary artery disease,

- hypertension,

- thrombophlebitis, thromboembolism

- myasthenia gravis,

- osteoporosis,

- gastric ulcer, diverticulitis, ulcerative colitis, recent intestinal anastomosis,

- exanthematous diseases,

- psychosis,

- Cushing's syndrome,

- diabetes mellitus,

- hypothyroidism,

- renal insufficiency, acute glomerulonephritis, chronic nephritis,

- cirrhosis,

- infections that cannot be treated with antibiotics,

- metastatic carcinoma.

All corticosteroids may increase calcium excretion.

The product must not be administered intravenously, intraocularly, epidurally or intrathecally.

Intra-articular injection should not be carried out in the presence of active infection in or near joints. The preparation should not be used to alleviate joint pain arising from infectious states such as gonococcal or tubercular arthritis.

The load on strained joints in particular should be lightened immediately after the injection to avoid overloading. Repeated injections may damage the joint. Severe joint destruction with necrosis of bone may occur if repeated intra-articular injections are given over a long period of time.

Undesirable effects may be minimised using the lowest effective dose for the minimum period. Frequent patient review is required to titrate the dose appropriately against disease activity (see 4.2).

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Withdrawal of corticosteroids after prolonged therapy must, therefore, always be gradual to avoid acute adrenal insufficiency and should be tapered off over weeks or months according to the dose and duration of treatment. During prolonged therapy any intercurrent illness, trauma or surgical procedure may require a temporary increase in dosage. If corticosteroids have been stopped following prolonged therapy they may need to be reintroduced temporarily.

Patients should carry steroid treatment cards, as appropriate, which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

Patients should not be vaccinated or immunized with live vaccines while they are under treatment with moderate or high dose corticosteroids for longer than 2 weeks treatment, since a possible lack of an antibody response may predispose to medical, and particularly neurological, complications. Intraarticular and periarticular corticosteroid use, or steroids given for less than 2 weeks, or in a long-term regular dosage of 10 mg daily are not considered a contraindication to use of live vaccines.

If, during treatment, the patient develops serious reactions or acute infections, the treatment must be stopped and appropriate treatment given.

Caution should be used in the event of exposure to chickenpox, measles or other communicable diseases, since the course of specific viral diseases such as chickenpox and measles may be particularly severe in patients treated with glucocorticoids. At particular risk are immunocompromised (immunosuppressed) children and individuals with no history of chickenpox or measles infection. If such individuals should come into contact with chickenpox or measles sufferers during treatment with Aphthaseal HEXACETONIDE, prophylactic treatment should be considered as appropriate.

Menstrual irregularities may occur and in postmenopausal women vaginal bleeding has been observed. This possibility should be mentioned to female patients but should not deter appropriate investigations as indicated.

Co-administration of Aphthaseal hexacetonide with CYP3A4 inhibitors is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. If the potential benefit of co-administration outweighs the increased risk of systemic corticosteroid side-effects, patients should be monitored for these effects.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Paediatric population

It is recommended to monitor growth and development of children on prolonged corticosteroid therapy.

This medicinal product must not be administered to infants born recently or prematurely because it contains benzyl alcohol. It may provoke toxic and anaphylactoid reactions in children under 3 years of age.

Benzyl alcohol has been linked to severe adverse reactions and death, especially in paediatric patients. Exposure to excessive quantities of benzyl alcohol has been linked to toxicity (hypotension and metabolic acidosis), especially in neonates, and to an increased incidence of kernicterus, mainly in premature infants. There have been rare cases of death, mainly in premature infants, linked to exposure to excessive quantities of benzyl alcohol.

“Gasping Syndrome” has been linked to benzyl alcohol. Although normal therapeutic doses of this product release substantially lower quantities of benzyl alcohol than those associated with “Gasping Syndrome”, the minimum quantity of benzyl alcohol capable of producing toxicity is not known. Premature and low-birth-weight infants, as well as patients taking high doses, are more likely to develop toxicity.

Aphthaseal HEXACETONIDE contains sorbitol. Patients with very rare hereditary problems of fructose intolerance should not take this medicine.

If there is any reason to suppose that adrenal function is impaired, care must be taken while transferring patients from systemic steroid treatment to Aphthaseal Allergy or Triamcinolone Nasal Spray. Patients taking steroids should consult their doctor before using this product.

In clinical studies with Aphthaseal Allergy or Triamcinolone Nasal Spray administered intranasally, the development of localised infections of the nose and pharynx with Candida albicans has rarely occurred. When such an infection develops it may require treatment with appropriate local therapy and discontinuation of treatment with Aphthaseal Allergy or Triamcinolone Nasal Spray.

Because of the inhibitory effect of corticosteroids on wound healing, patients who have had recent nasal surgery or recent prolonged nose-bleeds or any other nasal problems should consult their doctor before using this product.

Systemic effects of nasal corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Potential systemic effects may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

Treatment with higher than recommended doses may result in clinically significant adrenal suppression. If there is evidence of using higher than recommended doses then additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

This product should not be used for longer than 3 months without consulting a doctor.

Glaucoma and/or cataracts have been reported in patients receiving nasal corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma and/or cataracts.

Aphthaseal HEXACETONIDE has no or negligible influence on the ability to drive and use machines.

Aphthaseal Allergy or Triamcinolone Nasal Spray has no known effect on the ability to drive and operate machines.

For assessment of adverse reactions (ADRs) following terms regarding frequency are used:

not known (cannot be estimated from the available data)

Adverse effects depend on the dose and the duration of treatment. Systemic adverse effects are rare, but may occur as a result of repeated periarticular injection. As with other intraarticular steroid treatments, transient adrenocortical suppression has been observed during the first week after injection. This effect is enhanced if corticotropin or oral steroids are used concomitantly.

Immune system disorders

Very rare: anaphylaxis-type reactions

Not known: exacerbation or masking of infections

Endocrine disorders

Not known: menstrual irregularities, amenorrhoea and postmenopausal vaginal bleeding; hirsutism; development of a cushingoid state; secondary adrenocortical and pituitary unresponsiveness, particularly during periods of stress (e.g. trauma, surgery or illness); decreased carbohydrate tolerance; manifestation of latent diabetes mellitus

Psychiatric disorders

Not known: insomnia; exacerbation of existing psychiatric symptoms; depression (sometimes severe); euphoria; mood swings; psychotic symptoms

Nervous system disorders

Rare: vertigo

Not known: increased intracranial pressure with papilloedema (pseudotumor cerebri) usually after treatment; headache

Eye disorders

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Cardiac disorders

Not known: cardiac failure; arrhythmias

Vascular disorders

Very rare: thromboembolism

Not known: hypertension

Gastrointestinal disorders

Not known: peptic ulcers with possibility of subsequent perforation and haemorrhage; pancreatitis

Skin and subcutaneous tissue disorders

Very rare: hyperpigmentation or hypopigmentation

Not known: impaired wound healing; thin and fragile skin; petechiae and ecchymoses; facial erythema; increased sweating; purpurea; striae; acneiform eruptions; hives; rash

Musculoskeletal and connective tissue disorders

Very rare: calcinosis; tendon rupture

Not known: loss of muscle mass; osteoporosis; aseptic necrosis of the heads of the humerus and femur; spontaneous fractures; Charcot-like arthropathy

Renal and urinary disorders

Not known: negative nitrogen balance owing to protein catabolism

General disorders and administration site conditions

Common: Local reactions include sterile abscesses, post-injection erythema, pain, swelling and necrosis at the injection site.

Rare: Excess dosage or too-frequent administration of injections into the same site may cause local subcutaneous atrophy, which, due to the properties of the drug, will only return to normal after several months.

Paediatric population

Glucocorticoids may induce growth suppression in children.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The adverse events reported in clinical trials with Aphthaseal Allergy or Triamcinolone Nasal Spray most commonly involved the mucous membranes of the nose and throat.

The following frequency rating has been used, when applicable:

Very common > 10%; Common > 1 and < 10%; Uncommon > 0.1 and < 1%; Rare > 0.01 and < 0.1%; Very rare < 0.01% and not known (frequency cannot be estimated from available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The most frequent adverse reactions in adults were:

- Infections and infestations

Common: flu syndrome, pharyngitis, rhinitis

- Immune system disorders

Not known: hypersensitivity (including rash, urticaria, pruritus and facial oedema)

- Psychiatric disorders

Not known: insomnia

- Nervous system disorders

Common: headache

Not known: dizziness and alterations of taste and smell

- Eye disorders

Not known: cataract, glaucoma, increased ocular pressure

- Respiratory, thoracic and mediastinal disorders

Common: bronchitis, epistaxis, cough

Rare: nasal septum perforations

Not known: nasal irritation, dry mucous membrane, nasal congestion, sneezing, dyspnoea

- Gastrointestinal disorders

Common: dyspepsia, tooth disorder

Not known: nausea

- General disorders and administration site conditions

Not known: fatigue

- Investigations

Not known: decreased blood cortisol

Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods.

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 at: www.mhra.gov.uk/yellowcard

Excess dosage or too-frequent administration of injections into the same site may cause local subcutaneous atrophy. If this occurs, recovery may take several months due to the long-term effect of the drug.

Like any other nasally administered corticosteroid, acute overdosing with Aphthaseal Allergy or Triamcinolone Nasal Spray is unlikely in view of the total amount of active ingredient present. In the event that the entire contents of the bottle were administered all at once, via either oral or nasal application, clinically significant systemic adverse events would most likely not result. The patient may experience some gastrointestinal upset if taken orally.

Pharmacotherapeutic group: Corticosteroids for systemic use, glucocorticoids

ATC code: H02AB08

Mechanism of action

The mode of action of glucocorticoids is not fully known, but local injections are thought to have an anti-inflammatory effect.

Pharmacodynamic effects

Aphthaseal HEXACETONIDE is a synthetic glucocorticoid with pronounced anti-inflammatory activity. The product is a microcrystalline water suspension with a depot effect.

The anti-inflammatory potency of Aphthaseal on a milligram by milligram comparison is approximately five times that of hydrocortisone. Triaminolone has practically no mineralocorticoid effect, so no sodium retention occurs.

Paediatric population

The efficacy and safety of Aphthaseal hexacetonide in children and adolescents are based on the well-researched effects of glucocorticoids, which are the same in children and adults. Published studies and current therapeutic guidelines for treatment of Juvenile Idiopathic Arthritis (JIA) indicate efficacy and safety in children and adolescents for the treatment of JIA.

Pharmacotherapeutic group: nasal corticosteroid, ATC code: R 01 AD

Triamcinolone acetonide is a more potent derivative of triamcinolone and is approximately 8 times more potent than prednisone. Although the precise mechanism of corticosteroid anti-allergic action is unknown, corticosteroids are very effective in the treatment of allergic diseases in man.

Aphthaseal Allergy or Triamcinolone Nasal Spray does not have an immediate effect on allergic signs and symptoms. An improvement in some patient symptoms may be seen within the first day of treatment with Aphthaseal Allergy or Triamcinolone Nasal Spray and relief may be expected in 3 to 4 days. When Aphthaseal Allergy or Triamcinolone Nasal Spray is prematurely discontinued symptoms may not recur for several days.

In clinical studies performed in adults and children at doses up to 440 mcg/day intranasally, no suppression of the Hypothalamic-Pituitary-Adrenal (HPA) axis has been observed.

The hexacetonide ester is almost insoluble in water, so dissolution is slow and the effect in the tissue of the injection site lasts for a long time, from a few weeks to several months. Generally, the onset of effect after Aphthaseal HEXACETONIDE administration occurs after 24 hours and normally lasts for 4 to 6 weeks.

Aphthaseal hexacetonide is hydrolysed by human serum in vitro (43% hydrolysed after 24 hours), but following intra-articular injection, the substance does not disperse in situ.

Single dose intranasal administration of 220 micrograms of Aphthaseal Allergy or Triamcinolone Nasal Spray in normal adult subjects and in adult patients with allergic rhinitis demonstrated minimal absorption of triamcinolone acetonide. The mean peak plasma concentration was approximately 0.5 ng/mL (range 0.1 to 1 ng/mL) and occurred at 1.5 hours post dose. The mean plasma drug concentration was less than 0.06 ng/mL at 12 hours and below the assay detection limit at 24 hours. The average terminal half life was 3.1 hours. Dose proportionality was demonstrated in normal subjects and in patients following a single intranasal dose of 110 micrograms or 220 micrograms Aphthaseal Allergy or Triamcinolone Nasal Spray. Following multiple doses in paediatric patients, plasma drug concentrations, AUC, C_max and T_max were similar to those values observed in adult patients.

Aphthaseal hexacetonide is a potent teratogen in many animals. For example cleft palate has been reported in mice, rats, rabbits, and hamsters. CNS anomalies and cranial malformations have been observed in monkeys following gestational exposure. To date, however, no signs of teratogenicity of corticosteroids have been observed in humans.

Environmental Risk Assessment (ERA)

The environmental risk assessment has been performed according to European standards. From these results it is assumed that the medicinal product is unlikely to represent a risk for the environment following the recommended use in patients.

In pre-clinical studies, only the effects typical of glucocorticosteroids were observed

Like other corticosteroids, triamcinolone acetonide has been shown to be teratogenic in rats and rabbits. Teratogenic effects which occurred in the rat and in the rabbit included cleft palate and/or internal hydrocephaly and axial skeletal defects. Teratogenic effects, including CNS and cranial malformations, have also been observed in non-human primates.

No evidence of mutagenicity was detected in in vitro gene mutation tests

Carcinogenicity assays in rodents show no increase in the incidence of individual tumour types.

The use of solvents containing methylparaben, propylparaben, phenol, etc. should be avoided, since they may cause precipitation of the steroid.

None known.

Aphthaseal HEXACETONIDE ampoules must be inspected for discolouration of the contents prior to administration.

Shake gently before use.

If necessary, Aphthaseal HEXACETONIDE may be mixed with 1% or 2% lidocaine hydrochloride or other similar local anaesthetics. Aphthaseal HEXACETONIDE should be drawn into the syringe before drawing in the anaesthetic to prevent contamination of Aphthaseal HEXACETONIDE. The syringe should then be shaken gently, and the resulting solution used immediately thereafter.

No special requirements.