SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Triamcinolone Hexacetonide 20 mg/ml suspension for injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml suspension for injection contains 20 mg triamcinolone hexacetonide.

Excipients with known effect:

Contains 9 mg benzyl alcohol per ml and 455 mg sorbitol (E 420) per ml.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Suspension for injection

Milky white suspension, easily resuspendable.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

TRIAMCINOLONE 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

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

4.2 Posology and method of administration 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 1020 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 TRIAMCINOLONE 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 triamcinolone 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

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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.

TRIAMCINOLONE HEXACETONIDE is contraindicated in the case of:

-    active tuberculosis

-    herpes simplex keratitis,

-    acute psychoses,

systemic mycoses and parasitoses (strongyloid infections).

4.4 Special warnings and precautions for 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 intraarticular 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 TRIAMCINOLONE 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.

Effect on female fertility, see section 4.6.

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.

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

4.5 Interaction with other medicinal products and other forms of interaction

Amphotericin B injection and potassium-depleting agents: Patients should be monitored for additive hypokalaemia.

Anticholinesterases: The effect of anticholinesterase agent may be antagonised.

Anticholinergics (e.g. atropine): Additional increase of intraocular pressure is possible.

Anticoagulants, oral: Corticosteroids may potentiate or decrease anticoagulant effect. For this reason, patients receiving oral anticoagulants and corticosteroids should be closely monitored.

Antidiabetics (e.g. sulfonylurea derivatives) and insulin: Corticosteroids may increase the levels of glucose in the blood. Diabetic patients should be monitored, especially on instigation and discontinuation of treatment of corticosteroids and if the dosage is changed.

Antihypertensives, including diuretics: The reduction in arterial blood pressure may be diminished.

Antituberculosis drugs: Isoniazid serum concentrations may be decreased.

Cyclosporin: When used concomitantly, this substance may produce an increase in both cyclosporin and corticosteroid activity.

Digitalis glycosides: Concomitant administration may increase the likelihood of digitalis toxicity.

Hepatic Enzyme Inducers (e.g. barbiturates, phenytoin, carbamazepine, rifampicin, primidone, aminoglutethimide): There may be increased metabolic clearance of TRIAMCINOLONE HEXACETONIDE. Patients should be carefully observed for possible reduced effect of TRIAMCINOLONE HEXACETONIDE, and the dosage should be adjusted accordingly.

Human growth hormone (somatropin): The growth-promoting effect may be inhibited during long-term therapy with TRIAMCINOLONE HEXACETONIDE.

Hepatic enzyme inhibitors: protease inhibitors (including ritonavir) or ketoconazole may decrease corticosteroid clearance via CYP3A4 inhibition resulting in increased effects such as Cushing’s syndrome and adrenal suppression. Patients should be monitored for undesirable effects due to triamcinolone and the dose should be adjusted if needed.

Non-depolarising muscle relaxants: Corticosteroids may decrease or enhance the neuromuscular blocking action.

Non-steroidal anti-inflammatory agents (NSAIDs): Corticosteroids may increase the incidence and/or severity of gastrointestinal bleeding and ulceration associated with NSAIDs. Corticosteroids may also reduce serum salicylate levels and therefore decrease their efficacy. Conversely, discontinuing corticosteroids during high-dose salicylate therapy may result in salicylate toxicity. Caution must be exercised during concomitant use of acetylsalicylic acid and corticosteroids in patients with hypoprothrombinaemia.

Oestrogens, including oral contraceptives: Corticosteroid half-life and concentration may be increased and clearance decreased.

Thyroid drugs: Metabolic clearance of adrenocorticoids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustments to the dosage of adrenocorticoids.

Vaccines: Neurological complications and a diminished antibody response may occur when patients taking corticosteroids are vaccinated. (see section 4.3)

Medicines that prolong the QT interval or induce torsade de pointes:

Concomitant treatment with TRIAMCINOLONE HEXACETONIDE and class Ia antiarrhythmic agents such as disopyramide, quinidine and procainamide, or other class II antiarrhythmic drugs such as amiodarone, bepridil and sotalol, is not recommended.

Extreme caution is required in cases of concomitant administration with phenothiazines, tricyclic antidepressants, terfenadine and astemizole, vincamine, erythromycin i.v., halofantrine, pentamidine and sultopride.

Combination with agents that cause electrolyte disturbances such as hypokalaemia (potassium-depleting diuretics, amphotericin B i.v. and certain laxatives), hypomagnesaemia and severe hypocalcaemia is not recommended.

Interactions with laboratory tests

Corticosteroids may interfere with the nitroblue tetrazolium test for bacterial infection, producing false-negative results.

Athletes should be informed that this medicinal product contains an ingredient (e.g. triamcinolone hexacetonide) that may produce a positive result in anti-doping tests.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

Triamcinolone crosses the placenta. Corticosteroids are teratogenic in animal experiments. The significance of this fact for humans is not exactly known, but so far the use of corticosteroids has not been shown to increase the incidence of malformations. Long-term use of corticosteroids in humans and animals has led to a decrease in weight of the placenta and the newborn.

Long-term corticosteroid therapy is also associated with a risk of adrenocortical suppression in the newborn. The product should be used during pregnancy only if the benefit to the mother is clearly greater than the risk to the fetus.

Breast feeding

Triamcinolone hexacetonide is excreted in human milk, but is not likely to have any effect on the child at therapeutic doses. Caution must be observed in the long-term use of large doses.

Fertility

Women: Corticosteroid therapy may cause menstrual disorders and amenorrhea.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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

very common (>1/10) common    (>1/100 to <1/10)

uncommon    (>1/1,000 to <1/100)

rare (>1/10,000 to 1</1,000) very rare    (<1/10,000)

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

Not known: posterior subcapsular cataracts; increased intraocular pressure; glaucoma Cardiac disorders

Not known: cardiac failure; arrhythmias

Vascular disorders

Very rare: thromboembolism

Not known: hypertension

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.

4.9 Overdose

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.

5.1 Pharmacodynamic properties

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

TRIAMCINOLONE 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 triamcinolone 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 triamcinolone 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.

5.2 Pharmacokinetic properties

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 TRIAMCINOLONE HEXACETONIDE administration occurs after 24 hours and normally lasts for 4 to 6 weeks.

Triamcinolone 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.

5.3 Preclinical safety data

Triamcinolone 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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Liquid Sorbitol (E 420),

polysorbate 80, benzyl alcohol, water for injection.

6.2    Incompatibilities

The use of solvents containing methylparaben, propylparaben, phenol, etc. should be avoided, since they may cause precipitation of the steroid. This medical product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Carton containing ten colourless 1 ml glass ampoules.

6.6 Special precautions for disposal

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

Shake gently before use.

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

7    MARKETING AUTHORISATION HOLDER

Intrapharm Laboratories Ltd.

The Courtyard Barns

Choke Lane

Maidenhead Berkshire, SL6 6PT United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL17509/0061

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/12/2013

10 DATE OF REVISION OF THE TEXT

10/05/2016