Deltastab Injection

1. Name Of The Medicinal Product

Deltastab Injection

2. Qualitative And Quantitative Composition

Prednisolone Acetate BP 25 mg/ml

3. Pharmaceutical Form

A white or almost white suspension.

4. Clinical Particulars

4.1 Therapeutic Indications

Deltastab Injection is indicated for the local treatment, by intra-articular or periarticular injection, of the following conditions: rheumatoid arthritis; osteoarthritis; synovitis not associated with infection; tennis elbow; golfer's elbow, and bursitis.

Deltastab Injection is also suitable for administration by the intramuscular route in conditions requiring systemic corticosteroids, e.g. suppression of inflammatory and allergic disorders such as bronchial asthma, anaphylaxis, ulcerative colitis and Crohn's disease.

4.2 Posology And Method Of Administration

For intra-articular, periarticular or intramuscular injection.

Adults

For articular use: 5-25 mg depending upon the size of the joint. The injections may be repeated when relapse occurs. No more than three joints should be treated in one day.

For intramuscular use: Dosage will depend upon the clinical circumstances and the judgement of the physician. The suggested dose is 25-100 mg once or twice weekly.

Elderly

Steroids should be used cautiously in the elderly since adverse effects are enhanced by old age (see section 4.4, 'Special Warnings and Precautions for Use').

Undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible, as a single morning dose on alternate days. Frequent patient review is required to titrate the dose against disease activity.

4.3 Contraindications

Deltastab Injection is contra-indicated in patients with known hypersensitivity to any of the ingredients. It is also contra-indicated in patients with systemic infections (unless specific anti-infective therapy is employed) and in patients vaccinated with live vaccines (see section 4.4, 'Special Warnings and Precautions for Use').

Intra-articular and periarticular injections of Deltastab Injection are contra-indicated when the joint or surrounding tissues are infected. The presence of infection also precludes injection into tendon sheaths and bursae. Deltastab Injection must not be injected directly into tendons, nor should it be injected into spinal or other non-diarthrodial joints.

4.4 Special Warnings And Precautions For Use

A patient information leaflet should be supplied with this product.

Adrenal suppression

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, being tapered off over weeks or months according to the dose and duration of treatment. During prolonged therapy, any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage. If corticosteroids have been stopped following prolonged therapy, they may need to be temporarily re-introduced.

Patients should carry 'Steroid Treatment' cards 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.

Anti-inflammatory/immunosuppressive effects and infection

Suppression of inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised. New infections may appear during their use.

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunisation with varicella zoster immunoglobin (VZIG) is needed by exposed, non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

Patients should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs. Prophylaxis with intramuscular normal immunoglobulin may be needed.

Live vaccines should not be given to individuals with impaired immune responsiveness. Killed vaccines or toxoids may be given though their effects may be attenuated.

Particular care is required when prescribing systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary:

(a) Osteoporosis (postmenopausal females are particularly at risk).

(b) Hypertension or congestive heart failure.

(c) Existing or previous history of severe affective disorders (especially previous history of steroid psychosis).

(d) Diabetes mellitus (or a family history of diabetes).

(e) Previous history of tuberculosis or characteristic appearance on chest X-ray. The emergence of active tuberculosis can, however, be prevented by the prophylactic use of antituberculous therapy.

(f) Glaucoma (or a family history of glaucoma).

(g) Previous corticosteroid-induced myopathy.

(h) Liver failure.

(i) Renal insufficiency.

(j) Epilepsy.

(k) Peptic ulceration.

During treatment, the patient should be observed for ophthalmic side effects, psychotic reactions, muscular weakness, electrocardiographic changes, hypertension and untoward hormonal effects.

Corticosteroids should be used with caution in patients with hypothyroidism.

Use in children

Corticosteroids cause growth retardation in infancy, childhood and adolescence; this may be irreversible. Treatment should be limited to the minimum dosage for the shortest possible time, in order to minimise suppression of the hypothalamo-pituitary-adrenal (HPA) axis and growth retardation (see section 4.2, 'Posology and Method of Administration').

Use in the elderly

The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions (see section 4.2, 'Posology and Method of Administration').

Withdrawal

In patients who have received more than physiological doses of systemic corticosteroids (approximately 7.5 mg prednisolone or equivalent) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose equivalent to 7.5 mg of prednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 40 mg daily of prednisolone (or equivalent) for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks,

• When a short course has been prescribed within one year of cessation of long-term therapy (months or years),

• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy,

• Patients receiving doses of systemic corticosteroid greater than 40 mg daily of prednisolone (or equivalent),

• Patients repeatedly taking doses in the evening.

Patients/and or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see Section 4.8 Undesirable effects). Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure (see also Section 4.5 Interaction with other medicinal products and other forms of interaction), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most adverse reactions resolve after either dose reduction or withdrawal of the medicine, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or a previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The effectiveness of anticoagulants may be increased or decreased with concurrent corticosteroid therapy, and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

Serum levels of salicylates may increase considerably if corticosteroid therapy is withdrawn, possible causing intoxication. Since both salicylates and corticosteroids are ulcerogenic, it is possible that there will be an increased rate of gastrointestinal ulceration. There is an increased risk of gastrointestinal bleeding with aspirin and NSAIDs.

The desired actions of hypoglycaemic drugs (including insulin), antihypertensives and diuretics will be antagonised by corticosteroids. The growth promoting effect of somatropin may be inhibited by corticosteroids.

The potassium-depleting effects of amphotericin, carbenoxolone and diuretics (acetazolamide, loop diuretics and thiazides) are enhanced by corticosteroids and signs of hypokalaemia should be looked for during their concurrent use. There is also an increased risk of hypokalaemia with the simultaneous use of theophylline, and if high doses of corticosteroids are given with high doses of bambuterol, fenoterol, formoterol, ritodrine, salbutamol, salmeterol and terbutaline.

The toxicity of cardiac glycosides is increased if hypokalaemia occurs with corticosteroids.

There is a small amount of evidence that the simultaneous use of corticosteroids and methotrexate may cause increased methotrexate toxicity and possibly death, although this combination of drugs has been used very successfully.

The metabolism of corticosteroids may be enhanced and the therapeutic effects reduced by certain barbiturates (e.g. phenobarbitone), and by phenytoin, rifampicin, rifabutin, primidone, carbamazepine and aminoglutethimide. The effect of corticosteroids may be reduced for 3-4 days after taking mifepristone.

Ketoconazole may inhibit the metabolism of corticosteroids.

The plasma concentration of prednisolone and other corticosteroids may be increased by ritonavir, ciclosporin and oral contraceptives.

4.6 Pregnancy And Lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs. However, 88% of prednisolone is inactivated as it crosses the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities such as cleft palate/lip in man. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following pre-natal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential, however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Lactation

Corticosteroids are excreted in small amounts in breast milk. However, doses of up to 40 mg daily of prednisolone are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression but the benefits of breast feeding are likely to outweigh any theoretical risk.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

The incidence of predictable undesirable effects, including hypothalamo-pituitary-adrenal (HPA) suppression, correlates with the relative potency of the drug, dosage, timing of administration and the duration of treatment (see Section 4.4).

The following side effects may be associated with the long-term systemic use of corticosteroids.

Infections and Infestations

Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis (see section 4.4).

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.

Blood and lymphatic system disorders

Leukocytosis.

Immune system disorders

Hypersensitivity including anaphylaxis has been reported.

Endocrine disorders

Suppression of the HPA axis.

Cushingoid.

Impaired carbohydrate intolerance with increased requirement for anti-diabetic therapy, manifestation of latent diabetes mellitus.

Metabolism and nutrition disorders

Sodium and water retention, hypokalaemia, hypokalaemic alkalosis, increased appetite, negative protein and calcium balance.

Psychiatric disorders

Euphoric mood, psychological dependence, depressed mood, insomnia, aggravation of schizophrenia.

A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood, and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations, and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown.

Nervous system disorders

Dizziness, headache.

Increased intracranial pressure with papilloedema in children (pseudotumour cerebri) -usually after treatment withdrawal.

Aggravation of epilepsy.

Eye disorders

Glaucoma, papilloedema, posterior subcapsular cataracts, central serous chorioretinopathy, exophthalmos, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Myocardial rupture following recent myocardial infarction.

Congestive cardiac failure (in susceptible patients).

Vascular disorders

Hypertension, embolism.

Respiratory, thoracic and mediastinal disorders

Hiccups.

Gastrointestinal disorders

Dyspepsia, nausea, vomiting, abdominal distension, abdominal pain, diarrhoea, oesophageal ulceration, candidiasis, pancreatitis acute.

Peptic ulceration with perforation and haemorrhage.

Skin and subcutaneous tissue disorders

Skin Atrophy, skin striae, acne, telangiectasia, hyperhidrosis, rash, pruritus, urticaria, hirsutism.

Musculoskeletal and connective tissue disorders

Myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, myalgia.

Growth retardation in infancy, childhood and adolescence.

Reproductive system and breast disorders

Menstruation irregular, amenorrhoea.

General disorders and administration site conditions

Impaired healing, malaise.

Investigations

Weight increased.

Injury, poisoning and procedural complications

Tendon rupture, contusion (bruising).

Withdrawal Symptoms

Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death (See Section 4.4).

A 'withdrawal syndrome' may also occur including fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

In some instances, withdrawal symptoms may involve or resemble a clinical relapse of the disease for which the patient has been undergoing treatment.

Other effects that may occur during withdrawal or change of corticosteroid therapy include benign intracranial hypertension with headache and vomiting and papilloedema caused by cerebral oedema.

Latent rhinitis or eczema may be unmasked.

4.9 Overdose

Overdosage is unlikely with Deltastab Injection but there is no specific antidote available. Treatment should be symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Prednisolone is a glucocorticoid which has anti-inflammatory activity.

5.2 Pharmacokinetic Properties

Absorption following intramuscular injection is relatively slow. Systemic absorption occurs slowly after local, intra-articular injection. Prednisolone is extensively bound to plasma proteins. Excretion takes place via the urine as free and conjugated metabolites, together with an appreciable proportion of unchanged prednisolone.

5.3 Preclinical Safety Data

There is no pre-clinical data of relevance to a prescriber which is additional to that already included in other sections of the SmPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Water for injections, sodium chloride for injections, benzyl alcohol, sodium carboxymethylcellulose (Blanose 7M8SF), polysorbate 80 (Tween 80), with sodium hydroxide and/or sterile sodium hydroxide and/or hydrochloric acid as pH adjusters.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store at 15-25°C and protect from light.

6.5 Nature And Contents Of Container

1 ml flint neutral glass ampoules. 10 ampoules are packed in a polystyrene pack within a cardboard sleeve.

6.6 Special Precautions For Disposal And Other Handling

Shake the ampoule well before use.

Administrative Data

7. Marketing Authorisation Holder

Waymade PLC

T/A Sovereign Medical

Sovereign House

Miles Gray Road

Basildon

Essex

SS14 3FR

8. Marketing Authorisation Number(S)

PL 06464/0703

9. Date Of First Authorisation/Renewal Of The Authorisation

17/11/2005

10. Date Of Revision Of The Text

March 2010

11. Legal Category

POM