Levothyroxine 100mcg tablets

1. Name Of The Medicinal Product

Levothyroxine 100micrograms Tablets (Thyroxine 100 micrograms Tablets).

2. Qualitative And Quantitative Composition

Each tablet contains 100 micrograms Levothyroxine Sodium anhydrous also known as thyroxine sodium tablets.

3. Pharmaceutical Form

Tablet.

White uncoated biconvex tablets engraved on one face FW31 and with a breakline on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

Recommended clinical indications: Control of hypothyroidism, congenital hypothyroidism and juvenile myxoedema.

4.2 Posology And Method Of Administration

Adults:

Initially 50 to 100 micrograms daily, preferably taken before breakfast. Adjust at three to four week intervals by 50 micrograms until normal metabolism is steadily maintained: this may require doses of 100 to 200 micrograms daily.

For patients over 50 years, it is not advisable to exceed 50 micrograms daily initially and where there is cardiac disease, 25 micrograms daily or 50 micrograms on alternate days is more suitable initially. In this condition the daily dose may be increased by 25 micrograms at intervals of perhaps 4 weeks.

For patients younger than 50 years, and in the absence of heart disease, a serum Levothyroxine (T4) level of 70 to 160 nanomoles per litre, or a serum thyrotrophin level of less than 5 milli-units per litre should be targeted. For patients aged over 50 years, with or without cardiac disease, clinical response is probably a more acceptable criteria of dosage rather than serum levels.

A pre-therapy ECG is valuable because ECG changes due to hypothyroidism may be confused with ECG evidence of cardiac ischaemia. If too rapid an increase in metabolism is produced (causing diarrhoea, nervousness, rapid pulse, insomnia, tremors, and sometimes anginal pain where there is latent cardiac ischaemia), dosage must be reduced, or withheld for a day or two, and then re-started at a lower dose level.

Elderly: As for patients aged over 50 years.

Paediatric patients:

The maintenance dose is generally 100 to 150 micrograms per m² body surface area.

For neonates and infants with congenital hypothyroidism, where rapid replacement is important the initial recommended dosage is 10 to 15 micrograms per kg BW per day for the first 3 months. Thereafter, the dose should be adjusted individually according to the clinical findings and thyroid hormone and TSH values.

For children with acquired hypothyroidism, the initial recommended dosage is 12.5-50 micrograms per day. The dose should be increased gradually every 2-4 weeks according to the clinical findings and thyroid hormone and TSH values until the full replacement dose is reached. Infants should be given the total daily dose at least half an hour before the first meal of the day.

When applicable:

Tablets are to be disintegrated in some water (10 to 15 mL) and the resultant suspension, which must be prepared freshly as required, is to be administered with some more liquid (5-10 mL).

4.3 Contraindications

Thyrotoxicosis. Hypersensitivity to any components of Levothyroxine tablets.

4.4 Special Warnings And Precautions For Use

Patient with panhypopituitarism or other causes predisposing to adrenal insufficiency may react to Levothyroxine treatment, and it is advisable to start corticosteroid therapy before giving Levothyroxine to such patients.

Special care is needed for the elderly and for patients with symptoms of myocardial insufficiency, or ECG evidence of myocardial infarction. Thyroid replacement therapy may cause an increase in dosage requirements of insulin or other anti-diabetic therapy. Care is needed for patients with diabetes mellitus and diabetes insipidus.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Levothyroxine increases the effect of anticoagulants and it may be necessary to reduce the anticoagulation dosage if excessive, hypoprothrombinaemia and bleeding are to be avoided.

Acenocoumarol, pheninedione and warfarin enhances the effect of Levothyroxine.

Antiepileptics such as carbamazepine, phenobarbital, phenytoin, and primidone accelerate metabolism of Levothyroxine (may increase requirements in hypothyroidism) and may displace them from plasma proteins.

Initiation or discontinuation of anti-convulsant therapy may alter Levothyroxine dosage requirements.

If co-administered with cardiac glycosides adjustment of dosage may be necessary.

The effect of sympathomimetic agents are enhanced.

Blood sugar levels are raised and dosage of anti-diabetic agents may require adjustment.

Tricyclic anti-depressants response may be accelerated because Levothyroxine increases sensitivity to catecholamines.

Manufacturer of lofepramine advises to avoid Levothyroxine.

Colestyramine reduces the gastrointestinal absorption of Levothyroxine. Oral contraceptives may increase the requirement of thyroid therapy dosage. Other drugs may affect thyroid function tests and this must be considered when monitoring a patient on Levothyroxine therapy.

Rifampicin accelerates metabolism of Levothyroxine (may increase requirements in hypothyroidism).

Phenylbutazone shows false low total plasma-Levothyroxine concentration.

Amiodarone contain iodine and can cause disorders of Levothyroxine function; both hypothyroidism and hyperthyroidism may occur.

Metabolism of propranolol reduces the effect of Levothyroxine.

Sucralfate reduces absorption of Levothyroxine.

4.6 Pregnancy And Lactation

The safety of Levothyroxine treatment during pregnancy is not known, but any possible risk of foetal abnormalities should be weighed against the risk to the foetus of untreated hypothyroidism. Levothyroxine is excreted in breast milk in low concentrations, and it is contentious whether this can interfere with neonatal screening.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Side-effects are usually indicative of excessive dosage and usually disappear on reduction of dosage or withdrawal of treatment for a few days. Such effects include: anginal pain, cardiac arrhythmias, palpitations, cramps in skeletal muscles, tachycardia, diarrhoea, vomiting, tremors, restlessness, excitability, insomnia, headache, flushing, sweating, excessive loss of weight, and muscular weakness.

4.9 Overdose

Signs and symptoms may be an exaggeration of the side-effects, as well as agitation, confusion, irritability, hyperactivity, mydriasis, tachypnoea, pyrexia, increased bowel movements and convulsions. The appearance of clinical hyperthyroidism may be delayed for up to five days. Gastric lavage or emesis is required if the patient is seen within several hours of taking the dose. Treatment is symptomatic. Tachycardia may be controlled in an adult by 40mg doses of propanolol given every 6 hours. Other symptoms may be controlled by Diazepam and/or chlorpromazine as appropriate.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Levothyroxine 100 micrograms Tablets are tablets containing Levothyroxine sodium used for the treatment of hypothyroidism. Levothyroxine is deiodinated in peripheral tissues to form triiodothyronine which is thought to be the active tissue form of thyroid hormone. Triiodothyronine has a rapid action but a shorter duration of activity than Levothyroxine.

The chief action of Levothyroxine is to increase the rate of cell metabolism.

5.2 Pharmacokinetic Properties

Levothyroxine sodium is incompletely and variably absorbed from the gastrointestinal tract. It is almost completely bound to plasma proteins and has a half-life in the circulation of about a week in healthy subjects, but longer in patients with myxoedema.

A large portion of the Levothyroxine leaving the circulation is taken up by the liver.

Part of a dose of Levothyroxine is metabolised to triiodothyronine.

Levothyroxine is excreted in the urine as free drug, deiodinated metabolites and conjugates. Some Levothyroxine is excreted in the faeces. There is limited placental transfer of Levothyroxine.

5.3 Preclinical Safety Data

No further data of relevance

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Citrate

Lactose

Maize starch

Powdered Acacia

Magnesium Stearate

Purified Water

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months for polypropylene containers.

24 months for blister packs.

6.4 Special Precautions For Storage

Do not store above 25°C and store in the original container.

6.5 Nature And Contents Of Container

Polypropylene container with tamper-evident low density polyethylene lid, containing 28, 56,100, 112 or 1000 Levothyroxine 100microgram tablets.

Blister packaging PVC/PVdC film (heat treated foil/heat seal lacquer) containing 28, 56 and 112 Levothyroxine tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Forley Generics Limited

NLA Tower

12-16 Addiscombe Road

Croydon

CR0 0XT

United Kingdom

8. Marketing Authorisation Number(S)

PL 16201/0002

9. Date Of First Authorisation/Renewal Of The Authorisation

Aug 2004

10. Date Of Revision Of The Text

02/09/2010

SOMAVERT 10mg, 15mg & 20mg powder and solvent for solution for injection

1. Name Of The Medicinal Product

SOMAVERT 10 mg powder and solvent for solution for injection.

SOMAVERT 15 mg Powder and solvent for solution for injection.

SOMAVERT 20 mg Powder and solvent for solution for injection.

2. Qualitative And Quantitative Composition

Presentations
SOMAVERT 10mg	Each vial contains 10 mg of pegvisomant. After reconstitution, 1 ml of solution contains 10 mg pegvisomant.
SOMAVERT 15mg	Each vial contains 15 mg of pegvisomant. After reconstitution, 1 ml of solution contains 15 mg pegvisomant.
SOMAVERT 20mg	Each vial contains 20 mg of pegvisomant. After reconstitution, 1 ml of solution contains 20 mg pegvisomant.

Pegvisomant is produced in E Coli by recombinant DNA technology.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

The powder is white to slightly off-white.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of patients with acromegaly who have had an inadequate response to surgery and/or radiation therapy and in whom an appropriate medical treatment with somatostatin analogues did not normalize IGF-I concentrations or was not tolerated.

4.2 Posology And Method Of Administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of acromegaly.

For the different dosage regimens the following strengths are available: SOMAVERT 10 mg, SOMAVERT 15 mg and SOMAVERT 20 mg.

For instructions on preparation see section 6.6

A loading dose of 80 mg pegvisomant should be administered subcutaneously under medical supervision. Following this, SOMAVERT 10 mg reconstituted in 1 ml of solvent should be administered once daily as a subcutaneous injection.

The site of injection should be rotated daily to help prevent lipohypertrophy.

Dose adjustments should be based on serum IGF-I levels. Serum IGF-I concentrations should be measured every four to six weeks and appropriate dose adjustments made in increments of 5 mg/day in order to maintain the serum IGF-I concentration within the age-adjusted normal range and to maintain an optimal therapeutic response.

The maximum dose should not exceed 30 mg/day.

Elderly patients

No dose adjustment is required.

Paediatric patients

There is no experience in children

Patients with impaired hepatic or renal function

The safety and effectiveness of SOMAVERT in patients with renal or hepatic insufficiency has not been established.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Growth hormone-secreting pituitary tumours may sometimes expand, causing serious complications (for example, visual field defects). Treatment by SOMAVERT does not reduce tumour size. All patients with these tumours should be carefully monitored in order to avoid any eventual progression in tumour size under treatment.

SOMAVERT is a potent antagonist of growth hormone action. A growth hormone deficient state may result from SOMAVERT administration, despite the presence of elevated serum growth hormone levels. Serum IGF-I concentrations should be monitored and maintained within the age-adjusted normal range by adjustment of SOMAVERT dosing.

Serum concentrations of alanine aminotransferase (ALT) and aspartate transaminase (AST) should be monitored at four to six week intervals for the first six months of treatment with SOMAVERT, or at any time in patients exhibiting symptoms suggestive of hepatitis. Evidence of obstructive biliary tract disease should be ruled out in patients with elevations of ALT and AST or in patients with a prior history of treatment with any somatostatin analogue. Administration of SOMAVERT should be discontinued if signs of liver disease persist.

The study conducted with SOMAVERT in diabetic patients treated either by insulin or by oral hypoglycaemic medicinal products revealed the risk of hypoglycemia in this population. Therefore, in acromegalic patients with diabetes mellitus, doses of insulin or hypoglycaemic medicinal products may need to be decreased (see also section 4.5).

The therapeutic benefits of a reduction in IGF-I concentration which results in improvement of the patient's clinical condition could potentially increase fertility in female patients. Patients should be advised to use adequate contraception if necessary. SOMAVERT is not recommended during pregnancy (see also section 4.6).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed. It should be considered whether to continue treatment with somatostatin analogues. The use of SOMAVERT in combination with other medicinal products for the treatment of acromegaly has not been extensively investigated.

Patients receiving insulin or oral hypoglycaemic medicinal products may require dose reduction of these active substances due to the effect of pegvisomant on insulin sensitivity (see section 4.4).

SOMAVERT has significant structural similarity to growth hormone which causes it to cross-react in commercially available growth hormone assays. Since serum concentrations of therapeutically-effective doses of SOMAVERT are generally 100 to 1000 times higher than the actual serum growth hormone concentrations seen in acromegalics, measurements of serum growth hormone concentrations will be spuriously reported in commercially available growth hormone assays. SOMAVERT treatment should therefore not be monitored or adjusted based on serum growth hormone concentrations reported from these assays.

4.6 Pregnancy And Lactation

For pegvisomant no clinical data on exposed pregnancies are available.

Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential risk for humans is unknown.

SOMAVERT should not be used during pregnancy unless clearly necessary (see also section 4.4).

Use during lactation

The excretion of pegvisomant in breast milk has not been studied in animals. Clinical data are too limited (one reported case) to draw any conclusion on the excretion of pegvisomant in human breast milk. Therefore, SOMAVERT should not be used in breast-feeding women. However, breast-feeding may be continued if SOMAVERT is discontinued: this decision should take into account the benefit of SOMAVERT therapy to the mother and the benefit of breastfeeding to the child

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.

4.8 Undesirable Effects

The list below contains adverse reactions seen in clinical trials.

In clinical studies, for patients treated with pegvisomant (n=160), the majority of adverse reactions to pegvisomant were of mild to moderate intensity, of limited duration and did not require discontinuation of treatment.

The most commonly reported adverse reactions considered related to SOMAVERT occurring in

Adverse reactions are listed according to the following categories:

Very common:

Common:

Uncommon:

Blood and lymphatic system disorders:
Uncommon:	thrombocytopenia, leukopenia, leukocytosis, bleeding tendency
Nervous system disorders:
Common:	headache, dizziness, somnolence, tremor
Uncommon:	hypoesthesia, dysgeusia, migraine, narcolepsy
Eye disorders:
Uncommon:	asthenopia, eye pain
Ear and labyrinth disorders:
Uncommon:	Meniere's disease
Respiratory, thoracic and mediastinal disorders:
Uncommon:	dyspnea
Gastrointestinal disorders:
Common:	diarrhoea, constipation, nausea, vomiting, abdominal distension, dyspepsia, flatulence
Uncommon:	dry mouth, hemorrhoids, salivary hypersecretion, tooth disorder
Renal and urinary disorders:
Uncommon:	heamaturia, proteinuria, polyuria, renal impairment
Skin and subcutaneous tissue disorders:
Common:	sweating, pruritis, rash
Uncommon:	face oedema, dry skin, contusion, tendency to bruise, night sweats
Musculoskeletal and connective tissue disorders:
Common:	arthralgia, myalgia, peripheral swelling
Uncommon:	arthritis
Metabolism and nutrition disorders:
Common:	hypercholesterolemia, weight gain, hyperglycemia, hunger
Uncommon:	hypertriglyceridemia, hypoglycemia
Vascular disorders:
Common:	hypertension
General disorders and administration site conditions
Common:	influenza-like illness, fatigue, injection site bruising or bleeding, injection site reaction, (including injection site hypersensitivity), injection site hypertrophy, (e.g. lipohypertrophy)*
Uncommon:	oedema lower limb, pyrexia, weakness, asthenia, feeling abnormal, impaired healing, peripheral oedema
Hepatobiliary disorders
Common	abnormal liver function tests (e.g. transaminase elevation) (see section 4.4)
Psychiatric disorders :
Common:	abnormal dreams, sleep disorder
Uncommon:	anger, apathy, confusion, increased libido, panic attack, short term memory loss

*see Additional Information below.

Additional Information

Most injection site reactions characterised as localised erythemas and soreness, spontaneously resolved with local symptomatic treatment, while SOMAVERT therapy continued. Occurrence of injection site hypertrophies has been observed, including lipohypertrophy.

The development of isolated low-titre anti-growth hormone antibodies was observed in 16.9% of patients treated with SOMAVERT. The clinical significance of these antibodies is unknown.

4.9 Overdose

There is limited experience of overdosage with SOMAVERT. In the one reported incident of acute overdosage, where 80 mg/day was administered for 7 days, the patient experienced a slight increase in fatigue and dry mouth. In the week following discontinuation of treatment the adverse reactions noted were: insomnia, increased fatigue, a trace of foot oedema, fine tremor, and weight gain. Two weeks after stopping treatment, leukocytosis and moderate bleeding from injection and vein puncture sites was observed which were considered possibly related to SOMAVERT.

In cases of overdose, administration of SOMAVERT should be discontinued and not resumed until IGF-I levels return to within or above the normal range.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other anterior pituitary lobe hormones and analogues, ATC code: H01AX01.

Pegvisomant is an analogue of human growth hormone that has been genetically modified to be a growth hormone receptor antagonist. Pegvisomant binds to growth hormone receptors on cell surfaces, where it blocks growth hormone binding, and thus interferes with intracellular growth hormone signal transduction. Pegvisomant is highly selective for the GH receptor, and does not cross-react with other cytokine receptors, including prolactin. Inhibition of growth hormone action with pegvisomant leads to decreased serum concentrations of insulin-like growth factor-I (IGF-I), as well as other growth hormone-responsive serum proteins such as free IGF-I, the acid-labile subunit of IGF-I (ALS), and insulin-like growth factor binding protein-3 (IGFBP-3).

Acromegalic patients (n=112) have been treated in a 12-week, randomised, double-blind, multicentre study comparing placebo and pegvisomant. Dose-dependent, statistically significant reductions in mean IGF-I (p<0.0001), free IGF-I (p<0.05), IGFBP-3 (p<0.05) and ALS (p<0.05) were observed at all post-baseline visits in the pegvisomant treatment groups. The serum IGF-1 was normalised at the end of the study (week 12) in 9.7%, 38.5%, 75% and 82% of subjects treated with placebo, 10 mg/day, 15 mg/day or 20 mg/day SOMAVERT respectively.

Statistically significant differences from placebo (p<0.05) were observed for improvements in the total signs and symptoms score for all dose groups compared to placebo.

A cohort of 38 acromegalic subjects has been followed in a long-term, open-label, dose-titration study for at least 12 consecutive months of daily dosing with pegvisomant (mean = 55 weeks). The mean IGF-I concentration in this cohort fell from 917 ng/ml to 299 ng/ml on pegvisomant, with 92% achieving a normal (age-adjusted) IGF-I concentration.

5.2 Pharmacokinetic Properties

Absorption of pegvisomant following subcutaneous administration is slow and prolonged, and peak serum pegvisomant concentrations are not generally attained until 33-77 hours after administration. The mean extent of absorption of a subcutaneous dose was 57% relative to an intravenous dose.

The apparent volume of distribution of pegvisomant is relatively small (7-12 l). The mean total body systemic clearance of pegvisomant following multiple doses is estimated to be 28 ml/h for subcutaneous doses ranging from 10 to 20 mg/day. Renal clearance of pegvisomant is negligible and accounts for less than 1% of total body clearance. Pegvisomant is slowly eliminated from serum, with mean estimates of half-life generally ranging from 74 to 172 hours following either single or multiple-doses. The metabolism of pegvisomant is not studied.

After single subcutaneous pegvisomant administration no linearity is observed with rising doses of 10, 15 or 20 mg. Approximately linear pharmacokinetics is observed at steady state in the population pharmacokinetic studies. The data from 145 patients in two long-term studies who received daily doses of 10, 15, or 20 mg, demonstrate pegvisomant mean serum concentrations (± SD) of approximately 8800 ± 6300, 13200 ± 8000 and 15600 ± 10300 ng/ml, respectively.

The pharmacokinetics of pegvisomant are similar in normal healthy volunteers and acromegaly patients, although heavier individuals tend to have a higher total body clearance of pegvisomant than lighter individuals, and may thus require greater doses of pegvisomant.

No pharmacokinetic data in special populations (children, populations with renal and hepatic impairment) are available.

5.3 Preclinical Safety Data

Non-clinical data revealed no special hazard for humans based on studies of repeated dose toxicity in rat and monkey. However, due to the marked pharmacological response in monkey, systemic exposures higher than those achieved in patients at therapeutic doses have not been studied. Except for one segment II test in the rabbit, no other reproductive toxicity studies were conducted.

Malignant fibrous histiocytomas associated with fibrosis and histiocytic inflammation were observed at injection sites in males in the rat carcinogenicity study at exposure levels equivalent to three times the human exposure based on mean plasma concentrations in two long-term studies at a daily dose of 30 mg. The relevance of this response for humans is currently unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder:

Glycine

Mannitol (E421)

Sodium phosphate dibasic anhydrous

Sodium phosphate monobasic monohydrate

Solvent:

Water for Injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

3 years

After reconstitution, the product should be used immediately.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the container in the outer carton in order to protect from light.

After reconstitution:

Use immediately.

6.5 Nature And Contents Of Container

Powder in a vial (type I glass) with a rubber stopper (butyl) and 8 ml solvent in a vial (type I glass) with a (rubber butyl). Pack size: 30 vials of powder along with 30 vials of solvent. SOMAVERT 20 mg also available in pack size of 1 vial

6.6 Special Precautions For Disposal And Other Handling

Reconstitute using 1 ml solvent

Add solvent to vial with powder for injection. Gently dissolve the powder with a slow, swirling motion. Do not shake vigorously, as this might cause denaturation of the active ingredient.

After reconstitution, if the solution is cloudy or contains particulate matter, the product must be discarded.

For single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Pfizer Limited

Sandwich

Kent CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/02/240/001 - SOMAVERT 10 mg; pack size 30 vials

EU/1/02/240/002 - SOMAVERT 15 mg; pack size 30 vials

EU/1/02/240/003 - SOMAVERT 20 mg; pack size 30 vials

EU/1/02/240/004 - SOMAVERT 20 mg; pack size 1 vial

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorization: 13/11/2002

Date of last renewal: 20/09/2007

10. Date Of Revision Of The Text

June 2011

Ref: SV8_0

Firmagon 120mg Injection

1. Name Of The Medicinal Product

FIRMAGON

2. Qualitative And Quantitative Composition

Each vial contains 120 mg degarelix (as acetate). After reconstitution, each ml solution contains 40 mg of degarelix.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection (Powder for injection and solvent)

Powder: White to off-white powder

Solvent: Clear, colourless solution

4. Clinical Particulars

4.1 Therapeutic Indications

FIRMAGON is a gonadotrophin releasing hormone (GnRH) antagonist indicated for treatment of adult male patients with advanced hormone-dependent prostate cancer.

4.2 Posology And Method Of Administration

Posology

Starting dose	Maintenance dose – monthly administration
240 mg administered as two subcutaneous injections of 120 mg each	80 mg administered as one subcutaneous injection

The first maintenance dose should be given one month after the starting dose.

The therapeutic effect of degarelix should be monitored by clinical parameters and prostate specific antigen (PSA) serum levels. Clinical studies have shown that testosterone (T) suppression occurs immediately after administration of the starting dose with 96% of the patients having plasma testosterone levels corresponding to medical castration (T0.5 ng/ml) after three days and 100% after one month. Long term treatment with the maintenance dose up to 1 year shows that 97% of the patients have sustained suppressed testosterone levels (T0.5 ng/ml).

In case the patient's clinical response appears to be sub-optimal, it should be confirmed that serum testosterone levels are remaining sufficiently suppressed.

Since degarelix does not induce a testosterone surge it is not necessary to add an anti-androgen as surge protection at initiation of therapy.

Method of administration

FIRMAGON must be reconstituted prior to administration. For instructions on reconstitution and administration, please see section 6.6.

Subcutaneous use ONLY, not to be administered intravenously.

Intramuscular administration is not recommended as it has not been studied.

FIRMAGON is administered as a subcutaneous injection in the abdominal region. As with other medicinal products administered by subcutaneous injection, the injection site should vary periodically. Injections should be given in areas where the patient will not be exposed to pressure e.g. not close to waistband or belt and not close to the ribs.

Special patient populations

Elderly, hepatically or renally impaired patients:

There is no need to adjust the dose for the elderly or in patients with mild or moderate liver or kidney function impairment (see section 5.2). Patients with severe liver or kidney impairment have not been studied and caution is therefore warranted (see section 4.4).

There is no relevant indication for use of FIRMAGON in women, children and adolescents.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

The data available on efficacy and safety experience with degarelix is limited to a one year treatment.

Effect on QT/QTc interval

Long-term androgen deprivation therapy may prolong the QT interval. In the confirmatory study comparing FIRMAGON to leuprorelin periodic (monthly) ECGs were performed; both therapies showed QT/QTc intervals exceeding 450 msec in approximately 20% of the patients, and 500 msec in 1% and 2% of the degarelix and leuprorelin patients, respectively (see section 5.1). FIRMAGON has not been studied in patients with a history of a corrected QT interval over 450 msec, in patients with a history of or risk factors for torsades de pointes and in patients receiving concomitant medicinal products that might prolong the QT interval. Therefore in such patients, the benefit/risk ratio of FIRMAGON must be thoroughly appraised (see sections 4.5 and 4.8).

Hepatic impairment

Patients with known or suspected hepatic disorder have not been included in long-term clinical trials with degarelix. Mild, transient increases in ALT and AST have been seen, these were not accompanied by a rise in bilirubin or clinical symptoms. Monitoring of liver function in patients with known or suspected hepatic disorder is advised during treatment. The pharmacokinetics of degarelix has been investigated after single intravenous administration in subjects with mild to moderate hepatic impairment (see section 5.2).

Renal impairment

Degarelix has not been studied in patients with severe renal impairment and caution is therefore warranted.

Hypersensitivity

Degarelix has not been studied in patients with a history of severe untreated asthma, anaphylactic reactions or severe urticaria or angioedema.

Changes in bone density

Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist. It can be anticipated that long periods of testosterone suppression in men will have effects on bone density. Bone density has not been measured during treatment with degarelix.

Glucose tolerance

A reduction in glucose tolerance has been observed in men who have had orchiectomy or who have been treated with a GnRH agonist. Development or aggravation of diabetes may occur; therefore diabetic patients may require more frequent monitoring of blood glucose when receiving androgen deprivation therapy. The effect of degarelix on insulin and glucose levels has not been studied.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No formal drug-drug interaction studies have been performed.

Since androgen deprivation treatment may prolong the QTc interval, the concomitant use of degarelix with medicinal products known to prolong the QTc interval or medicinal products able to induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, cisapride, moxifloxacine, antipsychotics, etc. should be carefully evaluated (see section 4.4).

Degarelix is not a substrate for the human CYP450 system and has not been shown to induce or inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 to any great extent in vitro. Therefore, clinically significant pharmacokinetic drug-drug interactions in metabolism related to these isoenzymes are unlikely.

4.6 Pregnancy And Lactation

There is no relevant indication for use of FIRMAGON in women.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects of degarelix on the ability to drive and use machines have been performed. However, fatigue and dizziness are common adverse reactions that might influence the ability to drive and use machines.

4.8 Undesirable Effects

The most commonly observed adverse reactions during degarelix therapy in the confirmatory phase III study (N=409) were due to the expected physiological effects of testosterone suppression, including hot flushes and weight increase (reported in 25% and 7%, respectively, of patients receiving treatment for one year), or injection site adverse events. Transient chills, fever or influenza like illness were reported to occur hours after dosing (in 3%, 2% and 1% of patients, respectively).

The injection site adverse events reported were mainly pain and erythema, reported in 28% and 17% of patients, respectively, less frequently reported were swelling (6%), induration (4%) and nodule (3%). These events occurred primarily with the starting dose whereas during maintenance therapy with the 80 mg dose, the incidence of these events pr 100 injections was: 3 for pain and <1 for erythema, swelling, nodule and induration. The reported events were mostly transient, of mild to moderate intensity and led to very few discontinuations (<1%).

The frequency of undesirable effects listed below is defined using the following convention:

Very common (

Table 1: Frequency of adverse drug reactions reported in 1259 patients treated for a total of 1781 patient years (phase II and III studies).

MedDRA System Organ Class (SOC)	Very common	Common	Uncommon
Blood and lymphatic system disorders		Anaemia*
Immune system disorders			Hypersensitivity
Metabolism and nutrition disorders		Weight increase*	Hyperglycemia/Diabetes mellitus, cholesterol increased, weight decreased, appetite decreased, changes in blood calcium
Psychiatric disorders		Insomnia	Depression, libido decreased*
Nervous system disorders		Dizziness, headache	Mental impairment, hypoaesthesia
Eye disorders			Vission blurred
Cardiac disorders			Cardiac arrhythmia (incl. atrial fibrillation), palpitations, QT prolongation*(see sections 4.4 and 4.5)
Vascular disorders	Hot flush*		Hypertension, vasovagal reaction (incl. hypotension)
Respiratory, thoracic and mediastinal disorders			Dyspnoea
Gastrointestinal disorders		Diarrhoea, nausea	Constipation, vomiting, abdominal pain, abdominal discomfort, dry mouth
Hepatobiliary disorders		Liver transaminases increased	Bilirubin increased, alkaline phosphatase increased
Skin and subcutaneous tissue disorders		Hyperhidrosis (incl. night sweats)* , rash	Urticaria, skin nodule, alopecia, pruritus, erythema
Musculoskeletal, connective tissue and bone disorders		Musculoskeletal pain and discomfort	Osteoporosis/osteopenia, arthralgia, muscular weakness, muscle spasms, joint swelling/stiffness
Renal and urinary disorders			Pollakiuria, micturition urgency, dysuria, nocturia, renal impairment, incontinence
Reproductive system and breast disorders		Gynaecomastia*, testicular atrophy*, erectile dysfunction*	Testicular pain, breast pain, pelvic pain, genital irritation, ejaculation failure
General disorders and administration site conditions	Injection site adverse events	Chills, pyrexia, fatigue*, Influenza-like illness	Malaise, peripheral oedema

*Known physiological consequence of testosterone suppression

The following events have been reported as being related to treatment in single patients: Febrile neutropenia, myocardial infarction and congestive heart failure.

Changes in laboratory parameters

Changes in laboratory values seen during one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator. Markedly abnormal (>3*ULN) liver transaminase values (ALT, AST and GGT) were seen in 2-6% of patients with normal values prior to treatment, following treatment with both medicinal products. Marked decrease in haematological values, hematocrit (

Changes in ECG measurements

Changes in ECG measurements seen during one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator. Three (<1%) out of 409 patients in the degarelix group and four (2%) out of 201 patients in the leuprorelin 7.5 mg group, had a QTcF

4.9 Overdose

There is no clinical experience with the effects of an acute overdose with degarelix. In the event of an overdose the patient should be monitored and appropriate supportive treatment should be given, if considered necessary.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other hormone antagonists and related agents, ATC code: L02BX02

Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of testosterone (T) by the testes. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that removes the source of androgen. Unlike GnRH agonists, GnRH antagonists do not induce a LH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic flare after the initiation of treatment.

A single dose of 240 mg degarelix, followed by a monthly maintenance dose of 80 mg, rapidly causes a decrease in the concentrations of LH, FSH and subsequently testosterone. The plasma concentration of dihydrotestosterone (DHT) decreases in a similar manner to testosterone.

Degarelix is effective in achieving and maintaining testosterone suppression well below medical castration level of 0.5 ng/ml. Maintenance monthly dosing of 80 mg resulted in sustained testosterone suppression in 97% of patients for at least one year. Median testosterone levels after one year of treatment were 0.087 ng/ml (interquartile range 0.06-0.15) N=167.

Results of the confirmatory Phase III study

The efficacy and safety of degarelix was evaluated in an open-label, multi-centre, randomised, active comparator controlled, parallel-group study. The study investigated the efficacy and safety of two different degarelix monthly dosing regimens with a starting dose of 240 mg (40 mg/ml) followed by monthly doses subcutaneous administration of 160 mg (40 mg/ml) or 80 mg (20 mg/ml), in comparison to monthly intramuscular administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. In total 620 patients were randomised to one of the three treatment groups, of which 504 (81%) patients completed the study. In the degarelix 240/80 mg treatment group 41 (20%) patients discontinued the study, as compared to 32 (16%) patients in the leuprorelin group.

Of the 610 patients treated

• 31% had localised prostate cancer

• 29% had locally advanced prostate cancer

• 20% had metastatic prostate cancer

• 7% had an unknown metastatic status

• 13% had previous curative intent surgery or radiation and a rising PSA

Baseline demographics were similar between the arms. The median age was 74 years (range 47 to 98 years). The primary objective was to demonstrate that degarelix is effective with respect to achieving and maintaining testosterone suppression to below 0.5 ng/ml, during 12 months of treatment.

The lowest effective maintenance dose of 80 mg degarelix was chosen.

Attainment of serum testosterone (T)

FIRMAGON is effective in achieving fast testosterone suppression, see Table 2.

Table 2: Percentage of patients attaining T

Time	Degarelix 240/80 mg	Leuprorelin 7.5 mg
Day 1	52%	0%
Day 3	96%	0%
Day 7	99%	1%
Day 14	100%	18%
Day 28	100%	100%

Avoidance of testosterone surge

Surge was defined as testosterone exceeding baseline by

None of the degarelix-treated patients experienced a testosterone surge; there was an average decrease of 94% in testosterone at day 3. Most of the leuprorelin-treated patients experienced testosterone surge; there was an average increase of 65% in testosterone at day 3. This difference was statistically significant (p<0.001).

Figure 1: Percentage change in testosterone from baseline by treatment group until day 28 (median with interquartile ranges).

The primary end-point in the study was testosterone suppression rates after one year of treatment with degarelix or leuprorelin. The clinical benefit for degarelix compared to leuprorelin plus anti-androgen in the initial phase of treatment has not been demonstrated.

Long-term effect

Successful response in the study was defined as attainment of medical castration at day 28 and maintenance through day 364 where no single testosterone concentration was greater than 0.5 ng/ml.

Table 3: Cumulative probability of testosterone

	Degarelix 240/80 mg N=207	Leuprorelin 7.5 mg N=201
No. of responders	202	194
Response Rate (confidence intervals)*	97.2% (93.5; 98.8%)	96.4% (92.5; 98.2%)

* Kaplan Meier estimates within group

Attainment of prostate specific antigen (PSA) reduction

Tumour size was not measured directly during the clinical trial programme, but there was an indirect beneficial tumour response as shown by a 95% reduction after 12 months in median PSA for degarelix.

The median PSA in the study at baseline was:

• for the degarelix 240/80 mg treatment group 19.8 ng/ml (interquartile range: P25 9.4 ng/ml, P75 46.4 ng/ml)

• for the leuprorelin 7.5 mg treatment group 17.4 ng/ml (interquartile range: P25 8.4 ng/ml, P75 56.5 ng/ml)

Figure 2: Percentage change in PSA from baseline by treatment group until day 56 (median with interquartile ranges).

This difference was statistically significant (p<0.001) for the pre-specified analysis at day 14 and day 28.

Prostate specific antigen (PSA) levels are lowered by 64% two weeks after administration of degarelix, 85% after one month, 95% after three months, and remained suppressed (approximately 97%) throughout the one year of treatment.

From day 56 to day 364 there were no significant differences between degarelix and the comparator in the percentage change from baseline.

In the confirmatory study comparing FIRMAGON to leuprorelin periodic electrocardiograms were performed. Both therapies showed QT/QTc intervals exceeding 450 msec in approximately 20% of the patients. From baseline to end of study the median change for FIRMAGON was 12.0 msec and for leuprorelin it was 16.7 msec.

Anti-degarelix antibody development has been observed in 10% of patients after treatment with FIRMAGON for one year. There is no indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation after one year of treatment. Efficacy and safety data in relation to antibody development beyond one year is not available.

5.2 Pharmacokinetic Properties

Absorption

Following subcutaneous administration of 240 mg degarelix at a concentration of 40 mg/ml to prostate cancer patients in the pivotal study CS21, AUC_{0-28 days} was 635 (602-668) day*ng/ml, C_max was 66.0 (61.0-71.0) ng/ml and occurred at t_max at 40 (37-42) hours. Mean trough values were approximately 11-12 ng/ml after the starting dose and 11-16 ng/ml after maintenance dosing of 80 mg at a concentration of 20 mg/ml. Degarelix is eliminated in a biphasic fashion, with a median terminal half-life (t_½) of approximately 43 days for the starting dose or 28 days for the maintenance dose, as estimated based on population pharmacokinetics modelling. The long half-life after subcutaneous administration is a consequence of a very slow release of degarelix from the depot formed at the injection site(s). The pharmacokinetic behavior of the medicinal product is influenced by its concentration in the solution for injection. Thus, C_max and bioavailability tend to decrease with increasing dose concentration while the half-life is increased. Therefore, no other dose concentrations than the recommended should be used.

Distribution

The distribution volume in healthy elderly men is approximately 1 l/kg. Plasma protein binding is estimated to be approximately 90%.

Metabolism

Degarelix is subject to common peptidic degradation during the passage of the hepato-biliary system and is mainly excreted as peptide fragments in the faeces. No significant metabolites were detected in plasma samples after subcutaneous administration. In vitro studies have shown that degarelix is not a substrate for the human CYP450 system.

Excretion

In healthy men, approximately 20-30% of a single intravenously administered dose is excreted in the urine, suggesting that 70-80% is excreted via the hepato-biliary system. The clearance of degarelix when administered as single intravenous doses (0.864-49.4 µg/kg) in healthy elderly men was found to be 35-50 ml/h/kg.

Special populations:

Patients with renal impairment

No pharmacokinetic studies in renally impaired patients have been conducted. Only about 20-30% of a given dose of degarelix is excreted unchanged by the kidneys. A population pharmacokinetics analysis of the data from the confirmatory Phase III study has demonstrated that the clearance of degarelix in patients with mild to moderate renal impairment is reduced by approximately 23%; therefore, dose adjustment in patients with mild or moderate renal impairment is not recommended. Data on patients with severe renal impairment is scarce and caution is therefore warranted in this patient population.

Patients with hepatic impairment

Degarelix has been investigated in a pharmacokinetic study in patients with mild to moderate hepatic impairment. No signs of increased exposure in the hepatically impaired subjects were observed compared to healthy subjects. Dose adjustment is not necessary in patients with mild or moderate hepatic impairment. Patients with severe hepatic dysfunction have not been studied and caution is therefore warranted in this group.

5.3 Preclinical Safety Data

Animal reproduction studies showed that degarelix caused infertility in male animals. This is due to the pharmacological effect; and the effect was reversible.

In female reproduction toxicity studies degarelix revealed findings expected from the pharmacological properties. It caused a dosage dependent prolongation of the time to mating and to pregnancy, a reduced number of corpora lutea, and an increase in the number of pre- and post-implantation losses, abortions, early embryo/foetal deaths, premature deliveries and in the duration of parturition.

Preclinical studies on safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential revealed no special hazard for humans. Both in vitro and in vivo studies showed no signs of QT prolongation.

No target organ toxicity was observed from acute, subacute and chronic toxicity studies in rats and monkeys following subcutaneous administration of degarelix. Drug-related local irritation was noted in animals when degarelix was administered subcutaneously in high doses.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder

Mannitol (E421)

Solvent

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

3 years.

After reconstitution

Chemical and physical in-use stability has been demonstrated for 2 hours at 25ºC. From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Vials of glass Type I with bromobutyl rubber stopper and aluminium flip-off seal.

2 vials containing 120 mg powder for solution for injection

2 vials containing 6 ml solvent

2 syringes (5 ml)

2 reconstitution needles (21G 0.8 x 50 mm)

2 injection needles (27G 0.4 x 25 mm)

6.6 Special Precautions For Disposal And Other Handling

No special requirements for disposal.

Instructions for use:

The instructions for reconstitution must be followed carefully.

Administration of other concentrations is not recommended because the gel depot formation is influenced by the concentration. The reconstituted solution should be a clear liquid, free of undissolved matter.

NOTE:

• THE VIALS SHOULD BE KEPT VERTICAL AT ALL TIMES

• THE VIALS SHOULD NOT BE SHAKEN

The pack contains 2 sets of powder and solvent that must be prepared for subcutaneous injection. Hence, the instructions here below need to be repeated a second time.

1. Draw up 3.0 ml solvent for injection with the reconstitution needle (green needle, 21G / 0.8 x 50 mm). Discard the vial with the remaining solvent.
	2. Inject the solvent slowly into the vial with powder. DO NOT REMOVE THE SYRINGE AND THE NEEDLE, to keep the medicinal product and syringe sterile.
	3. KEEP THE VIAL IN AN UPRIGHT POSITION. Swirl very gently until the liquid looks clear and without undissolved powder or particles. In case the powder adheres to the vial over the liquid surface, the vial can be tilted slightly. AVOID SHAKING TO PREVENT FOAM FORMATION. A ring of small air bubbles on the surface of the liquid is acceptable. The reconstitution procedure may take, in some cases, up to 15 minutes, but usually takes a few minutes.
	4. Tilt the vial slightly and keep the needle in the lowest part of the vial. Withdraw 3.0 ml of the solution without turning the vial upside down .
5. Exchange the green needle with the white needle for deep subcutaneous injection (27G / 0.4 x 25 mm). Remove any air bubbles.
	6. Grasp the skin of the abdomen, elevate the subcutaneous tissue. Perform a profound subcutaneous injection. To do so, insert the needle deeply at an angle of not less than 45 degrees.
7. Inject 3.0 ml of FIRMAGON 120 mg immediately after reconstitution.*
8. Do not inject directly into a vein. Gently pull back the plunger to check if blood is aspirated. If blood appears in the syringe, the medicinal product can no longer be used. Discontinue the procedure and discard the syringe and the needle (reconstitute a new dose for the patient).
9. Repeat the reconstitution procedure for the second dose. Choose a different injection site and inject 3.0 ml.

Please be aware:

• No injections should be given in areas where the patient will be exposed to pressure, e.g. around the belt or waistband or close to the ribs.

* Chemical and physical in-use stability has been demonstrated for 2 hours at 25ºC. From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

7. Marketing Authorisation Holder

Ferring Pharmaceuticals A/S

Kay Fiskers Plads 11

DK-2300 Copenhagen S

Denmark

Tel: +45 88 33 88 34

8. Marketing Authorisation Number(S)

EU/1/08/504/002

9. Date Of First Authorisation/Renewal Of The Authorisation

17/02/2009

10. Date Of Revision Of The Text

30/07/2009

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

Transiderm-Nitro 5 and 10

Transiderm-Nitro 5 and 10

(glyceryl trinitrate)

What you need to know about Transiderm-Nitro 5 and 10

Your doctor has decided that you need this medicine to help treat your condition.

Please read this leaflet carefully before you start to use the patches. It contains important information. Keep the leaflet in a safe place because you may want to read it again.

If you have any other questions, or if there is something you don’t understand, please ask your doctor or pharmacist.

This medicine has been prescribed for you. Never give it to someone else. It may not be the right medicine for them even if their symptoms seem to be the same as yours.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.

This product will be referred to as Transiderm-Nitro in this leaflet.

In this leaflet:

• 1. What Transiderm-Nitro patches are and what they are used for


• 2. Things to consider before you start to use Transiderm-Nitro patches


• 3. How to use Transiderm-Nitro


• 4. Possible side effects


• 5. How to store Transiderm-Nitro


• 6. Further information

What Transiderm-Nitro patches are and what they are used for

Transiderm-Nitro is a patch which you stick on your skin. The patch contains a supply of glyceryl trinitrate which is released from the patch and absorbed through the skin and into the blood vessels. This is called a transdermal patch.

Glyceryl trinitrate, the active ingredient in the patches is one of a group of medicines called vasodilators. These cause blood vessels to relax, increasing the supply of blood and oxygen to the heart and reducing the amount of work the heart has to do.

Transiderm-Nitro 5 and 10 are used

• to prevent angina attacks. Angina means a painful tightness in the chest. This is a good description of a typical attack, although the pain may also be felt in the arm or neck. The pain really comes from the heart muscle and is a sign that part of the muscle is not getting enough blood supply for the amount of work it has to do.

Transiderm-Nitro 5 is also used in patients who are receiving food or drugs directly into a vein (intravenously)

• to prevent irritation and the intravenous fluid leaking into the surrounding tissues.

Things to consider before you start to use Transiderm-Nitro patches

Some people MUST NOT use Transiderm-Nitro patches. Talk to your doctor if:

• you think you may be allergic to glyceryl trinitrate or other nitrates or to any of the other ingredients of the patch. (These are listed at the end of the leaflet.)


• you have very low blood pressure.


• you have headaches, vomiting or seizures as a result of raised pressure inside the skull.


• you have any problems with your heart because of faulty valves or inflammation.


• you are taking any medicines for erectile dysfunction (male impotence).

You should also ask yourself these questions before using the patch:

• Have you recently had a heart attack or do you have heart failure or other heart problems?


• Do you suffer from anaemia or lung disease?


• Are you pregnant or trying to become pregnant?


• Are you breast feeding?

If the answer to any of these questions is YES, tell your doctor or pharmacist because Transiderm-Nitro might not be the right medicine for you.

Are you taking other medicines?

Transiderm-Nitro interacts with a large number of other medicines. Tell your doctor or pharmacist if you are taking any of the following:

• Medicines for depression


• Ergotamine products which are usually given for migraine


• Medicines for erectile dysfunction (male impotence)


• Medicines for high blood pressure or heart problems


• Aspirin or other painkillers called NSAIDs (non-steroidal anti-inflammatory drugs)


• Diuretics ("water tablets")


• Tranquillisers (e.g. chlorpromazine, flupenthixol, haloperidol, clozapine).

Always tell the doctor or pharmacist about all of the medicines you are taking. This means medicines you have bought yourself, as well as medicines on prescription from the doctor.

Will there be any problems with driving or using machinery?

Some people have reported feeling faint or dizzy when they have started to use the patches. You should not drive or operate machinery if you are affected.

Other special warnings

Be careful when drinking alcohol as the patch may affect you more than usual and you might feel faint or dizzy.

You might find that your GTN (glyceryl trinitrate) tablets or spray aren’t working as well as they used to. Discuss this with your doctor.

You must tell the doctor or nurse if you are wearing a patch before an MRI scan (Magnetic Resonance Imaging scan to visualise internal organs and tissues of the body), diathermy treatment (treatment using hot wires) and before electrical treatment on the heart.

How to use Transiderm-Nitro patches

It is important to follow what your doctor says about how and when to use your patches. The dose will be on the pharmacist’s label. Check the label carefully. If you are not sure, ask your doctor or pharmacist.

The doctor will tell you how often to change the patch. Discard the old patch carefully because it will still contain a little of the active ingredient.

The side of the chest is a suitable place to apply the patch. Choose a different area of skin each time you apply a new patch. Leave several days before you use the same patch of skin again.

How to apply the patch

• 
  1. Decide where you will put the patch. It is important that you put it on a hairless area to ensure that it sticks well. The side of the chest is recommended.

• 
  2. Wash the skin and dry it thoroughly to make sure the patch sticks well. Wait a minute until the skin feels quite dry. Do not use powder.

• 
  3. Remove one sachet from the box and tear open the sachet at the notch. Use your fingers as cutting with scissors might damage the patch inside. Remove the patch from the sachet.

• 
  4. Peel off the white plastic backing and discard it. Do not touch the sticky surface of the patch.

• 
  5. Place the sticky side of the patch on the clean skin, press firmly while you count slowly up to five.

• 
  6. Run your finger around the edge of the patch to make sure no air or water can get in. If you have applied the patch correctly you can bathe, shower or swim with little risk of the patch coming off.

To prevent angina

The usual dosage for adults and the elderly is one or two patches applied daily. The doctor will have decided which strength of patch you need.

You may be told to wear a patch all of the time or for only part of the day. Don’t forget to follow the doctor’s instructions exactly.

Do not stop using the patches suddenly without consulting your doctor first.

Sometimes patches are not enough to prevent all of your angina attacks and you may be given tablets as well. Make sure you know when you need to take the tablets.

To prevent skin irritation when you are receiving drugs intravenously (into a vein)

One Transiderm-Nitro 5 patch will be applied when the treatment is started and the patch changed every 3-4 days until the treatment is stopped.

Transiderm-Nitro is not suitable for children.

What if you forget to change your patch?

If you forget to change your patch, do not worry. Put on a new one as soon as you remember. Then go on as before.

What if you accidentally use too many patches?

If you accidentally apply too many Transiderm-Nitro patches, tell your doctor or nearest hospital casualty department immediately. Take your medicine pack with you.

Possible side effects

Transiderm-Nitro patches are suitable for most people. However, like all medicines they can sometimes cause side effects.

The side effects listed below have been reported:

More than 10% of people have experienced

• Nausea (feeling sick) or vomiting (being sick).

Up to 1 in 10 people have experienced:

• Headaches. These will probably wear off after a few days. If necessary you can take mild painkillers e.g. paracetamol.

Up to 1 in 100 people have experienced:

• Reddening, itching or burning of the skin at the site of the patch. Be sure to put your patch in a different place each day.


• Allergic skin reactions such as reddening or itching anywhere on the body.

Up to 1 in 1,000 people have experienced:

• Increased heart rate or palpitations.


• Feeling faint or light-headed on standing, or feeling dizzy.


• Flushing of the face.

If any of the symptoms become troublesome, or if you notice anything else not mentioned here, please go and see your doctor. He/she may want to reduce the dose or give you a different medicine.

How to store Transiderm-Nitro patches

Keep your patches below 25ºC. Do not open the sealed satchet until you are going to use the patch.

Keep all medicines out of the reach and sight of children.

Do not use the patches after the expiry date which is printed on the outside of the pack.

If your doctor tells you to stop using Transiderm-Nitro patches, please take any which are left back to your pharmacist to be destroyed. Only keep them if the doctor tells you to. Do not throw them away with your normal household water or waste. This will help to protect the environment.

Further information

The patches come in two sizes. Each Transiderm-Nitro 5 patch contains 25 mg glyceryl trinitrate; your body will absorb approximately 5 mg over 24 hours. Each Transiderm-Nitro 10 patch contains 50 mg glyceryl trinitrate; your body will absorb approximately 10 mg over 24 hours. The patches also contain the inactive ingredients lactose, silicone oil, silica dioxide, ethylene-vinyl acetate copolymer and medical adhesive CH15 (a silicone-based adhesive).

Transiderm-Nitro 5 and 10 come in packs containing 28 patches. Each patch comes in a sealed sachet inside the pack.

The product licence holder is

Novartis Pharmaceuticals UK Limited

trading as Ciba Laboratories

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

England

Transiderm-Nitro patches are made by

Novartis Pharmaceuticals UK Limited

Wimblehurst Road

Horsham

West Sussex

RH12 5AB

This leaflet was revised in September 2009

If you would like any more information, or would like the leaflet in a different format, please contact Medical Information at Novartis Pharmaceuticals UK Ltd, telephone number 01276 698370.

Transiderm-Nitro is a registered trade mark

Copyright Novartis Pharmaceuticals UK Limited