Cardura XL

1. Name Of The Medicinal Product

CARDURA™ XL 4mg CARDURA™ XL 8mg

2. Qualitative And Quantitative Composition

Doxazosin mesilate:

4.85mg equivalent to 4mg doxazosin.

9.70mg equivalent to 8mg doxazosin.

For excipients, see 6.1.

3. Pharmaceutical Form

Modified release tablet

Cardura XL 4mg and 8mg tablets are white, round, biconvex shaped tablets with a hole in one side, marked CXL4 and CXL8.

4. Clinical Particulars

4.1 Therapeutic Indications

Hypertension: Cardura XL is indicated for the treatment of hypertension and can be used as the sole agent to control blood pressure in the majority of patients. In patients inadequately controlled on single antihypertensive therapy, Cardura XL may be used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist or an angiotensin-converting enzyme inhibitor.

Benign prostatic hyperplasia: Cardura XL is indicated for the treatment of urinary outflow obstruction and symptoms associated with benign prostatic hyperplasia (BPH).

Cardura XL may be used in BPH patients who are either hypertensive or normotensive. While the blood pressure changes in normotensive patients with BPH are not usually clinically significant, patients with hypertension and BPH have had both conditions effectively treated with doxazosin monotherapy.

4.2 Posology And Method Of Administration

Hypertension and benign prostatic hyperplasia: The initial dose of Cardura XL is 4mg once daily. Over 50% of patients with mild to moderate severity hypertension will be controlled on Cardura XL 4mg once daily. Optimal effect of Cardura XL may take up to 4 weeks. If necessary, the dosage may be increased following this period to 8mg once daily according to patient response.

The maximum recommended dose of Cardura XL is 8mg once daily.

Cardura XL can be taken with or without food.

The tablets should be swallowed whole with a sufficient amount of liquid.

Children: The safety and efficacy of Cardura XL in children have not been established.

Elderly: Normal adult dosage.

Patients with renal impairment: Since there is no change in pharmacokinetics in patients with impaired renal function the usual adult dose of Cardura XL is recommended. Doxazosin is not dialysable.

Patients with hepatic impairment: As with any drug wholly metabolised by the liver, Cardura XL should be administered with caution to patients with evidence of impaired hepatic function (see section 4.4 and section 5.2).

4.3 Contraindications

Cardura XL is contraindicated in:

1) Patients with a known hypersensitivity to quinazolines, (e.g. doxazosin, prazosin, terazosin), or any of the excipients.

2) Patients with a history of orthostatic hypotension

3) Patients with benign prostatic hyperplasia and concomitant congestion of the upper urinary tract, chronic urinary tract infection or bladder stones.

4) Patients with a history of gastro-intestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract.

5) During lactation (see section 4.6)

6) Patients with hypotension (for benign prostatic hyperplasia indication only)

Doxazosin is contraindicated as monotherapy in patients with either overflow bladder or anuria with or without progressive renal insufficiency.

4.4 Special Warnings And Precautions For Use

Information to be given to the Patient: Patients should be informed that Cardura XL tablets should be swallowed whole. Patients should not chew, divide or crush the tablets.

In Cardura XL, the active compound is surrounded by an inert, non-absorbable shell that has been specially designed to control the release of the drug over a prolonged period. After transit through the gastrointestinal tract the empty tablet shell is excreted. Patients should be advised that they should not be concerned if they occasionally observe remains in their stools that look like a tablet.

Abnormally short transit times through the gastrointestinal tract (e.g. following surgical resection) could result in incomplete absorption. In view of the long half life of doxazosin the clinical significance of this is unclear.

Postural hypotension / syncope:

Initiation of therapy - As with all alpha-blockers, a very small percentage of patients have experienced postural hypotension evidenced by dizziness and weakness, or rarely loss of consciousness (syncope), particularly with the commencement of therapy. Therefore, it is prudent medical practice to monitor blood pressure on initiation of therapy to minimise the potential for postural effects.

When instituting therapy with any effective alpha-blocker, the patient should be advised how to avoid symptoms resulting from postural hypotension and what measures to take should they develop. The patient should be cautioned to avoid situations where injury could result should dizziness or weakness occur during the initiation of Cardura XL therapy.

Use in patients with Acute Cardiac Conditions:

As with any other vasodilatory anti-hypertensive agent it is prudent medical practice to advise caution when administering doxazosin to patients with the following acute cardiac conditions:

- pulmonary oedema due to aortic or mitral stenosis

- high-output cardiac failure

- right-sided heart failure due to pulmonary embolism or pericardial effusion

- left ventricular heart failure with low filling pressure.

Use in Hepatically Impaired Patients:

As with any drug wholly metabolised by the liver, Cardura XL should be administered with particular caution to patients with evidence of impaired hepatic function (see section 4.2 and section 5.2). Since there is no clinical experience in patients with severe hepatic impairment use in these patients is not recommended.

Use with PDE-5 Inhibitors: Concomitant administration of doxazosin with phosphodiesterase-5-inhibitors (eg sildenafil, tadalafil, and vardenafil) should be done with caution as both drugs have vasodilating effects and may lead to symptomatic hypotension in some patients. To reduce the risk of orthostatic hypotension it is recommended to initiate the treatment with phosphodiesterase-5-inhibitors only if the patient is hemodynamically stabilized on alpha-blocker therapy. Furthermore, it is recommended to initiate phosphodiesterase-5-inhibitor treatment with the lowest possible dose and to respect a 6-hour time interval from intake of doxazosin. No studies have been conducted with doxazosin prolonged release formulations.

Use in patients undergoing cataract surgery: The 'Intraoperative Floppy Iris Syndrome' (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with tamsulosin. Isolated reports have also been received with other alpha-1 blockers and the possibility of a class effect cannot be excluded. As IFIS may lead to increased procedural complications during the cataract operation current or past use of alpha-1 blockers should be made known to the ophthalmic surgeon in advance of surgery.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Phosphodiesterase-5-inhibitors (eg. sildenafil, tadalafil, vardenafil)

Concomitant administration of doxazosin with a PDE-5 inhibitor may lead to symptomatic hypotension in some patients (see section 4.4). No studies have been conducted with doxazosin prolonged-release formulations.

Doxazosin is highly bound to plasma proteins (98%). In vitro data in human plasma indicates that doxazosin has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin or indomethacin).

Conventional doxazosin has been administered without any adverse drug interactions in clinical experience with thiazide diuretics, frusemide, beta-blocking agents, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycaemic drugs, uricosuric agents, or anticoagulants. However, data from formal drug/drug interaction studies are not present.

Doxazosin potentiates the blood pressure lowering activity of other alpha-blockers and other antihypertensives.

In an open-label, randomized, placebo-controlled trial in 22 healthy male volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin, and no statistically significant changes in mean Cmax and mean half-life of doxazosin. The 10% increase in the mean AUC for doxazosin with cimetidine is within intersubject variation (27%) of the mean AUC for doxazosin with placebo.

4.6 Pregnancy And Lactation

For the hypertension indication:

Use during pregnancy: As there are no adequate and well-controlled studies in pregnant women, the safety of Cardura XL during pregnancy has not yet been established. Accordingly, Cardura XL should be used only when, in the opinion of the physician, the potential benefit outweighs the potential risk.

Although no teratogenic effects were seen in animal testing, reduced foetal survival was observed in animals at extremely high doses (see section 5.3). These doses were approximately 300 times the maximum recommended human dose.

Use during lactation: Doxazosin is contraindicated during lactation as animal studies have shown that doxazosin accumulates in milk of lactating rats, and there is no information about the excretion of the drug into the milk of lactating women.

Alternatively, mothers should stop breast-feeding when treatment with doxazosin is necessary (Please see section 5.3).

For the benign prostatic hyperplasia indication: The section is not applicable

4.7 Effects On Ability To Drive And Use Machines

The ability to drive or use machinery may be impaired, especially when initiating therapy.

4.8 Undesirable Effects

In clinical trials, the most common reactions associated with Cardura XL therapy were of a postural type (rarely associated with fainting) or non-specific.

Frequencies used are as follows: Very common

MedDRA System Organ Class	Frequency	Undesirable Effects
Infections and infestations	Common	Respiratory tract infection, urinary tract infection
Blood and lymphatic system disorders	Very Rare	Leukopenia, thrombocytopenia
Immune System Disorders	Uncommon	Allergic drug reaction
Metabolism and Nutrition Disorders	Uncommon	Anorexia, gout, increased appetite
Psychiatric Disorders	Uncommon	Anxiety, depression, insomnia
	Very Rare	Agitation, nervousness
Nervous System Disorders	Common	Dizziness, headache, somnolence
	Uncommon	Cerebrovascular accident, hypoesthesia, syncope, tremor
	Very Rare	Postural dizziness, paresthesia
Eye Disorders	Very Rare	Blurred vision
	Unknown	Introperative floppy iris syndrome (see Section 4.4)
Ear and Labyrinth Disorders	Common	Vertigo
	Uncommon	Tinnitus
Cardiac Disorders	Common	Palpitation, tachycardia
	Uncommon	Angina pectoris, myocardial infarction
	Very Rare	Bradycardia, cardiac arrhythmias
Vascular Disorders	Common	Hypotension, postural hypotension
	Very Rare	Flush
Respiratory, Thoracic and Mediastinal Disorders	Common	Bronchitis, cough, dyspnea, rhinitis
	Uncommon	Epistaxis
	Very Rare	Bronchospasm
Gastrointestinal Disorders	Common	Abdominal pain, dyspepsia, dry mouth, nausea
	Uncommon	Constipation, diarrhoea, flatulence, vomiting, gastroenteritis
Hepatobiliary Disorders	Uncommon	Abnormal liver function tests
	Very Rare	Cholestasis, hepatitis, jaundice
Skin and Subcutaneous Tissue Disorders	Common	Pruritus
	Uncommon	Skin rash
	Very Rare	Alopecia, purpura, urticaria
Musculoskeletal and Connective Tissue Disorders	Common	Back pain, myalgia
	Uncommon	Arthralgia
	Very Rare	Muscle cramps, muscle weakness
Renal and Urinary Disorders	Common	Cystitis, urinary incontinence
	Uncommon	Dysuria, hematuria, micturition frequency
	Very Rare	Micturition disorder, nocturia, polyuria, increased diuresis
Reproductive System and Breast Disorders	Uncommon	Impotence
	Very Rare	Gynecomastia, priapism
	Unknown	Retrograde ejaculation
General Disorders and Administration Site Conditions	Common	Asthenia, chest pain, influenza-like symptoms, peripheral oedema
	Uncommon	Pain, facial oedema
	Very Rare	Fatigue, malaise,
Investigations	Uncommon	Weight increase

The adverse events for Cardura XL are similar to those with immediate release doxazosin tablets.

4.9 Overdose

Should overdosage lead to hypotension, the patient should be immediately placed in a supine, head down position. Other supportive measures should be performed if thought appropriate in individual cases. Since doxazosin is highly protein bound, dialysis is not indicated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Doxazosin is a potent and selective post-junctional alpha-1-adrenoceptor antagonist.

Administration of Cardura XL to hypertensive patients causes a clinically significant reduction in blood pressure as a result of a reduction in systemic vascular resistance. This effect is thought to result from selective blockade of the alpha-1-adrenoreceptors located in the vasculature. With once daily dosing, clinically significant reductions in blood pressure are present throughout the day and at 24 hours post dose. The majority of patients are controlled on the initial dose. In patients with hypertension, the decrease in blood pressure during treatment with Cardura XL was similar in both the sitting and standing position.

Subjects treated with immediate release doxazosin tablets can be transferred to Cardura XL 4mg and the dose titrated upwards as needed.

Doxazosin has been shown to be free of adverse metabolic effects and is suitable for use in patients with coexistent diabetes mellitus, gout and insulin resistance.

Doxazosin is suitable for use in patients with co-existent asthma, left ventricular hypertrophy and in elderly patients. Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation and enhanced activity of tissue plasminogen activator. Additionally, doxazosin improves insulin sensitivity in patients with impairment.

Doxazosin, in addition to its antihypertensive effect, has in long term studies produced a modest reduction in plasma total cholesterol, LDL-cholesterol and triglyceride concentrations and therefore may be of particular benefit to hypertensive patients with concomitant hyperlipidaemia.

Administration of Cardura XL to patients with symptomatic BPH results in a significant improvement in urodynamics and symptoms. The effect in BPH is thought to result from selective blockade of the alpha-adrenoceptors located in the prostatic muscular stroma, capsule and bladder neck.

5.2 Pharmacokinetic Properties

Absorption:After oral administration of therapeutic doses, Cardura XL is well absorbed with peak blood levels gradually reached at 8 to 9 hours after dosing. Peak plasma levels are approximately one third of those of the same dose of immediate release doxazosin tablets. Trough levels at 24 hours are, however, similar.

Peak/trough ratio of Cardura XL is less than half that of immediate release doxazosin tablets.

At steady-state, the relative bioavailability of doxazosin from Cardura XL compared to immediate release form was 54% at the 4mg dose and 59% at the 8mg dose.

Pharmacokinetic studies with Cardura XL in the elderly have shown no significant alterations compared to younger patients.

Biotransformation/elimination: The plasma elimination is biphasic with the terminal elimination half-life being 22 hours and hence this provides the basic for once daily dosing. Doxazosin is extensively metabolised with <5% excreted as unchanged drug.

Pharmacokinetic studies with doxazosin in patients with renal impairment also showed no significant alterations compared to patients with normal renal function.

There are only limited data in patients with liver impairment and on the effects of drugs known to influence hepatic metabolism (e.g. cimetidine). In a clinical study in 12 subjects with moderate hepatic impairment, single dose administration of doxazosin resulted in an increase in AUC of 43% and a decrease in apparent oral clearance of 40%.

Approximately 98% of doxazosin is protein-bound in plasma.

Doxazosin is primarily metabolised by O-demethylation and hydroxylation.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional animal studies in safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity. For further information see section 4.6.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Polyethylene oxide, sodium chloride, hypromellose, red ferric oxide (E172), titanium dioxide (E171), magnesium stearate, cellulose acetate, Macrogol, pharmaceutical glaze, black iron oxide (E172), ammonium hydroxide and propylene glycol.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Do not store above 30°C.

Store in the original package.

6.5 Nature And Contents Of Container

Blister strips of aluminium foil/aluminium foil of 7 tablets in pack size of 28 tablets.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pfizer Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

Cardura XL 4mg PL 00057/0417

Cardura XL 8mg PL 00057/0418

9. Date Of First Authorisation/Renewal Of The Authorisation

6^th November 2006

10. Date Of Revision Of The Text

September 2009

11. LEGAL CATEGORY

POM

Ref: CX8_2 UK

Carboplatin 10mg / ml concentrate for solution for infusion

1. Name Of The Medicinal Product

Carboplatin 10 mg/ml concentrate for solution for infusion

2. Qualitative And Quantitative Composition

One ml of concentrate contains 10 mg carboplatin.

A vial of 5 ml of concentrate contains 50 mg carboplatin.

A vial of 15 ml of concentrate contains 150 mg carboplatin.

A vial of 45 ml of concentrate contains 450 mg carboplatin.

A vial of 60 ml of concentrate contains 600 mg carboplatin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion.

Clear, colourless solution, free from particles.

4. Clinical Particulars

4.1 Therapeutic Indications

Carboplatin is indicated for the treatment of:

1. advanced ovarian carcinoma of epithelial origin in:

- first line therapy

- second line therapy, after other treatments have failed

2. small cell carcinoma of the lung.

4.2 Posology And Method Of Administration

Dosage and administration

Carboplatin should be used by the intravenous route only. The recommended dosage of carboplatin in previously untreated adult patients with normal kidney function, i.e. creatinine clearance > 60 ml/min is 400 mg/m² as a single short term IV dose administered by a 15 to 60 minutes infusion. Alternatively, the Calvert's formula shown below may be used to determine dosage:

Dose (mg) = target AUC (mg/ml x min) x [GFR ml/min + 25]

Dose (mg) = target AUC (mg/ml x min) x [GFR ml/min + 25]
Target AUC	Planned chemotherapy	Patient treatment status
5-7 mg/ml.min	single agent carboplatin	Previously untreated
4-6 mg/ml.min	single agent carboplatin	Previously treated
4-6 mg/ml.min	Carboplatin plus cyclophosphamide	Previously untreated

Note: With the Calvert's formula, the total dose of carboplatin is calculated in mg, not in mg/m².

Calvert's formula should not be used in patients who have received extensive pretreatment **.

**Patients are considered heavily pretreated if they have received any of the following:

- Mitomycin C

- Nitrosourea

- Combination therapy with doxorubicin/ cyclophosphamide/ cisplatin

- Combination therapy with 5 or more agents

- Radiation therapy

Therapy with carboplatin should be discontinued in the case of an unresponsive tumour, progressive disease and/or occurrence of not tolerable side effects.

Therapy should not be repeated until four weeks after the previous carboplatin course and/or until the neutrophil count is at least 2000 cells/mm³ and the platelet count is at least 100.000 cells/ mm³.

Reduction of the initial dosage by 20-25% is recommended for those patients who present with risk factors such as prior myelosuppressive treatment and low performance status (ECOG-Zubrod 2-4 or Karnofsky below 80).

Determination of the haematological nadir by weekly blood counts during the initial courses of treatment with carboplatin is recommended for future dosage adjustment.

Impaired renal function

Patients with creatinine clearance values of less than 60 ml/min are at greater risk to develop myelosuppression.

The optimal use of carboplatin in patients presenting with impaired renal function requires adequate dosage adjustments and frequent monitoring of both haematological nadirs and renal function.

In case of glomerular filtration rate of

Combination therapy

The optimal use of carboplatin in combination with other myelosuppressive agents requires dosage adjustments according to the regimen and schedule to be adopted.

Use in children

As no sufficient experience of carboplatin use in children is available, no specific dosage recommendations can be given.

Elderly

Dosage adjustment, initially or subsequently, may be necessary, dependent on the physical conditions of the patient.

Dilution and reconstitution

The product must be diluted prior to infusion, see section 6.6.

4.3 Contraindications

Carboplatin is contra-indicated in patients with:

- hypersensitivity to the active substance or to other platinum containing compounds

- breast feeding

- severe myelosuppression

- bleeding tumours

- pre-existing severe renal impairment (with creatinine clearance of

4.4 Special Warnings And Precautions For Use

Warnings:

Carboplatin should be administered by individuals under the supervision of a qualified physician who is experienced in the use of anti-neoplastic therapy. Diagnostic and treatment facilities should be readily available for management of therapy and possible complications.

Carboplatin myelosuppression is closely related to its renal clearance. Patients with abnormal kidney function or receiving concomitant therapy with other drugs with nephrotoxic potential are likely to experience more severe and prolonged myelotoxicity. Renal functions parameters should therefore be carefully assessed before and during therapy.

Carboplatin infusion courses should not be repeated more frequently than monthly under normal circumstances. Thrombocytopenia, leukopenia and anaemia occur after administration of carboplatin. Frequent monitoring of peripheral blood counts is recommended throughout and following therapy with carboplatin. Carboplatin combination therapy with other myelosuppressive compounds must be planned very carefully with respect to dosages and timing in order to minimise additive effects. Supportive transfusional therapy may be required in patients who suffer severe myelosuppression.

Carboplatin can cause nausea and vomiting. Pre-medication with anti-emetics has been reported to be useful in reducing the incidence and intensity of these effects.

Renal and hepatic function impairment may be encountered with carboplatin. Very high doses of carboplatin (

The incidence and severity of nephrotoxicity may increase in patients who have impaired kidney function before carboplatin treatment. Impairment of renal function is also more likely in patients who have previously experienced nephrotoxicity as a result of cisplatin therapy. Although no clinical evidence on compounding nephrotoxicity has been accumulated, it is recommended not to combine carboplatin with aminoglycosides or other nephrotoxic compounds.

Infrequent allergic reactions to carboplatin have been reported, e.g. erythematous rash, fever with no apparent cause or pruritus. Rarely anaphylaxis, angio-oedema and anaphylactoid reactions including bronchospasm, urticaria and facial oedema have occurred. These reactions are similar to those observed after administration of other platinum containing compounds and may occur within minutes. The incidence of allergic reactions may increase with previous exposure to platinum therapy; however, allergic reactions have been observed upon initial exposure to carboplatin. Patients should be observed carefully for possible allergic reactions and managed with appropriate supportive therapy, including antihistamines, adrenaline and/or glucocorticoids.

Neurological evaluation and an assessment of hearing should be performed on a regular basis, especially in patients receiving high dose carboplatin. Neurotoxicity, such as parasthesia, decreased deep tendon reflexes, and ototoxicity are more likely seen in patients previously treated with other platinum treatments and other ototoxic agents.

The carcinogenic potential of carboplatin has not been studied but compounds with similar mechanisms of action and mutagenicity have been reported to be carcinogenic (see section 5.3)

Safety and effectiveness of carboplatin administration in children are not proven.

Aluminium containing equipment should not be used during preparation and administration of carboplatin (see section 6.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concurrent therapy with nephrotoxic drugs or ototoxic drugs such as amino glycoside, vancomycin, capreomycin and diuretics is not recommended, since this may lead to increased or exacerbated toxicity due to carboplatin induced changes in renal clearance of these substances.

When combining carboplatin with other myelosuppressive compounds, the myelosuppressive effect of carboplatin and/or the other compounds may be more pronounced. Patients receiving concomitant therapy with other nephrotoxic agents are likely to experience more severe and prolonged myelotoxicity due to decreased renal clearance of carboplatin.

Caution should be exercised when carboplatin in used concomitantly with warfarin, as cases increased INR have been reported.

A decrease in phenytoin serum levels has been observed in case of concurrent administration of carboplatin and phenytoin. This may lead to reappearance of seizure and may require an increase of phenytoin dosages.

The concurrent administration of carboplatin and chelating agents should be avoided as it can therapeutically lead to a decrease of the antineoplastic effect of carboplatin. However, the antineoplastic effect of carboplatin was not influenced by diethyl-dithiocarbamate in animal experiments or in clinical use.

4.6 Pregnancy And Lactation

Pregnancy

The safe use of carboplatin during pregnancy has not been established: Studies in animals have shown reproductive toxicity (see section 5.3.). Carboplatin has been shown to be an embryo toxin and teratogen in rats and mutagenic in vivo and in vitro. Carboplatin should not be used during pregnancy unless clearly indicated. If carboplatin is used during pregnancy the patient should be apprised of the potential hazard to the fetus.

Fertility

Women of childbearing potential should be advised to avoid becoming pregnant by using effective contraception during treatment and up to 6 months after therapy. For women who are pregnant or become pregnant during therapy, genetic counseling should be provided.

Carboplatin is genotoxic. Men being treated with carboplatin are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with carboplatin.

Lactation

It is not known whether carboplatin is excreted in human milk.

Because of the possibility of harmful effects in suckling infants, breast-feeding must be discontinued if the mother is treated with carboplatin (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

Carboplatin has no or negligible influence on the ability to drive and use machines. However carboplatin may cause nausea and vomiting, indirectly impairing the ability to drive and use machines.

4.8 Undesirable Effects

Incidences of adverse reactions reported here under are based on cumulative data obtained in a large group of patients with various pre-treatment prognostic features.

The following frequencies have been used:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000), not known (cannot be estimated from the available data).

Cardiac disorders

Very rare: Cardiovascular events (cardiac failure, embolism) as well as cerebrovascular events (apoplexy) have been reported in single cases (causal relationship with carboplatin not established). Single cases of hypertension have been reported.

Blood and lymphatic system disorders

Very common: Myelosuppression is the dose-limiting toxicity of carboplatin. Myelosuppression may be more severe and prolonged in patients with impaired renal function, extensive prior treatment, poor performance status and age above 65. Myelosuppression is also worsened by therapy combining carboplatin with other compounds that are myelosuppressive. Myelosuppression is usually reversible and not cumulative when carboplatin is used as a single agent and at the recommended dosages and frequencies of administration.

At maximum tolerated dosages of carboplatin administered as a single agent, thrombocytopenia, with nadir platelet counts of less than 50 x 10⁹/l, occurs in about a third of the patients. The nadir usually occurs between days 14 and 21, with recovery within 35 days from the start of therapy.

Leukopenia has also occurred in approximately 20% of patients but its recovery from the day of nadir (day 14-28) may be slower and usually occurs within 42 days from the start of therapy. Neutropenia with granulocyte counts below 1 x 10⁹/l occurs in approximately one fifth of patients. Haemoglobin values below 9.5 mg/100 ml have been observed in 48% of patients with normal base-line values. Anaemia occurs frequently and may be cumulative.

Common: Haemorrhagic complications, usually minor, have also been reported.

Uncommon: Infectious complications have occasionally been reported.

Rare: Cases of febrile neutropenia have been reported. Single cases of life-threatening infections and bleeding have occurred.

Respiratory, thoracic and mediastinal disorders

Very rare: Pulmonary fibrosis manifested by tightness of the chest and dyspnoea. This should be considered if a pulmonary hypersensitivity state is excluded (see General disorders below).

Nervous system disorders

Common: The incidence of peripheral neuropathies after treatment with carboplatin is 6%. In the majority of the patients neurotoxicity is limited to paraesthesia and decreased deep tendon reflexes. The frequency and intensity of this side effect increases in elderly patients and those previously treated with cisplatin. Paraesthesia present before commencing carboplatin therapy, particularly if related to prior cisplatin treatment, may persist or worsen during treatment with carboplatin (see Precautions).

Uncommon: Central nervous symptoms have been reported, however, they seem to be frequently attributed to concomitant antiemetic therapy.

Eye disorders

Rare: Transient visual disturbances, sometimes including transient sight loss, have been reported rarely with platinum therapy. This is usually associated with high dose therapy in renally impaired patients. Optic neuritis has been reported in post marketing surveillance.

Ear and labyrinth disorders

Very common: Subclinical decrease in hearing acuity, consisting of high-frequency (4000-8000 Hz) hearing loss determined by audiogram, has been reported in 15% of the patients treated with carboplatin.

Common: Clinical ototoxicity. Only 1% of patients present with clinical symptoms, manifested in the majority of cases by tinnitus. In patients who have been previously treated with cisplatin and have developed hearing loss related to such treatment, the hearing impairment may persist or worsen.

At higher than recommended doses in combination with other ototoxic agents, clinically significant hearing loss has been reported to occur in paediatric patients when carboplatin was administered.

Gastrointestinal disorders

Very common: Nausea without vomiting occurs in about a quarter of patients receiving carboplatin, vomiting has been reported in over half of the patients and about one-third of these suffer severe emesis. Nausea and vomiting are generally delayed until 6 to 12 hours after administration of carboplatin, usually disappear within 24 hours after treatment and are usually responsive to (and may be prevented by) anti-emetic medication. A quarter of patients experience no nausea or vomiting. Vomiting that could not be controlled by drugs was observed in only 1% of patients. Vomiting seems to occur more frequently in previously treated patients, particularly in patients pre-treated with cisplatin.

Painful gastro-intestinal disorders occurred in 17% of patients.

Common: Diarrhoea (6%), constipation (4%), mucositis.

Rare: Taste alteration. Cases of anorexia have been reported.

Renal and urinary disorders

Very common: Renal toxicity is usually not dose-limiting in patients receiving carboplatin, nor does it require preventive measures such as high volume fluid hydration or forced diuresis. Nevertheless, increasing blood urea and blood urea nitrogen levels or serum creatinine levels can occur.

Common: Renal function impairment, as defined by a decrease in the creatinine clearance below 60 ml/min, may also be observed. The incidence and severity of nephrotoxicity may increase in patients who have impaired kidney function before carboplatin treatment.

It is not clear whether an appropriate hydration programme might overcome such an effect, but dosage reduction or discontinuation of therapy is required in the presence of moderate alteration of renal function (creatinine clearance 41-59 ml/min) or severe renal impairment (creatinine clearance 21-40 ml/min). Carboplatin is contra-indicated in patients with a creatinine clearance at or below 20 ml/min.

Skin and subcutaneous tissue disorders

Common: Alopecia.

Metabolism and nutrition disorders

Very common: Decreases in serum electrolytes (sodium, magnesium, potassium and calcium) have been reported after treatment with carboplatin but have not been reported to be severe enough to cause the appearance of clinical signs or symptoms.

Rare: Cases of hyponatraemia have been reported.

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

Uncommon: Secondary malignancies (including promyelocytic leukaemia which occurred 6 years after monotherapy with carboplatin and preceding irradiation) have been reported following administration of carboplatin as a single agent or in combination therapy (causal relationship not established).

General disorders and administration site conditions

Very common: Hyperuricaemia is observed in about one quarter of patients. Serum levels of uric acid can be decreased by allopurinol. Asthenia.

Common: Malaise, urticaria, flu-like syndrome, erythematous rash, pruritis.

Uncommon: Fever and chills without evidence of infection; injection site reactions such as pain, erythema, swelling, urticaria and necrosis.

Rare: Haemolytic uraemic syndrome.

Immune system disorders

Common: Allergic reactions to carboplatin have been reported in less than 2% of patients, e.g., skin rash, urticaria, erythematous rash, and fever with no apparent cause or pruritus. These reactions are similar to those observed after administration of other platinum containing compounds and should be managed with appropriate supportive therapy.

Rare: Anaphylaxis, anaphylactic shock, angio-oedema and anaphylactoid reactions, including bronchospasm, urticaria, facial odema and facial flushing, dyspnoea, hypotension, dizziness, wheezing, and tachycardia have occurred (see section 4.4).

Hepatobiliary disorders

Very common: Abnormalities of liver function tests (usually mild to moderate) have been reported with carboplatin in about one-third of the patients with normal baseline values. The alkaline phosphatase level is increased more frequently than SGOT, SGPT or total bilirubin. The majority of these abnormalities regress spontaneously during the course of treatment.

Rare: Severe hepatic dysfunction (including acute liver necrosis) has been reported after administration of higher than recommended carboplatin dosages.

4.9 Overdose

Symptoms of overdose

Carboplatin was administered in Phase I studies at a dosage of up to 1600mg/m² i.v. per course. At this dosage, life-threatening haematological side effects with granulocytopenia, thrombocytopenia and anaemia were observed. The granulocyte, thrombocyte and haemoglobin nadir were observed between days 9-25 (median: days 12-17). The granulocytes had reached values of

The following non-haematological side effects also occurred: renal function disturbances with a 50% drop in the glomerular filtration rate, neuropathy, ototoxicity, sight loss, hyperbilirubinaemia, mucositis, diarrhoea, nausea and vomiting with headache, erythema, and severe infection. In the majority of cases, hearing disturbances were transient and reversible.

Therapy of overdose

There is no known antidote for carboplatin over dosage. The anticipated complications of over dosage would be related to myelosuppression as well as impairment of hepatic and renal function. Bone marrow transplantation and transfusions (thrombocytes, blood) can be effective measures of managing haematological side effects.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, platinum compounds

ATC code: L01X A02

Carboplatin is an antineoplastic agent. Its activity has been demonstrated against several murine and human cell lines.

Carboplatin exhibited comparable activity to cisplatin against a wide range of tumours regardless of implant site.

Alkaline elution techniques and DNA binding studies have demonstrated the qualitatively similar modes of action of carboplatin and cisplatin. Carboplatin, like cisplatin, induces changes in the superhelical conformation of DNA which is consistent with a “DNA shortening effect”.

Paediatric patients: safety and efficacy in children have not been established.

5.2 Pharmacokinetic Properties

Following administration of carboplatin in man, linear relationship exists between dose and plasma concentrations of total and free ultra-filterable platinum. The area under the plasma concentration versus time curve for total platinum also shows a linear relationship with the dose when creatinine clearance

Repeated dosing during four consecutive days did not produce an accumulation of platinum in plasma. Following the administration of carboplatin reported values for the terminal elimination half-lives of free ultrafilterable platinum and carboplatin in man are approximately 6 hours and 1.5 hours respectively. During the initial phase, most of the free ultra-filterable platinum is present as carboplatin. The terminal half-life for total plasma platinum is 24 hours. Approximately 87% of plasma platinum is protein bound within 24 hours following administration. Carboplatin is excreted primarily in the urine, with recovery of approximately 70% of the administered platinum within 24 hours. Most of the drug is excreted in the first 6 hours. Total body and renal clearance of free ultra-filterable platinum correlate with the rate of glomerular filtration but not tubular secretion.

Carboplatin clearance has been reported to vary by 3- to 4- fold in paediatric patients. As for adult patients, literature data suggest that renal function may contribute to the variation in carboplatin clearance.

5.3 Preclinical Safety Data

Carboplatin has been shown to be embryotoxic and teratogenic in rats It is mutagenic in vivo and in vitro and although the carcinogenic potential of carboplatin has not been studied, compounds with similar mechanisms of actions and mutagenicity have been reported to be carcinogenic.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Water for injections.

6.2 Incompatibilities

Needles, syringes, catheters or intravenous sets containing aluminum parts that may come into contact with carboplatin should not be used for preparation or administration of carboplatin.

6.3 Shelf Life

Unopened product: 24 months.

Diluted product:

8 hours at room temperature (15-25°C), or 24 hours under refrigeration (2-8°C)

From a microbiological point of view, the product should be used immediately. If not used immediately, in use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution / dilution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Do not store above 25°C. Do not refrigerate or freeze.

Keep vial in the outer carton in order to protect from light.

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

6.5 Nature And Contents Of Container

Colourless EP Type 1 glass vials, with teflon coated grey chlorobutyl rubber stoppers sealed with an orange center flip-off aluminium seal.

Pack sizes:

Vials of 5 ml, 15 ml and 45 ml.

Boxes of 1, 5 and 10 vials.

Colourless EP Type 1 glass vials, with teflon coated grey chlorobutyl rubber stoppers sealed with a parrot green center flip-off aluminium seal.

Pack sizes:

Vial of 60 ml.

Boxes of 1, 5 and 10 vials.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The medicinal product is for single use only. Any unused infusion solution should be discarded.

Instructions for dilution

The product must be diluted prior to infusion, with 5% Glucose for Injection or 0.9% Sodium Chloride for Injection, to concentrations as low as 0.5 mg/ml (500 micrograms/ml). When diluted as directed, carboplatin is chemically and physically stable for 8 hours at room temperature (15-25°C) and for 24 hours at 2-8°C.

From a microbiological point of view, the infusion preparation should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8 ºC, unless dilution has taken place under controlled and validated conditions.

The solution is to be inspected visually for particulate matter and discoloration prior to administration.

The solution should only be used if the solution is clear and free from particles.

Guidelines for the safe handling of anti-neoplastic agents:

1 Carboplatin should be prepared for administration only by professionals who have been trained in the safe use of chemotherapeutic agents.

2 This should be performed in a designated area.

3 Adequate protective gloves should be worn.

4 Precautions should be taken to avoid the drug accidentally coming into contact with the eyes. In the event of contact with the eyes, wash with water and/or saline.

5 The cytotoxic preparation should not be handled by pregnant staff.

6 Adequate care and precautions should be taken in the disposal of items (syringes, needles, etc.) used to reconstitute cytotoxic drugs. Excess material and body waste may be disposed of by placing in double sealed polythene bags and incinerating at a temperature of 1,000 °C. Liquid waste may be flushed with copious amounts of water.

7 The work surface should be covered with disposable plastic-backed absorbent paper.

8 Use Luer-Lock fittings on all syringes and sets. Large bore needles are recommended to minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of a venting needle.

Disposal

Remnants of carboplatin as well as all materials that have been used for dilution and administration must be destroyed according to hospital standard procedures applicable to cytotoxic agents in accordance with local requirements related to the disposal of hazardous waste.

7. Marketing Authorisation Holder

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87

2132 JH Hoofddorp

The Netherlands

8. Marketing Authorisation Number(S)

PL 31750/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

11/03/2010

10. Date Of Revision Of The Text

April 2010

Cedocard Retard 40 Tablets

1. Name Of The Medicinal Product

Cedocard Retard 40

2. Qualitative And Quantitative Composition

Isosorbide Dinitrate BP 40.0 mg

3. Pharmaceutical Form

Uncoated sustained release tablets for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

Cedocard Retard is indicated for prophylactic treatment of angina pectoris.

4.2 Posology And Method Of Administration

Children:

There is no recommended dose for children.

Adults:

One or two tablets to be taken twice daily.

Elderly:

Dosage as for other adults.

4.3 Contraindications

Isosorbide dinitrate is contra-indicated in patients with a history of sensitivity to the drug. Sildenafil has been shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitrates, or nitric oxide donors is therefore contra-indicated.

4.4 Special Warnings And Precautions For Use

Tolerance and cross-tolerance to other nitrates and nitrites may occur.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Tolerance and cross-tolerance to other nitrates and nitrites may occur. The hypotensive effects of nitrates are potentiated by concurrent administration of sildenafil.

4.6 Pregnancy And Lactation

No data have been reported which would indicate the possibility of adverse effects resulting from the use of isosorbide dinitrate in pregnancy. Safety in pregnancy however, has not been established. Isosorbide dinitrate should only be used in pregnancy if, in the opinion of the physician, the possible benefits of treatment outweigh the possible hazards. Lactation - there are no data available on the transfer of isosorbide dinitrate in breast milk or its effect on breast fed children.

4.7 Effects On Ability To Drive And Use Machines

Side effects include throbbing headache and dizziness. Patients are advised not to drive or operate machinery if so affected.

4.8 Undesirable Effects

Side effects include throbbing headache and dizziness. Patients are advised not to drive or operate machinery if so affected.

4.9 Overdose

No available data.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Isosorbide dinitrate is a vasodilator. It relaxes vascular smooth muscle and produces coronary vasodilation, reduction in peripheral resistance and venous return, alteration of myocardial metabolism and reduction of the myocardial oxygen demand.

5.2 Pharmacokinetic Properties

The mean plasma concentrations of ISDN at the end of each 12 hour dosage interval (Cmin) during the period of administration of 40 mg as the sustained release tablets were 0.6 ng/ml, 0.6 ng/ml, 0.9 ng/ml and 0.6 ng/ml after the first, second, third and fourth doses respectively and was 0.9 ng/ml at 12 hours after the last dose. At 1, 4 and 8 hours after the first dose the mean plasma levels of ISDN were 1.3 ng/ml, 4.0 ng/ml and 2.2 ng/ml respectively. At 1, 4 and 8 hours after the 3rd dose the mean plasma levels of ISDN were 2.1 ng/ml, 4.0 ng/ml and 2.0 ng/ml respectively and after the last dose, the peak plasma concentrations of ISDN of 12.7 ng/ml occurred at 5 hours and thereafter mean concentrations of ISDN declined to 0.4 ng/ml at 14 hours after the last dose.

5.3 Preclinical Safety Data

Due to the age and well established safety nature of this product, preclinical data has not been included.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose	Ph. Eur
Talc	Ph. Eur
Magnesium stearate	Ph. Eur

Polyvinyl acetate

Red (E124)

Yellow-orange S (E110)

Potato starch	Ph. Eur
Methylene chloride	USP

Water

Sodium chloride

Sodium sulphate

6.2 Incompatibilities

None known.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Protect from heat and moisture.

6.5 Nature And Contents Of Container

PVC/Aluminium blisters in packs of 60 or 1000 tablets.

6.6 Special Precautions For Disposal And Other Handling

There are no special instructions for handling.

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

8. Marketing Authorisation Number(S)

PL 00032/0332

9. Date Of First Authorisation/Renewal Of The Authorisation

12 December 2002

10. Date Of Revision Of The Text

August 2007

Company Ref: CD1_0

Catapres Tablets 100mcg

1. Name Of The Medicinal Product

Catapres Tablets 100 micrograms

2. Qualitative And Quantitative Composition

Each tablet contains 100 micrograms of clonidine hydrochloride.

For excipients see 6.1

3. Pharmaceutical Form

Tablet

White, circular, flat, bevel-edged tablets impressed with the identifying code

4. Clinical Particulars

4.1 Therapeutic Indications

Catapres is indicated for the treatment of all grades of essential and secondary hypertension.

4.2 Posology And Method Of Administration

Catapres Tablets are for oral administration only.

Adults:

Oral treatment should commence with 50 - 100 micrograms three times daily. This dose should be increased gradually every second or third day until control is achieved. Most patients will be controlled on divided daily doses of 300 - 1200 micrograms. However, some patients may require higher doses, e.g. 1800 micrograms or more.

Catapres may be added to an existing antihypertensive regimen where blood pressure control has not been satisfactorily achieved. If side-effects with existing therapy are troublesome the concomitant use of Catapres may allow a lower dose of the established regimen to be employed. Patients changing treatment should have their existing therapy reduced gradually whilst Catapres is added to their regimen.

Patients undergoing anaesthesia should continue their Catapres treatment before, during and after anaesthesia using oral or i.v. administration according to individual circumstances.

No specific information on the use of this product in the elderly is available. Clinical trials have included patients over 65 years and no adverse reactions specific to this age group have been reported.

Paediatric Population:

There is insufficient evidence for the application of clonidine in children and adolescents younger than 18 years. Therefore the use of clonidine is not recommended in paediatric subjects under 18 years.

4.3 Contraindications

Catapres should not be used in patients with known hypersensitivity to the active ingredient or other components of the product, and in patients with severe bradyarrhythmia resulting from either sick sinus syndrome or AV block of 2^nd or 3^rd degree.

In case of rare hereditary conditions that may be incompatible with an excipient of the product (please refer to section 4.4 Special Warnings and Precautions for Use) the use of the product is contraindicated.

4.4 Special Warnings And Precautions For Use

Caution should be exercised in patients with Raynaud's disease or other peripheral vascular disease. As with all drugs used in hypertension Catapres should be used with caution in patients with cerebrovascular or coronary insufficiency.

Catapres should also be used with caution in patients with mild to moderate bradyarrhythmia such as low sinus rhythm, and with polyneuropathy or constipation.

Patients with a known history of depression should be carefully supervised while under long-term treatment with Catapres as there have been occasional reports of further depressive episodes during oral treatment in such patients.

As with other antihypertensive drugs, treatment with Catapres should be monitored particularly carefully in patients with heart failure.

In hypertension caused by phaeochromocytoma no therapeutic effect of Catapres can be expected.

Clonidine, the active ingredient of Catapres, and its metabolites are extensively excreted in the urine. Dosage must be adjusted to the individual antihypertensive response, which can show high variability in patients with renal insufficiency; careful monitoring is required. Since only a minimal amount of clonidine is removed during routine haemodialysis there is no need to give supplemental clonidine following dialysis.

Sudden withdrawal of Catapres, particularly in those patients receiving high doses, may result in rebound hypertension. Cases of agitation, restlessness, palpitations, nervousness, tremor, headache and abdominal symptoms have also been reported. Patients should be instructed not to discontinue therapy without consulting their physician. When discontinuing therapy the physician should reduce the dose gradually. However, if withdrawal symptoms should nevertheless occur, these can usually be treated with reintroduction of clonidine or with alpha and beta adrenoceptor blocking agents.

If Catapres is being given concurrently with a beta-blocker, Catapres should not be discontinued until several days after the withdrawal of the beta-blocker.

Patients who wear contact lenses should be warned that treatment with Catapres may cause decreased lacrimation.

This product contains 36.1 mg of lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The use and the safety of clonidine in children and adolescents has little supporting evidence in randomized controlled trials and therefore cannot be recommended for use in this population.

Serious adverse events, including sudden death, have been reported in concomitant use with methylphenidate. The safety of using methylphenidate in combination with clonidine has not been systematically evaluated.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The reduction in blood pressure induced by clonidine can be further potentiated by concurrent administration of other hypotensive agents. This can be of therapeutic use in the case of other antihypertensive agents such as diuretics, vasodilators, beta-receptor blockers, calcium antagonists and ACE-inhibitors, but the effect of alpha₁-blockers is unpredictable.

The antihypertensive effect of clonidine may be reduced or abolished and orthostatic hypotension may be provoked or aggravated by concomitant administration of tricyclic antidepressants or neuroleptics with alpha-receptor blocking properties.

Substances which raise blood pressure or induce a sodium ion (Na⁺) and water retaining effect such as non-steroidal anti-inflammatory agents can reduce the therapeutic effect of clonidine.

Substances with alpha₂-receptor blocking properties, such as mirtazapine, may abolish the alpha₂-receptor mediated effects of clonidine in a dose-dependent manner.

Concomitant administration of substances with a negative chronotropic or dromotropic effect such as beta-receptor blockers or digitalis glycosides can cause or potentiate bradycardic rhythm disturbances.

It cannot be ruled out that concomitant administration of a beta-receptor blocker will cause or potentiate peripheral vascular disorders.

Based on observations in patients in a state of alcoholic delirium it has been suggested that high intravenous doses of clonidine may increase the arrhythmogenic potential (QT-prolongation, ventricular fibrillation) of high intravenous doses of haloperidol. Causal relationship and relevance for antihypertensive treatment have not been established.

The effects of centrally depressant substances or alcohol can be potentiated by clonidine.

4.6 Pregnancy And Lactation

This product should only be used in pregnancy if considered essential by the physician. Careful monitoring of mother and child is recommended.

Clonidine passes the placental barrier and may lower the heart rate of the foetus. Post partum, a transient rise in blood pressure in the new born cannot be excluded.

During pregnancy the oral forms of Catapres should be preferred. Intravenous injection of clonidine should be avoided.

There is no adequate experience regarding the long-term effects of prenatal exposure.

The use of Catapres during lactation is not recommended due to a lack of supporting information.

4.7 Effects On Ability To Drive And Use Machines

This product may cause drowsiness. Patients who are affected should not drive or operate machinery. Sedation due to the drug may be increased by the concomitant use of other central nervous system depressants.

4.8 Undesirable Effects

Most adverse effects are mild and tend to diminish with continued therapy.

Adverse events have been ranked under headings of frequency using the following convention:

Very common	> 1/10
Common	> 1/100, <1/10
Uncommon	>1/1000, <1/100
Rare	>1/10000, <1/1000
Very rare	<1/10000
Not known	Cannot be estimated from the available data
Endocrine disorders:
Gynaecomastia	rare
Psychiatric disorders:
Confusional state	not known
Delusional perception	uncommon
Depression	common
Hallucination	uncommon
Libido decreased	not known
Nightmare	uncommon
Sleep disorder	common
Nervous system disorders:
Dizziness	very common
Headache	common
Paraesthesia	uncommon
Sedation	very common
Eye disorders:
Accommodation disorder	not known
Lacrimation decreased	rare
Cardiac disorders:
Atrioventricular block	rare
Bradyarrhythmia	not known
Sinus bradycardia	uncommon
Vascular disorders:
Orthostatic hypotension	very common
Raynaud's phenomenon	uncommon
Respiratory, thoracic and mediastinal disorders:
Nasal dryness	rare
Gastrointestinal disorders:
Colonic pseudo-obstruction	rare
Constipation	common
Dry mouth	very common
Nausea	common
Salivary gland pain	common
Vomiting	common
Skin and subcutaneous tissue disorders:
Alopecia	rare
Pruritus	uncommon
Rash	uncommon
Urticaria	uncommon
Reproductive system and breast disorders:
Erectile dysfunction	common
General disorders and administration site conditions:
Fatigue	common
Malaise	uncommon
Investigations:
Blood glucose increased	rare

There are occasional reports of fluid retention during initial stages of oral treatment. This is usually transitory and can be corrected by the addition of a diuretic.

Occasional reports of abnormal liver function tests and two cases of hepatitis have also been reported.

4.9 Overdose

Symptoms:

Manifestations of intoxication are due to a generalised sympathetic depression and include pupillary constriction, lethargy, bradycardia, hypotension, hypothermia, somnolence including coma and respiratory depression including apnoea. Paradoxical hypertension caused by stimulation of peripheral alpha₁-receptors may occur. Transient hypertension may be seen if the total dose is over 10 mg.

Treatment:

There is no specific antidote for clonidine overdose. Administration of activated charcoal should be performed where appropriate.

Supportive care may include atropine sulphate for symptomatic bradycardia, and intravenous fluids and/or inotropic sympathomimetic agents for hypotension. Severe persistent hypertension may require correction with alpha-adrenoceptor blocking drugs.

Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Catapres has been shown to have both central and peripheral sites of action. With long-term treatment Catapres reduces the responsiveness of peripheral vessels to vasoconstrictor and vasodilator substances and to sympathetic nerve stimulation. Early in treatment, however, blood pressure reduction is associated with a central reduction of sympathetic outflow and increased vagal tone.

Clinically, there may be reduced venous return and slight bradycardia resulting in reduced cardiac output. Although initially peripheral resistance may be unchanged, it tends to be reduced as treatment continues. There is no interference with myocardial contractility. Studies have shown that cardiovascular reflexes, as shown by the lack of postural hypotension and exercise hypotension, are preserved.

The efficacy of clonidine in the treatment of hypertension has been investigated in five clinical studies in paediatric patients. The efficacy data confirms the properties of clonidine in reduction of systolic and diastolic blood pressure. However, due to limited data and methodological insufficiencies, no definitive conclusion can be drawn on the use of clonidine for hypertensive children.

The efficacy of clonidine has also been investigated in a few clinical studies with paediatric patients with ADHD, Tourette syndrome and stuttering. The efficacy of clonidine in these conditions has not been demonstrated.

There were also two small paediatric studies in migraine, neither of which demonstrated efficacy. In the paediatric studies the most frequent adverse events were drowsiness, dry mouth, headache, dizziness and insomnia. These adverse events might have serious impact on daily functioning in paediatric patients.

Overall, the safety and efficacy of clonidine in children and adolescents have not been established (see section 4.2).

5.2 Pharmacokinetic Properties

The pharmacokinetics of clonidine is dose-proportional in the range of 75-300 micrograms; over this range, dose linearity has not been fully demonstrated. Clonidine, the active ingredient of Catapres, is highly absorbed and undergoes a minor first pass effect. Peak plasma concentrations are reached within 1-3 h after oral administration. Clonidine is rapidly and extensively distributed into tissues and crosses the blood-brain barrier, the placenta barrier and is distributed in to breast milk. The plasma protein binding is 30-40%.

The plasma half-life of clonidine has been found to range between 5.2 h and 24 h. It can be prolonged in patients with severely impaired renal function up to 41 hours.

About 70% of the dose administered is excreted with the urine mainly in form of the unchanged parent drug (40-60% of the dose). The main metabolite p-hydroxy-clonidine is pharmacologically inactive. Approximately 20% of the total amount is excreted with the faeces. There is no definitive data about food or race effects on the pharmacokinetics of clonidine.

The antihypertensive effect is reached at plasma concentrations between about 0.2 and 1.5 ng/ml in patients with normal renal function. A further rise in the plasma levels will not enhance the antihypertensive effect. The hypotensive effect decreases with plasma concentrations above 1.5 ng/ml.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate

Calcium hydrogen phosphate (anhydrous)

Maize starch, dried

Colloidal silica (anhydrous)

Povidone

Soluble starch

Stearic acid

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 30°C.

Keep the blisters in the outer carton

6.5 Nature And Contents Of Container

Opaque PVC 250µm thick/PVDC 40 g/m² blisters with aluminium lidding foil 20µm in packs of 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom

8. Marketing Authorisation Number(S)

PL 00015/5009R

9. Date Of First Authorisation/Renewal Of The Authorisation

10/05/2006

10. Date Of Revision Of The Text

June 2011

LEGAL CATEGORY

POM