Movelat Gel / Movelat Relief Gel

1. Name Of The Medicinal Product

Movelat Gel

Movelat Relief Gel

Movelat Relief Sport Gel

2. Qualitative And Quantitative Composition

Mucopolysaccharide polysulphate (MPS)	0.2% w/w
Salicylic acid	2.0% w/w

3. Pharmaceutical Form

Topical Gel.

4. Clinical Particulars

4.1 Therapeutic Indications

Movelat/Movelat Relief/Movelat Relief Sport is a mild to moderate anti-inflammatory and analgesic topical preparation for the symptomatic relief of muscular pain and stiffness, sprains and strains and pain due to rheumatic and non-serious arthritic conditions.

4.2 Posology And Method Of Administration

Adults, the elderly and children over 12 years of age:

Two to six inches (5 -15 cm) to be applied to the affected area up to four times a day.

Children:

The use of Movelat/Movelat Relief/Movelat Relief Sport is contra-indicated in children under 12 years of age.

4.3 Contraindications

Not to be used on large areas of skin, broken or sensitive skin or on mucous membranes. Not to be used on children under 12 years of age. Not to be used in individuals with a known sensitivity to any active or inactive component of the formulation.

Hypersensitivity to aspirin or other non-steroidal anti-inflammatory drugs (including when taken by mouth) especially where associated with a history of asthma.

4.4 Special Warnings And Precautions For Use

For external use only. The stated dose should not be exceeded. If the condition persists or worsens, consult a Doctor. Although systemic absorption of topical salicylate is much less than for oral dosage forms, the side effects of salicylates are theoretically possible.

Consult a doctor before use if pregnant, breast-feeding, asthmatic or on any prescribed medicines.

Some people may experience discomfort, particularly those with sensitive skin or if used in hot weather or after a bath. Wash hands immediately after use.

Discontinue use if excessive irritation or other unwanted effects occur.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Although no adequately controlled interaction studies have been undertaken, it is possible that excessive use of topical salicylates may increase the effect of coumarin anticoagulants. It is therefore advisable that caution be exercised with patients who are taking coumarin anticoagulants.

4.6 Pregnancy And Lactation

Do not use during the first trimester or during late pregnancy. As with most medicines, patients must seek the doctor's advice before using if they are pregnant or breast feeding.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

Allergic skin reactions (which may include redness, burning sensation or rashes) may occur in individuals sensitive to salicylates.

4.9 Overdose

Following accidental ingestion of Movelat/Movelat Relief/Movelat Relief Sport, individuals may present with the symptoms of salicylate poisoning (hyperventilation, tinnitus, deafness, vasodilation, sweating). The stomach should be emptied and plasma salicylate, plasma pH and electrolytes should be monitored. Forced alkaline diuresis may be required if the plasma salicylate levels are in excess of 500 mg/litre (3.6 mmol/litre) in adults or 300 mg/litre (2.2 mmol/litre) in children.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The Mucopolysaccharide polysulphate component of Movelat/Movelat Relief/Movelat Relief Sport is recognised as having:

A weak inhibitory effect of PGE₂ synthesis and an indirect effect on LTB₄ production based on in vitro studies.

Anti-coagulant activity: as a heparinoid.

Thrombolytic activity: through potentiation of urokinase activity.

Anti-exudatory activity: through inhibition of hyaluronidase.

Salicylic acid is employed in the formulation of Movelat/Movelat Relief/Movelat Relief Sport for its keratolytic activity.

5.2 Pharmacokinetic Properties

Radiochemical studies of absorption following cutaneous application of mucopolysaccharide polysulphate have shown that between 0.3 and 4% of the mucopolysaccharide administered is absorbed by tissues other than at the site of application within the first eight hours. Typically between 1.7% and 4.6% will be absorbed within two to four days. Animal studies have also shown that mucopolysaccharide is bound intracellularly within the subcutis. Peak serum concentrations following cutaneous application are below the threshold of physiological relevance for coagulation.

Mucopolysaccharide is excreted in the urine partly unchanged and partly as depolymerized, shorter chain length molecules.

The plasma level of salicylic acid following cutaneous application of Movelat/Movelat Relief/Movelat Relief Sport has been shown to remain constant at approximately 0.2 μg/ml even after repeated dosing. The total excretion of salicylate reaches a constant figure of approximately 12 mg/day. Over a seven-day period, approximately 6.9% of the administered dose is excreted renally, primarily as salicylic acid.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Isopropyl alcohol

Monoethanolamine

Carbomer (Carbopol 940)

Disodium edetate (Titriplex III)

Polyethylene glyceryl-oleate (Tagat O)

Rosemary oil

Purified water

6.2 Incompatibilities

None.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Lacquered aluminium tubes.

Pack sizes: 14, 40, 50, 80, 100, 125 g

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Genus Pharmaceuticals Limited

T/A Genus Pharmaceuticals

Park View House

65 London Road

Newbury

Berkshire RG14 1JN

United Kingdom

8. Marketing Authorisation Number(S)

PL 06831/0177

9. Date Of First Authorisation/Renewal Of The Authorisation

24/05/2006

10. Date Of Revision Of The Text

14/12/2009

MicardisPlus 80 mg / 25 mg Tablets

1. Name Of The Medicinal Product

MicardisPlus 80 mg/25 mg tablets

2. Qualitative And Quantitative Composition

Each tablet contains 80 mg telmisartan and 25 mg hydrochlorothiazide.

Excipients: Each tablet contains 99 mg of lactose monohydrate and 338 mg sorbitol (E420).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet.

Yellow and white oval shaped tablet engraved with the company logo and the code 'H9'.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of essential hypertension.

MicardisPlus fixed dose combination (80 mg telmisartan/25 mg hydrochlorothiazide) is indicated in patients whose blood pressure is not adequately controlled on MicardisPlus 80 mg/12.5 mg (80 mg telmisartan/12.5 mg hydrochlorothiazide) or patients who have been previously stabilised on telmisartan and hydrochlorothiazide given separately.

4.2 Posology And Method Of Administration

Adults

MicardisPlus should be taken once daily with liquid, with or without food in patients whose blood pressure is not adequately controlled by telmisartan alone. Individual dose titration with each of the two components is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered

• MicardisPlus 80 mg/25 mg may be administered in patients whose blood pressure is not adequately controlled by MicardisPlus 80 mg/12.5 mg or in patients who have been previously stabilised on telmisartan and hydrochlorothiazide given separately.

MicardisPlus is also available at the dose strengths 40 mg/12.5 mg and 80 mg/ 12.5 mg

Renal impairment: Periodic monitoring of renal function is advised (see section 4.4).

Hepatic impairment: In patients with mild to moderate hepatic impairment the posology should not exceed MicardisPlus 40 mg/12.5 mg once daily. MicardisPlus is not indicated in patients with severe hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function (see section 4.4).

Elderly: No dosage adjustment is necessary.

Children and adolescents: MicardisPlus is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

4.3 Contraindications

• Hypersensitivity to any of the active substances or to any of the excipients (see section 6.1).

• Hypersensitivity to other sulphonamide-derived substances (since hydrochlorothiazide is a sulphonamide-derived medicinal product).

• Second and third trimesters of pregnancy (see section s 4.4 and 4.6).

• Cholestasis and biliary obstructive disorders.

• Severe hepatic impairment.

• Severe renal impairment (creatinine clearance <30 ml/min).

• Refractory hypokalaemia, hypercalcaemia.

4.4 Special Warnings And Precautions For Use

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Hepatic impairment: MicardisPlus should not be given to patients with cholestasis, biliary obstructive disorders or severe hepatic insufficiency (see section 4.3) since telmisartan is mostly eliminated with the bile. These patients can be expected to have reduced hepatic clearance for telmisartan.

In addition, MicardisPlus should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with MicardisPlus in patients with hepatic impairment.

Renovascular hypertension: There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation: MicardisPlus should not be used in patients with severe renal impairment (creatinine clearance <30 ml/min) (see section 4.3). There is no experience regarding the administration of MicardisPlus in patients with recent kidney transplantation. Experience with MicardisPlus is modest in the patients with mild to moderate renal impairment, therefore periodic monitoring of potassium, creatinine and uric acid serum levels is recommended. Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function.

Intravascular hypovolaemia: Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of MicardisPlus.

Dual blockade of the renin-angiotensin-aldosterone system: As a consequence of inhibiting the renin-angiotensin-aldosterone system, hypotension, syncope, hyperkalaemia, and changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system. Dual blockade of the renin-angiotensin-aldosterone system (e.g. by adding an ACE-inhibitor to an angiotensin II receptor antagonist) is therefore not recommended in patients with already controlled blood pressure and should be limited to individually defined cases with close monitoring of renal function.

Other conditions with stimulation of the renin-angiotensin-aldosterone system: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (see section 4.8).

Primary aldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of MicardisPlus is not recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Metabolic and endocrine effects: Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

An increase in cholesterol and triglyceride levels has been associated with thiazide diuretic therapy; however, at the 12.5 mg dose contained in MicardisPlus, minimal or no effects were reported.

Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.

Electrolyte imbalance: As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, asthenia, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).

- Hypokalaemia

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with telmisartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients with cirrhosis of liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or Adrenocorticotropic hormone (ACTH) (see section 4.5).

- Hyperkalaemia

Conversely, due to the antagonism of the angiotensin II (AT₁) receptors by the telmisartan component of MicardisPlus, hyperkalaemia might occur. Although clinically significant hyperkalaemia has not been documented with MicardisPlus, risk factors for the development of hyperkalaemia include renal insufficiency and/or heart failure, and diabetes mellitus. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be co-administered cautiously with MicardisPlus (see section 4.5).

- Hyponatraemia and hypochloraemic alkalosis

There is no evidence that MicardisPlus would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment.

- Hypercalcaemia

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

- Hypomagnesaemia

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia (see section 4.5).

Sorbitol and Lactose Monohydrate: This medicinal product contains lactose monohydrate and sorbitol. Patients with rare hereditary problems of fructose intolerance and/or with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ethnic differences: As with all other angiotensin II receptor antagonists, telmisartan is apparently less effective in lowering blood pressure in black patients than in non blacks, possibly because of higher prevalence of low renin states in the black hypertensive population.

Other: As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

General: Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If a photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Rare cases have also been reported with angiotensin II receptor antagonists (including MicardisPlus). Co-administration of lithium and MicardisPlus is not recommended (see section 4.4). If this combination proves essential, careful monitoring of serum lithium level is recommended during concomitant use.

Medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid and derivatives): If these substances are to be prescribed with the hydrochlorothiazide-telmisartan combination, monitoring of potassium plasma levels is advised. These medicinal products may potentiate the effect of hydrochlorothiazide on serum potassium (see section 4.4).

Medicinal products that may increase potassium levels or induce hyperkalaemia (e.g. ACE inhibitors, potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, cyclosporin or other medicinal products such as heparin sodium): If these medicinal products are to be prescribed with the hydrochlorothiazide-telmisartan combination, monitoring of potassium plasma levels is advised. Based on the experience with the use of other medicinal products that blunt the renin- angiotensin system, concomitant use of the above medicinal products may lead to increases in serum potassium and is, therefore, not recommended (see section 4.4).

Medicinal products affected by serum potassium disturbances: Periodic monitoring of serum potassium and ECG is recommended when MicardisPlus is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics) and the following torsades de pointes inducing medicinal products (which include some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes.

- class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide)

- class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)

- some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)

- others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, sparfloxacine, terfenadine, vincamine IV.)

Digitalis glycosides: Thiazide-induced hypokalaemia or hypomagnesaemia favours the onset of digitalis-induced arrhythmia (see section 4.4).

Other antihypertensive agents: Telmisartan may increase the hypotensive effect of other antihypertensive agents.

Antidiabetic medicinal products (oral agents and insulin): Dosage adjustment of the antidiabetic medicinal products may be required (see section 4.4).

Metformin: Metformin should be used with precaution: risk of lactic acidosis induced by a possible functional renal failure linked to hydrochlorothiazide.

Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.

Non-steroidal anti-inflammatory medicinal products: NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics and the antihypertensive effects of angiotensin II receptor antagonists.

In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the AUC_0-24 and C_max of ramipril and ramiprilat. The clinical relevance of this observation is not known.

Pressor amines (e.g. noradrenaline): The effect of pressor amines may be decreased.

Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

Medicinal products used in the treatment for gout (e.g. probenecid, sulfinpyrazone and allopurinol): Dosage adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide may increase the incidence of hypersensitivity reactions of allopurinol.

Calcium salts: Thiazide diuretics may increase serum calcium levels due to the decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Beta-blockers and diazoxide: The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Amantadine: Thiazides may increase the risk of adverse effects caused by amantadine.

Cytotoxic agents (e.g. cyclophosphamide, methotrexate): Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.

Based on their pharmacological properties it can be expected that the following medicinal product may potentiate the hypotensive effects of all antihypertensives including telmisartan: Baclofen, amifostine.

Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics or antidepressants.

4.6 Pregnancy And Lactation

Pregnancy:

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

There are no adequate data from the use of MicardisPlus in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor antagonist therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).

Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see sections 4.3 and 4.4).

Thiazides cross the placental barrier and appear in cord blood. They may cause foetal electrolyte disturbances and possibly other reactions that have occurred in the adults. Cases of neonatal thrombocytopenia, of foetal or neonatal jaundice have been reported with maternal thiazide therapy.

Lactation:

Because no information is available regarding the use of MicardisPlus during breast-feeding, MicardisPlus is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Thiazides appear in human milk and may inhibit lactation.

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. However, when driving vehicles or operating machinery it should be taken into account that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy.

4.8 Undesirable Effects

Fixed Dose Combination

The overall incidence and pattern of adverse events reported with MicardisPlus 80 mg/25 mg was comparable with MicardisPlus 80 mg/12.5 mg. A dose-relationship of undesirable effects was not established and they showed no correlation with gender, age or race of the patients.

Adverse reactions reported in all clinical trials and occurring more frequently (p

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

very common (

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Infections and infestations
Rare: Not known:	Bronchitis Pharyngitis, sinusitis
Metabolism and nutrition disorders
Uncommon: Rare:	Hypokalaemia, Hyperuricaemia, hyponatraemia
Psychiatric disorders
Uncommon: Rare:	Anxiety Depression
Nervous system disorders
Common: Uncommon: Rare:	Dizziness Syncope, paraesthesia Insomnia, sleep disorders
Eye disorders
Rare:	Visual disturbance, vision blurred
Ear and labyrinth disorders
Uncommon:	Vertigo
Cardiac disorders
Uncommon:	Tachycardia, arrhythmias
Vascular disorders
Uncommon:	Hypotension, orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Uncommon: Rare:	Dyspnoea Respiratory distress (including pneumonitis and pulmonary oedema)
Gastrointestinal disorders
Uncommon: Rare: Not known:	Diarrhoea, dry mouth, flatulence Abdominal pain, constipation, dyspepsia, vomiting Gastritis
Hepatobiliary disorders
Rare:	Abnormal hepatic function/liver disorder
Skin and subcutaneous tissue disorders
Rare:	Angioedema, erythema, pruritus, rash, hyperhidrosis, urticaria
Muscoloskeletal, connective tissue and bone disorders
Uncommon: Rare:	Back pain, muscle spasms, myalgia Arthralgia, muscle cramps, pain in limb
Reproductive system and breast disorders
Uncommon:	Erectile dysfunction
General disorders and administration site conditions
Uncommon: Rare:	Chest pain Influenza-like illness, pain
Investigations
Uncommon: Rare:	Blood uric acid increased Blood creatinine increased, blood creatine phosphokinase increased, hepatic enzyme increased

Additional information on individual components

Undesirable effects previously reported with one of the individual components may be potential undesirable effects with MicardisPlus, even if not observed in clinical trials with this product.

Telmisartan:

Undesirable effects occurred with similar frequency in placebo and telmisartan treated patients.

The overall incidence of adverse events reported with telmisartan (41.4 %) was usually comparable to placebo (43.9 %) in placebo controlled trials. The following adverse drug reactions listed below have been accumulated from all clinical trials in patients treated with telmisartan for hypertension or in patients 50 years or older at high risk of cardiovascular events.

Adverse reactions of unknown frequency reported with the use of telmisartan alone include:

Infections and infestations
Not known:	Upper respiratory tract infection, urinary tract infection including cystitis, sepsis including fatal outcome*
Blood and lymphatic system disorders
Not known:	Eosinophilia, anaemia, thrombocytopenia
Immune system disorders
Not known:	Hypersensitivity, anaphylactic reactions
Metabolism and nutrition disorders
Not known:	Hyperkalaemia
Cardiac disorders
Not known:	Bradycardia
Gastrointestinal disorders
Not known:	Stomach discomfort
Skin and subcutaneous tissue disorders
Not known:	Eczema, drug eruption, toxic skin eruption
Musculoskeletal, connective tissue and bone disorders
Not known:	Arthrosis, tendon pain
Renal and urinary disorders
Not known:	Renal dysfunction, renal impairment (including acute renal failure)
General disorders and administration site conditions
Not known:	Asthenia
Investigations
Not known:	Haemoglobin decreased

*In the PRoFESS trial, an increased incidence of sepsis was observed with telmisartan compared with placebo. The event may be a chance finding or related to a mechanism currently not known (see section 5.1).

Hydrochlorothiazide:

Hydrochlorothiazide may cause or exacerbate hypovolaemia which could lead to electrolyte imbalance (see section 4.4).

Adverse reactions of unknown frequency reported with the use of hydrochlorothiazide alone include:

Infections and infestations
Not known:	Sialoadenitis
Blood and lymphatic system disorders
Not known:	Anaemia aplastic, haemolytic anaemia, bone marrow failure, leukopenia, neutropenia, agranulocytosis, thrombocytopenia
Immune system disorders
Not known:	Anaphylactic reactions, hypersensitivity
Endocrine disorders
Not known:	Diabetes mellitus inadequate control
Metabolism and nutrition disorders
Not known:	Anorexia, appetite decreased, electrolyte imbalance, hypercholesterolaemia, hyperglycaemia, hypovolaemia
Psychiatric disorders
Not known:	Restlessness
Nervous system disorders
Not known:	Light-headedness
Eye disorders
Not known:	Xanthopsia
Vascular disorders
Not known:	Vasculitis necrotizing
Gastrointestinal disorders
Not known:	Pancreatitis, stomach discomfort
Hepatobiliary disorders
Not known:	Jaundice hepatocellular, jaundice cholestatic
Skin and subcutaneous tissue disorders
Not known:	Lupus-like syndrome, photosensitivity reactions, skin vasculitis, toxic epidermal necrolysis
Musculoskeletal, connective tissue and bone disorders
Not known:	Weakness
Renal and urinary disorders
Not known:	Nephritis interstitial, renal dysfunction, glycosuria
General disorders and administration site conditions
Not known:	Pyrexia
Investigations
Not known:	Triglycerides increased

4.9 Overdose

There is limited information available for telmisartan with regard to overdose in humans. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.

Symptoms: The most prominent manifestations of telmisartan overdose were hypotension and tachycardia; bradycardia, dizziness, vomiting, increase in serum creatinine, and acute renal failure have also been reported. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and/or accentuate arrhythmia associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.

Treatment: Telmisartan is not removed by haemodialysis. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Angiotensin II receptor antagonists and diuretics, ATC code: C09DA07

MicardisPlus is a combination of an angiotensin II receptor antagonist, telmisartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone. MicardisPlus once daily produces effective and smooth reductions in blood pressure across the therapeutic dose range.

Telmisartan is an orally effective and specific angiotensin II receptor subtype 1 (AT₁) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT₁ receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT₁ receptor. Telmisartan selectively binds the AT₁ receptor. The binding is long-lasting. Telmisartan does not show affinity for other receptors, including AT₂ and other less characterised AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan. Plasma aldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore, it is not expected to potentiate bradykinin-mediated adverse effects.

An 80 mg dose of telmisartan administered to healthy volunteers almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up

Modrenal®

1. Name Of The Medicinal Product

Modrenal Capsules – 60 mg and 120 mg

2. Qualitative And Quantitative Composition

Each Modrenal capsule contains either 60 mg or 120 mg Trilostane (4α, 5-epoxy -17β - hydroxy -3 -OXO -5α -androstane -2α -carbonitrile.) (For excipients see 6.1)

3. Pharmaceutical Form

60 mg capsules: opaque pink/black Size 3 hard gelatine capsules marked with 60 on one end.

120 mg capsules: opaque pink/yellow Size 1 hard gelatine capsules marked with 120 on one end.

4. Clinical Particulars

4.1 Therapeutic Indications

(a) For the control of the manifestation of adrenal cortical hyperfunction in such conditions as hypercortisolism and primary aldosteronism.

(b) For the treatment of postmenopausal advanced breast cancer following relapse to initial hormone therapy e.g. oestrogen receptor antagonists.

4.2 Posology And Method Of Administration

Modrenal for oral administration only.

Adrenal Cortical Hyperfunction - 240 mg/day in divided doses for at least three days, then dose adjustment according to the patient's clinical response and appropriate biochemical monitoring. The usual dose is 120–480 mg/day but may be increased to 960 mg.

Postmenopausal Breast Cancer - The daily dose given in divided doses should increase stepwise every three days from 240 mg to 480 mg to 720 mg to 960 mg. This dose should be maintained but if it cannot be tolerated it may be reduced to 720 mg/day. From the start of Trilostane therapy a physiological replacement dose of a glucocorticoid (e.g. Hydrocortisone 30 mg/day in divided doses) should be given to prevent activation of the HPA axis.

Elderly - There are no special dosage recommendations.

4.3 Contraindications

Trilostane is contraindicated in pregnancy and children.

4.4 Special Warnings And Precautions For Use

Pregnancy should be excluded before beginning treatment and nonhormonal contraceptive methods should be used during therapy where appropriate.

As with all drugs that are metabolised by the liver and excreted by the kidney, caution should be exercised when treating patients with gross hepatic or renal impairment. It is advisable to monitor response when treating adrenal cortical hyperfunction, by regular assays of blood electrolytes and circulating corticosteroids, and adjust the dose accordingly. In some patients the suppression of aldosterone production may cause hyperkalaemia and hyponatraemia with subsequent hypotension – under these circumstances a mineralocorticoid should be given, e.g. Fludro-cortisone 0.1 mg/day. In other patients it is possible to produce corticosteroid insufficiency, especially if the production of ACTH is limited, and then a glucocorticoid may be necessary.

When treating hypercortisolism due to excess ACTH production (whether ectopic or pituitary), an initial response may be followed by a relapse if the hypophyseal/pituitary/adrenal (HPA) axis is still intact and is not suppressed. If, however, the excessive steroid production is due to an adrenal cortical tumour, or the HPA axis is no longer able to respond to lowered levels of circulating glucocorticoids, the condition will remain responsive to Trilostane.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

When administered concurrently with thiazide diuretics the inhibition of aldosterone production caused by Trilostane reduces potassium loss whilst maintaining the natriuretic effect.

4.6 Pregnancy And Lactation

The production of progesterone, which is necessary for the maintenance of pregnancy, is suppressed by Trilostane and so pregnancy may be limited.

No information is available on the secretion of Trilostane in breast milk.

4.7 Effects On Ability To Drive And Use Machines

Although there have been occasional reports of lethargy or drowsiness, Trilostane is unlikely to impair ability.

4.8 Undesirable Effects

Flushing, tingling in mouth, palatal swelling, rhinorrhoea, sickness, vomiting, diarrhoea, and cramps have been reported commonly. These are generally mild and reversible on adjusting dose, administering with food, stopping therapy and/or symptomatic treatment (e.g. antacid, antidiarrhoeal with a small dose of aspirin). More severe signs of stomach upset, e.g. bleeding or ulcer, usually occur with concurrent administration of nonsteroidal anti-inflammatory drugs – reducing the dose of these latter drugs and/or adding an H2 blocker will usually resolve these problems.

Skin rashes can occur occasionally but are usually self limiting.

Very rarely, in cancer patients whose bone marrow is compromised by disease or chemotherapy, granulocytopenia has been reported - it is reversible on stopping therapy.

4.9 Overdose

The LD50 in rats and mice is more than 16 grams/ kilogram.

In humans, if recently ingested, the drug should be removed by emesis or gastric lavage. Subsequent treatment will depend on the effect of the drug on blood electrolytes and corticosteroids.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Trilostane selectively and reversibly inhibits the enzyme system - 3β- hydroxysteroid dehydrogenase ∆5-4 isomerase – essential for the synthesis of all steroids in the adrenals, ovaries, testes and placenta. When used to treat adrenal cortical hyperfunction, it therefore lowers both glucocorticoid and mineralocorticoid steroids; however, providing there is a functioning HPA axis, when treating primary aldosteronism, the normal feedback mechanism prevents excessive lowering of glucocorticoids: equally a normally functioning renin/angiotensin/adrenal system prevents undue lowering of mineralocorticoids when treating hypercortisolism.

Trilostane's mechanism of action in postmenopausal breast cancer is attributed to similar inhibition of oestrogen biosynthesis, since oestrogen is a known growth promoter in breast tumours. Oestrogen also affects cell proliferation in breast cancer directly. The Two major pathways of oestrogen-dependent regulation of gene transcription and cell proliferation are:

- Ligand-bound oestrogen receptors (ERs) dimerise and bind to oestrogen response elements (EREs) in the promoter region of target genes.

- ERs also affect the transcriptional potency of the growth factor/tyrosine kinase activated growth promoting pathways by blocking activation of AP-1 protein (a heterodimer of c-fos/c-jun proto-oncogene products) at the AP1 activation site in target gene promoters.

In vitro study findings show that trilostane non-competitively inhibits the actions of oestrogen/ERs at both of these locations. This dual mode of action is achieved by (1) direct inhibition of ERα promoted transcription at EREs; (2) modulating ERβ so that the binding preference of oestrogen changes from the ERα subtype to favour binding to ERβ. This ERβ-modulation is particularly important at theAP-1 site, where ERβ is thought to inhibit the stimulatory actions of ERα.

5.2 Pharmacokinetic Properties

After oral administration, Trilostane is widely distributed, metabolised by the liver and excreted by the kidney. The major metabolite is 17-oxo Trilostane which has the same enzyme inhibiting activity as Trilostane. Following 120 mg orally, the Cmax is 0.69 µg/ml for Trilostane and 1.64 µg/ml for 17-oxo Trilostane at 2 hours; the half life of both is 1.2 hours.

5.3 Preclinical Safety Data

All species tested display a hyperplasia of the adrenal cortex due to compensatory overproduction of ACTH to correct the enzyme block. This is not a problem unless the HPA axis is compromised (see 4.4).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose, maize starch, magnesium stearate and, in capsule shell, gelatine, E171 and E172.

6.2 Incompatibilities

None.

6.3 Shelf Life

5 years

6.4 Special Precautions For Storage

The product should be stored below 25ºC.

6.5 Nature And Contents Of Container

60 mg capsules – brown, glass bottles containing 100 capsules with metal or LDPE screw top.

120 mg capsules – brown, glass bottles containing 100 capsules with metal or LDPE screw cap; or HDPE tablet containers with LDPE closure.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Bioenvision Limited

Bassett House, 5 Southwell Park Road, Camberley, Surrey GU15 3PU

8. Marketing Authorisation Number(S)

60 mg capsules - PL 19999/0002

120 mg capsules - PL 19999/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

27 June 1990

10. Date Of Revision Of The Text

05 February 2007

Mimpara

1. Name Of The Medicinal Product

Mimpara^® 30 mg film-coated tablets.

Mimpara^® 60 mg film-coated tablets.

Mimpara^® 90 mg film-coated tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 30 mg cinacalcet (as hydrochloride).

Each tablet contains 60 mg cinacalcet (as hydrochloride).

Each tablet contains 90 mg cinacalcet (as hydrochloride).

Each 30 mg tablet contains 2.74 mg of lactose.

Each 60 mg tablet contains 5.47 mg of lactose.

Each 90 mg tablet contains 8.21 mg of lactose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet (tablet).

30 mg: Light green, oval, film-coated tablets marked “AMG” on one side and “30” on the other.

60 mg: Light green, oval, film-coated tablets marked “AMG” on one side and “60” on the other.

90 mg: Light green, oval, film-coated tablets marked “AMG” on one side and “90” on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD) on maintenance dialysis therapy.

Mimpara may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate (see section 5.1).

Reduction of hypercalcaemia in patients with:

• parathyroid carcinoma.

• primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated.

4.2 Posology And Method Of Administration

Secondary hyperparathyroidism

Adults and elderly (> 65 years)

The recommended starting dose for adults is 30 mg once per day. Mimpara should be titrated every 2 to 4 weeks to a maximum dose of 180 mg once daily to achieve a target parathyroid hormone (PTH) in dialysis patients of between 150-300 pg/ml (15.9-31.8 pmol/l) in the intact PTH (iPTH) assay. PTH levels should be assessed at least 12 hours after dosing with Mimpara.Reference should be made to current treatment guidelines.

PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Mimpara. PTH should be monitored approximately every 1-3 months during maintenance. Either the intact PTH (iPTH) or bio-intact PTH (biPTH) may be used to measure PTH levels; treatment with Mimpara does not alter the relationship between iPTH and biPTH.

During dose titration, serum calcium levels should be monitored frequently, and within 1 week of initiation or dose adjustment of Mimpara. Once the maintenance dose has been established, serum calcium should be measured approximately monthly. If serum calcium levels decrease below the normal range, appropriate steps should be taken, including adjustment of concomitant therapy (see section 4.4).

Children and adolescents

Mimpara is not indicated for use in children and adolescents due to a lack of data on safety and efficacy (see section 5.2).

Parathyroid carcinoma and primary hyperparathyroidism

Adults and elderly (> 65 years)

The recommended starting dose of Mimpara for adults is 30 mg twice per day. The dose of Mimpara should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to reduce serum calcium concentration to or below the upper limit of normal. The maximum dose used in clinical trials was 90 mg four times daily.

Serum calcium should be measured within 1 week after initiation or dose adjustment of Mimpara. Once maintenance dose levels have been established, serum calcium should be measured every 2 to 3 months. After titration to the maximum dose of Mimpara, serum calcium should be periodically monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of Mimpara therapy should be considered (see section 5.1).

Children and adolescents

Mimpara is not indicated for use in children and adolescents due to a lack of data on safety and efficacy (see section 5.2).

Hepatic impairment

No change in starting dose is necessary. Mimpara should be used with caution in patients with moderate to severe hepatic impairment and treatment should be closely monitored during dose titration and continued treatment (see sections 4.4 and 5.2).

Method of administration

For oral use. It is recommended that Mimpara be taken with food or shortly after a meal, as studies have shown that bioavailability of cinacalcet is increased when taken with food (see section 5.2). Tablets should be taken whole and not divided.

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

Seizures

In three clinical studies of Chronic Kidney Disease (CKD) patients on dialysis, 5% of the patients in both the Mimpara and placebo groups reported a history of seizure disorder at baseline. In these studies, seizures were observed in 1.4% of Mimpara treated patients and 0.4% of placebo-treated patients. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels.

Hypotension and/or worsening heart failure

In post-marketing safety surveillance, isolated, idiosyncratic cases of hypotension and/or worsening heart failure have been reported in patients with impaired cardiac function, in which a causal relationship to cinacalcet could not be completely excluded and may be mediated by reductions in serum calcium levels. Clinical trial data showed hypotension occurred in 7% of cinacalcet-treated patients, 12% of placebo-treated patients, and heart failure occurred in 2% of patients receiving cinacalcet or placebo.

Serum calcium

Mimpara treatment should not be initiated in patients with a serum calcium (corrected for albumin) below the lower limit of the normal range. Since cinacalcet lowers serum calcium, patients should be monitored carefully for the occurrence of hypocalcaemia (see section 4.2). In CKD patients receiving dialysis who were administered Mimpara, 4% of serum calcium values were less than 7.5 mg/dl (1.875 mmol/l). In the event of hypocalcaemia, calcium-containing phosphate binders, vitamin D sterols and/or adjustment of dialysis fluid calcium concentrations can be used to raise serum calcium. If hypocalcaemia persists, reduce the dose or discontinue administration of Mimpara. Potential manifestations of hypocalcaemia may include paraesthesias, myalgias, cramping, tetany and convulsions.

Cinacalcet is not indicated for CKD patients not on dialysis. Investigational studies have shown that CKD patients not on dialysis treated with cinacalcet have an increased risk for hypocalcaemia (serum calcium levels < 8.4 mg/dl [2.1 mmol/l]) compared with cinacalcet-treated CKD patients on dialysis, which may be due to lower baseline calcium levels and/or the presence of residual kidney function.

General

Adynamic bone disease may develop if PTH levels are chronically suppressed below approximately 1.5 times the upper limit of normal with the iPTH assay. If PTH levels decrease below the recommended target range in patients treated with Mimpara, the dose of Mimpara and/or vitamin D sterols should be reduced or therapy discontinued.

Testosterone levels

Testosterone levels are often below the normal range in patients with end-stage renal disease. In a clinical study of ESRD patients on dialysis, free testosterone levels decreased by a median of 31.3% in the Mimpara-treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment. An open-label extension of this study showed no further reductions in free and total testosterone concentrations over a period of 3 years in Mimpara-treated patients. The clinical significance of these reductions in serum testosterone is unknown.

Hepatic impairment

Due to the potential for 2 to 4 fold higher plasma levels of cinacalcet in patients with moderate to severe hepatic impairment (Child-Pugh classification), Mimpara should be used with caution in these patients and treatment should be closely monitored (see sections 4.2 and 5.2).

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effect of other medications on cinacalcet

Cinacalcet is metabolised in part by the enzyme CYP3A4. Co-administration of 200 mg bid ketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcet levels. Dose adjustment of Mimpara may be required if a patient receiving Mimpara initiates or discontinues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducer (e.g. rifampicin) of this enzyme (see section 4.4).

In vitro data indicate that cinacalcet is in part metabolised by CYP1A2. Smoking induces CYP1A2; the clearance of cinacalcet was observed to be 36-38% higher in smokers than non-smokers. The effect of CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) on cinacalcet plasma levels has not been studied. Dose adjustment may be necessary if a patient starts or stops smoking or when concomitant treatment with strong CYP1A2 inhibitors is initiated or discontinued.

Calcium carbonate: Co-administration of calcium carbonate (single 1,500 mg dose) did not alter the pharmacokinetics of cinacalcet.

Sevelamer: Co-administration of sevelamer (2400 mg tid) did not affect the pharmacokinetics of cinacalcet.

Pantoprazole: Co-administration of pantoprazole (80 mg od) did not alter the pharmacokinetics of cinacalcet.

Effect of cinacalcet on other medications

Medicinal products metabolised by the enzyme P450 2D6 (CYP2D6): Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments of concomitant medicinal products may be required when Mimpara is administered with individually titrated, narrow therapeutic index substances that are predominantly metabolised by CYP2D6 (e.g., flecainide, propafenone, metoprolol given in heart failure, desipramine, nortriptyline, clomipramine) (see section 4.4).

Desipramine: Concurrent administration of 90 mg cinacalcet once daily with 50 mg desipramine, a tricyclic antidepressant metabolised primarily by CYP2D6, significantly increased desipramine exposure 3.6-fold (90 % CI 3.0, 4.4) in CYP2D6 extensive metabolisers.

Warfarin: Multiple oral doses of cinacalcet did not affect the pharmacokinetics or pharmacodynamics (as measured by prothrombin time and clotting factor VII) of warfarin.

The lack of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and the absence of auto-induction upon multiple dosing in patients indicates that cinacalcet is not an inducer of CYP3A4, CYP1A2 or CYP2C9 in humans.

Midazolam: Co-administration of cinacalcet (90 mg) with orally administered midazolam (2 mg), a CYP3A4 and CYP3A5 substrate, did not alter the pharmacokinetics of midazolam. These data suggest that cinacalcet would not affect the pharmacokinetics of those classes of drugs that are metabolized by CYP3A4 and CYP3A5, such as certain immunosuppressants, including cyclosporine and tacrolimus.

4.6 Pregnancy And Lactation

There are no clinical data from the use of cinacalcet in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, parturition or postnatal development. No embryonal/foetal toxicities were seen in studies in pregnant rats and rabbits with the exception of decreased foetal body weights in rats at doses associated with maternal toxicities (see section 5.3). Mimpara should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

It is not known whether cinacalcet is excreted in human milk. Cinacalcet is excreted in the milk of lactating rats with a high milk to plasma ratio. Following careful benefit/risk assessment, a decision should be made to discontinue either breast-feeding or treatment with Mimpara.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, certain adverse reactions may affect the ability to drive and use machines (see section 4.8).

4.8 Undesirable Effects

Secondary hyperparathyroidism

Data presented from controlled studies include 656 patients who received Mimpara and 470 patients who received placebo for up to 6 months. The most commonly reported adverse reactions were nausea and vomiting, occurring in 31% Mimpara and 19% placebo treated patients, and 27% Mimpara and 15% placebo treated patients, respectively. Nausea and vomiting were mild to moderate in severity and transient in nature in the majority of patients. Discontinuation of therapy as a result of undesirable effects was mainly due to nausea (1% placebo; 5% cinacalcet) and vomiting (< 1% placebo; 4% cinacalcet).

Adverse reactions, considered at least possibly attributable to cinacalcet treatment based on best-evidence assessment of causality and reported in excess of placebo in double-blind clinical studies are listed below using the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Immune system disorders

Uncommon: hypersensitivity reactions

Metabolism and nutrition disorders

Common: anorexia

Nervous system disorders

Common: dizziness, paraesthesia

Uncommon: seizures

Gastrointestinal disorders

Very common: nausea, vomiting

Uncommon: dyspepsia, diarrhoea

Skin and subcutaneous tissue disorders

Common: rash

Musculoskeletal, connective tissue and bone disorders

Common: myalgia

General disorders and administration site conditions

Common: asthenia

Investigations

Common: hypocalcaemia (see section 4.4), reduced testosterone levels (see section 4.4)

Parathyroid carcinoma and primary hyperparathyroidism

The safety profile of Mimpara in these patient populations is generally consistent with that seen in patients with Chronic Kidney Disease. The most frequent ADRs in these patient populations were nausea and vomiting.

Post-marketing experience

The following adverse reactions have been identified during postmarketing use of Mimpara, the frequencies of which cannot be estimated from available data:

• There have been reports of isolated, idiosyncratic cases of hypotension and/or worsening heart failure in cinacalcet-treated patients with impaired cardiac function in post marketing safety surveillance.

• Allergic reactions, including angioedema and urticaria.

4.9 Overdose

Doses titrated up to 300 mg once daily have been safely administered to patients receiving dialysis.

Overdose of Mimpara may lead to hypocalcaemia. In the event of overdose, patients should be monitored for signs and symptoms of hypocalcaemia, and treatment should be symptomatic and supportive. Since cinacalcet is highly protein-bound, haemodialysis is not an effective treatment for overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: anti-parathyroid agents. ATC code: H05BX01.

Mechanism of action

The calcium sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Cinacalcet is a calcimimetic agent which directly lowers PTH levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.

Reductions in PTH levels correlate with cinacalcet concentration. Soon after dosing, PTH begins to decrease until a nadir at approximately 2 to 6 hours post dose, corresponding with cinacalcet C_max. Thereafter, as cinacalcet levels begin to decline, PTH levels increase until 12 hours post-dose, and then PTH suppression remains approximately constant to the end of the once-daily dosing interval. PTH levels in Mimpara clinical trials were measured at the end of the dosing interval.

After steady state is reached, serum calcium concentrations remain constant over the dosing interval.

Secondary Hyperparathyroidism

Three, 6-month, double-blind, placebo-controlled clinical studies were conducted in ESRD patients with uncontrolled secondary HPT receiving dialysis (n=1136). Demographic and baseline characteristics were representative of the dialysis patient population with secondary HPT. Mean baseline iPTH concentrations across the 3 studies were 733 and 683 pg/ml (77.8 and 72.4 pmol/l) for the cinacalcet and placebo groups, respectively. 66% of patients were receiving vitamin D sterols at study entry, and > 90% were receiving phosphate binders. Significant reductions in iPTH, serum calcium-phosphorus product (Ca x P), calcium, and phosphorus were observed in the cinacalcet treated patients compared with placebo-treated patients receiving standard of care, and the results were consistent across the 3 studies. In each of the studies, the primary endpoint (proportion of patients with an iPTH

Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment. Cinacalcet decreased iPTH and Ca x P, calcium and phosphorus levels regardless of baseline iPTH or Ca x P level, dialysis modality (PD versus HD), duration of dialysis, and whether or not vitamin D sterols were administered.

Reductions in PTH were associated with non-significant reductions of bone metabolism markers (bone specific alkaline phosphatase, N-telopeptide, bone turnover and bone fibrosis). In post-hoc analyses of pooled data from 6 and 12 months clinical studies, Kaplan-Meier estimates of bone fracture and parathyroidectomy were lower in the cinacalcet group compared with the control group.

Investigational studies in patients with CKD and secondary HPT not undergoing dialysis indicated that cinacalcet reduced PTH levels to a similar extent as in patients with ESRD andsecondary HPT receiving dialysis. However, efficacy, safety, optimal doses and treatment targets have not been established in treatment of predialytic renal failure patients. These studies show that CKD patients not undergoing dialysis treated with cinacalcet have an increased risk for hypocalcaemia compared with cinacalcet-treated ESRD patients receiving dialysis, which may be due to lower baseline calcium levels and/or the presence of residual kidney function.

Parathyroid carcinoma and Primary Hyperparathyroidism

In a key study, 46 patients (29 with parathyroid carcinoma and 17 with primary HPT (who had failed or had contraindications to parathyroidectomy) received cinacalcet for up to 3 years (mean of 328 days for patients with parathyroid carcinoma and mean of 347 days for patients with primary HPT). Cinacalcet was administered at doses ranging from 30 mg twice daily to 90 mg four times daily. The primary endpoint of the study was a reduction of serum calcium of

5.2 Pharmacokinetic Properties

After oral administration of Mimpara, maximum plasma cinacalcet concentration is achieved in approximately 2 to 6 hours.

Based on between-study comparisons, the absolute bioavailability of cinacalcet in fasted subjects has been estimated to be about 20-25%. Administration of Mimpara with food results in an approximate 50 – 80% increase in cinacalcet bioavailability.Increases in plasma cinacalcet concentration are similar, regardless of the fat content of the meal.

After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of approximately 6 hours and a terminal half-life of 30 to 40 hours. Steady state drug levels are achieved within 7 days with minimal accumulation. The AUC and C_max of cinacalcet increase approximately linearly over the dose range of 30 to 180 mg once daily. At doses above 200 mg, the absorption was saturated probably due to poor solubility. The pharmacokinetics of cinacalcet does not change over time. The volume of distribution is high (approximately 1000 litres), indicating extensive distribution. Cinacalcet is approximately 97% bound to plasma proteins and distributes minimally into red blood cells.

Cinacalcet is metabolised by multiple enzymes, predominantly CYP3A4 and CYP1A2 (the contribution of CYP1A2 has not been characterised clinically). The major circulating metabolites are inactive.

Based on in vitro data, cinacalcet is a strong inhibitor of CYP2D6, but is neither an inhibitor of other CYP enzymes at concentrations achieved clinically, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 nor an inducer of CYP1A2, CYP2C19 and CYP3A4.

After administration of a 75 mg radiolabelled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolised by oxidation followed by conjugation. Renal excretion of metabolites was the prevalent route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the faeces.

Elderly:There are no clinically relevant differences due to age in the pharmacokinetics of cinacalcet.

Renal Insufficiency:The pharmacokinetic profile of cinacalcet in patients with mild, moderate, and severe renal insufficiency, and those on haemodialysis or peritoneal dialysis is comparable to that in healthy volunteers.

Hepatic Insufficiency:Mild hepatic impairment did not notably affect the pharmacokinetics of cinacalcet. Compared to subjects with normal liver function, average AUC of cinacalcet was approximately 2-fold higher in subjects with moderate impairment and approximately 4-fold higher in subjects with severe impairment. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not affected by impaired hepatic function. Because doses are titrated for each subject based on safety and efficacy parameters, no additional dose adjustment is necessary for subjects with hepatic impairment (see sections 4.2 and 4.4).

Gender: Clearance of cinacalcet may be lower in women than in men. Because doses are titrated for each subject, no additional dose adjustment is necessary based on gender.

Paediatric Population : The pharmacokinetics of cinacalcet have been studied in 12 paediatric patients (6_max values (23.5 (range 7.22 to 77.2) ng*hr/ml and 7.26 (range 1.80 to 17.4) ng/ml, respectively) were within approximately 30% of the means for AUC and C_max values observed in a single study in healthy adults following a single 30 mg dose (33.6 (range 4.75 to 66.9) ng*hr/ml and 5.42 (range 1.41 to 12.7) ng/ml, respectively). Due to the limited data in paediatric subjects, the potential for higher exposures in the lighter/younger relative to heavier/older paediatric subjects for a given dose of cinacalcet cannot be excluded. The pharmacokinetics in paediatric subjects after multiple doses has not been studied.

Smoking: Clearance of cinacalcet is higher in smokers than in non-smokers, likely due to induction of CYP1A2- mediated metabolism. If a patient stops or starts smoking, cinacalcet plasma levels may change and dose adjustment may be necessary.

5.3 Preclinical Safety Data

Cinacalcet was not teratogenic in rabbits when given at a dose of 0.4 times, on an AUC basis, the maximum human dose for secondary HPT (180 mg daily). The non-teratogenic dose in rats was 4.4 times, on an AUC basis, the maximum dose for secondary HPT. There were no effects on fertility in males or females at exposures up to 4 times a human dose of 180 mg/day (safety margins in the small population of patients administered a maximum clinical dose of 360 mg daily would be approximately half those given above).

In pregnant rats, there were slight decreases in body weight and food consumption at the highest dose. Decreased foetal weights were seen in rats at doses where dams had severe hypocalcaemia. Cinacalcet has been shown to cross the placental barrier in rabbits.

Cinacalcet did not show any genotoxic or carcinogenic potential. Safety margins from the toxicology studies are small due to the dose-limiting hypocalcaemia observed in the animal models. Cataracts and lens opacities were observed in the repeat dose rodent toxicology and carcinogenicity studies, but were not observed in dogs or monkeys or in clinical studies where cataract formation was monitored. Cataracts are known to occur in rodents as a result of hypocalcaemia.

In in vitro studies, IC₅₀ values for the serotonin transporter and K_ATP channels were found to be 7 and 12 fold greater, respectively, than the EC₅₀ for the calcium-sensing receptor obtained under the same experimental conditions. The clinical relevance is unknown, however, the potential for cinacalcet to act on these secondary targets cannot be fully excluded.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet Core

Pre-gelatinised starch (maize)

Microcrystalline cellulose

Povidone

Crospovidone

Magnesium stearate

Colloidal anhydrous silica

Tablet Coat

Carnauba wax

Opadry II green:	(Lactose monohydrate, hypromellose, titanium dioxide (E171), glycerol triacetate, FD&C Blue (E132), iron oxide yellow (E172)
Opadry clear:	(Hypromellose, macrogol)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Blister: 4 years.

Bottle: 4 years.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Aclar/PVC/PVAc/Aluminium blister containing 14 tablets. Pack sizes of 1 blister (14 tablets), 2 blisters (28 tablets), 6 blisters (84 tablets) per carton.

High Density Polyethylene (HDPE) bottle with a cotton coil, and a child-resistant polypropylene cap with an induction seal, packed into a carton. Each bottle contains 30 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

The Netherlands

8. Marketing Authorisation Number(S)

EU/1/04/292/001-003

EU/1/04/292/004

EU/1/04/292/005-007

EU/1/04/292/008

EU/1/04/292/009-011

EU/1/04/292/012

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 22 October 2004

Date of renewal of the authorisation: 23 September 2009

10. Date Of Revision Of The Text

31 August 2009

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