Perdix 7.5 mg film-coated tablets

Each Perdix 7.5 mg tablet contains moexipril hydrochloride 7.5 mg.

Excipients:

Each tablet contains 71 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

Film-coated tablet.

Each Perdix 7.5 mg tablet is pink, round, convex, with a break line above and marked SP/7.5 on the upper side and 707 on the lower side.

The tablet can be divided into equal halves.

For the treatment of hypertension as monotherapy.

As second line therapy for the treatment of hypertension in combination with diuretics or calcium antagonists e.g. hydrochlorothiazide or nifedipine.

Initial therapy:

In patients with uncomplicated essential hypertension not on diuretic therapy, the recommended initial dose is 7.5 mg once a day. Dosage should be adjusted according to blood pressure response. The maintenance dose is 7.5 to 15 mg moexipril daily, administered in a single dose. Some patients may benefit from a further increase to 30 mg per day.

Doses over 30 mg have been used, but do not appear to give a greater effect.

If blood pressure is not controlled with Perdix alone, a low dose of a diuretic may be added. Hydrochlorothiazide 12.5 mg has been shown to provide an additive effect. With concomitant diuretic therapy, it may be possible to reduce the dose of Perdix.

Diuretic treated patients:

In hypertensive patients who are currently being treated with a diuretic, symptomatic hypotension may occur occasionally following the initial dose of Perdix. The diuretic should be discontinued, if possible, for two to three days before beginning therapy with Perdix to reduce the likelihood of hypotension (see section 4.4). The dosage of Perdix should be adjusted according to blood pressure response. If the patient's blood pressure is not controlled with Perdix alone, diuretic therapy may be resumed as described above.

If the diuretic cannot be discontinued or the diuretic has recently been withdrawn, an initial dose of 3.75 mg (half 7.5 mg tablet) should be used under medical supervision for at least two hours and until blood pressure has stabilised for at least an additional hour (see section 4.4).

Concomitant administration of Perdix with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see section 4.4).

Patients on antihypertensive treatment:

As add-on therapy, Perdix has been investigated in combination with nifedipine. If Perdix is used as add-on therapy to nifedipine or other antihypertensive agents, the starting dose of Perdix should be 3.75 mg (half 7.5 mg tablet).

Elderly patients:

In elderly patients, an intial dosage of 3.75 mg (half 7.5 mg tablet) once daily is recommended followed by titration to the optimal response.

Renal failure:

• Severe Renal Failure (creatinine clearance < 40 ml/min): An initial dose of 3.75 mg of Perdix (half 7.5 mg tablet) once daily must be given cautiously. Doses may be titrated upward to a maximum daily dose of 15 mg.

• Moderate Renal Impairment (creatinine clearance> 40 ml/min: Based on the available studies with Perdix, no dose adaptation is necessary. However a decreased initial dose could be considered, e.g. 3.75 mg (half 7.5 mg tablet).

Hepatic cirrhosis:

In patients with hepatic cirrhosis, an intial dose of 3.75 mg of moexipril (half 7.5 mg tablet) is recommended.

Afro-Caribbean patients:

Where Perdix is used as a single agent in hypertension, Afro-Caribbean patients may show a reduced therapeutic response.

Paediatric population:

Not recommended. Safety and efficacy in children has not been established.

Perdix must not be used in:

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

• History of angioneurotic oedema associated with previous ACE inhibitor therapy

• Hereditary/idiopathic angioneurotic oedema

• Second and third trimesters of pregnancy. (See sections 4.4 and 4.6).

Perdix should be used with caution in patients with:

• Renal artery stenosis (bilateral or stenosis of an anatomic or functional solitary kidney)

• Recent kidney transplantation

• Hemodynamic important aortic or mitral valve stenosis

• Hypertrophic cardiomyopathy

• Severely impaired renal function (creatinine clearance < 40 ml/min)

• Hyperkalaemia

• Decreased immune response

• Collagenous vascular diseases (e.g. lupus erythematosus, sclerodermia)

• Concomitant systemic drug therapy suppressing the immune response (e.g. corticosteroids, cytostatic agents, antimetabolites) and allopurinol, procainamide, or lithium

There is a risk of life-threatening anaphylactic reactions when ACE inhibitors are used

• During dialysis or hemofiltration with poly-(acrylonitrile, natrium-2-methylallylsulfonat)-high-flux-membranes

• During low density lipoprotein (LDL) apheresis with dextrane sulphate

• During desensitization therapy for insect poisons (e.g. bee or wasp stings).

Consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent in such patients.

Owing to the lack of sufficient therapeutic experience, Perdix is not recommended in:

• Patients with primary liver disease or impaired liver function

• Patients with untreated decompensated heart failure

Especially at the beginning of the ACE inhibitor therapy the blood pressure and the respective laboratory values must be monitored carefully in patients with:

• Impaired renal function (creatinine clearance 40-60 ml/min)

• Renal hypertension

• Cardiac failure

• Salt and/or fluid volume depletion

• Age of more than 65 years

Hypotension:

Perdix may cause a profound fall of blood pressure, especially at the beginning of the therapy with symptoms of dizziness, feeling of weakness, and disturbances of vision. Rarely syncope may occur. Symptomatic hypotension is rare in uncomplicated hypertensive patients and is more likely to occur in patients who have been volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea, or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with Perdix.

Excessive hypotension caused by ACE inhibitor therapy in patients with congestive heart failure, with or without concomitant renal insufficiency, may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. Those patients must be followed closely at the beginning of therapy and whenever the dose of Perdix is increased.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, sodium chloride infusion given. Perdix treatment usually can be continued when adequate blood pressure and correction of the fluid volume is achieved.

Diuretic treated patients

In hypertensive patients who are currently being treated with a diuretic, symptomatic hypotension may occur occasionally following the initial dose of Perdix. (See also section 4.2).

Renal vascular hypertension

Before ACE inhibitor therapy is started, renal function has to be controlled. There is an increased risk of severe hypotension and renal insufficiency when patients with renal vascular hypertension are treated with Perdix. Loss of renal function may occur with only mild changes in serum creatinine.

Impaired renal function:

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure, whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including Perdix, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

In hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with other ACE inhibitors suggests that these increases are usually reversible upon discontinuation of ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Perdix has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. A reduction in the dose of Perdix and/or discontinuation of the diuretic may be required.

Evaluation of hypertensive patients should always include assessment of renal function.

Impaired renal function decreases total clearance of moexiprilat and approximately doubles AUC.

Angioneurotic oedema:

Angioneurotic oedema of the face, lips, mucous membranes, tongue, glottis or larynx and of the extremities has been reported in patients treated with ACE inhibitors, especially during the first weeks of treatment. However, in rare cases severe angioneurotic oedema may develop even after long-term treatment with an ACE inhibitor. Treatment must promptly be discontinued and replaced by another class of antihypertensive medicinal products.

Angioneurotic oedema involving the tongue, glottis or larynx, may be fatal due to airway obstruction. Emergency therapy must include intravenous administration of corticosteroids, H₁-receptor antagonists and H₂-receptor antagonists. If the condition of the patient does not improve with the above mentioned therapy, epinephrine must be administered slowly intravenously monitored by ECG control.

In case of hereditary angioneurotic oedema due to C1-inactivator deficiency associated with ACE inhibitor therapy, additionally a C1-inactivator must be administered.

Furthermore, intubation or tracheotomy must be considered. (See section 4.8).

Intestinal angioneurotic oedema:

Intestinal angioneurotic oedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea and vomiting). In some cases there was no prior history of facial angioneurotic oedema and C1-esterase levels were normal. Intestinal angioneurotic oedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery. Symptoms resolved after stopping the ACE inhibitor. Intestinal angioneurotic oedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Pregnancy

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor 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 ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Cough:

During treatment with an ACE inhibitor a dry and non-productive cough may occur which disappears after discontinuation.

Hyperkalaemia:

In clinical trials, persistent hyperkalaemia (serum potassium> 5.4 mEq/l) occurred in approximately 2.6% of hypertensive patients. In clinical trials, 0.1% of patients (two patients) were discontinued from therapy due to elevated serum potassium. Risk factors for the development of hyperkalaemia with ACE inhibitors include renal insufficiency and/or heart failure, diabetes mellitus and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Perdix.

Elderly

Some elderly patients may be more responsive to Perdix than younger patients. Control of renal function before start and during therapy is recommended. For dosage recommendations in elderly patients see 4.2.

Surgery/anaesthesia:

In patients undergoing surgery or during anaesthesia with agents that produce hypotension, Perdix will block the effect of compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion (see section 4.8)

Neutropenia/agranulocytosis:

Other ACE inhibitors have been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more frequently in patients with renal impairment, especially if they also have a collagenosis such as systemic lupus erythematosus or dermatosclerosis. Available data from clinical trials of Perdix are insufficient to show that it does not cause agranulocytosis at similar rates. Monitoring of white blood cell counts should be considered for patients with collagenosis, especially if the disease is associated with impaired renal function.

Lactose

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption must not take Perdix.

Diuretics:

Excessive reductions in blood pressure, especially in patients in whom diuretic therapy was recently instituted, have been reported with ACE inhibitors. The possibility of hypotensive effects with Perdix can be minimised by discontinuing diuretic therapy or increasing salt intake for several days before initiation of treatment with Perdix. If this is not possible, the starting dose should be reduced (see sections 4.2 and 4.4).

Antihypertensive agents:

The co-administration of antihypertensive agents, including nifedipine, with Perdix gives rise to an enhanced antihypertensive effect.

Potassium supplements and potassium-sparing diuretics:

Perdix can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride) potassium supplements or potassium-containing salt substitutes have been shown to increase the risk of hyperkalaemia when used concomitantly with ACE inhibitors. Therefore, if concomitant use of such agents is indicated, because of demonstrated hypokalemia, they should be given with caution and with frequent monitoring of serum potassium.

Oral anticoagulants:

Interaction studies with warfarin failed to identify any clinically important effects on the serum concentrations of the anticoagulants or on their anticoagulant effects.

Lithium:

Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be co-administered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Anaesthetic medicinal products:

Perdix may enhance the hypotensive effects of certain anaesthetic medicinal products.

Narcotic medicinal products/Antipsychotics:

Postural hypotension may occur.

Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide:

Concomitant administration with Perdix may lead to an increased risk of leucopenia.

Antacids:

Decreased bioavailability of ACE inhibitiors may occur.

Sympathomimetics:

Sympathomimetics may reduce the antihypertensive effects of Perdix. Patients must be carefully monitored to confirm that the desired effect is being achieved.

Gold:

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension leading to collapse) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor.

Non-Steroidal anti-inflammatory drugs:

The administration of NSAIDs may reduce the antihypertensive effect of Perdix. Furthermore, it has been reported that NSAIDs and ACE inhibitors exert an additive effect on increase in serum potassium, whereas renal function may decrease. These effects are in principle reversible, and occur especially in patients with compromised renal function.

Alcohol:

Alcohol enhances the hypotensive effect of Perdix.

Antidiabetic medicinal products:

Antidiabetic medicinal products (insulins or sulphonylureas). A reduction in blood sugar may occur.

Other agents:

No clinically important pharmacokinetic interactions occurred when Perdix was administered concomitantly with hydrochlorothiazide, digoxin, cimetidine, or nifedipine in healthy volunteers. However, in hypertensive patients, the antihypertensive effect of Perdix was enhanced when given in combination with diuretics, or calcium antagonists.

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. Unless continued ACE inhibitor 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 ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).

Lactation

Because no information is available regarding the use of Perdix during breast-feeding, Perdix is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

The intake of ACE inhibitors may – as any antihypertensive therapy – induce hypotension with subsequent impairment of reactivity. Alcohol intake may enhance this effect.

The most commonly reported undesirable effects (more than 1% of patients treated with Perdix in controlled trials) were cough (4.0%), headache (3.6%), dizziness (3.3%), fatigue (1.2%), flushing (1.2%), and rash (1.0%).

Other adverse experiences possibly or probably related, or of uncertain relationship to therapy, reported in controlled or uncontrolled clinical trials occurring in less than 1% of Perdix patients and less frequent clinically significant events which have been attributed to ACE inhibitors include the following:

Cardiovascular:

Symptomatic hypotension, postural hypotension, or syncope was seen in < 1% of patients; these reactions led to discontinuation of therapy in controlled trials in 2 patients (0.1%) who had received Perdix monotherapy and in 1 patient (0.05%) who had received Perdix with hydrochlorothiazide. Other reports included chest pain, angina/myocardial infarction, tachycardia, palpitations, rhythm disturbances, transient ischaemic attacks, cerebrovascular accident.

Renal:

Of hypertensive patients with no apparent pre-existing renal disease, 0.8% of patients receiving Perdix alone and 1.5% of patients receiving Perdix with hydrochlorothiazide have experienced increases in serum creatinine to at least 140% of their baseline values.

Acute renal failure has been reported for ACE inhibitors including Perdix (see section 4.4 Special Warnings and Precautions for use).

Gastrointestinal:

Abdominal pain, dyspepsia, constipation, nausea, vomiting, diarrhoea, appetite/weight change, dry mouth, pancreatitis, hepatitis.

Intestinal Angioedema:

Intestinal Angioedema has been reported in patients treated with ACE inhibitors (see section 4.4 Special Warnings and Precautions for use).

Respiratory:

Upper respiratory infection, pharyngitis, sinusitis/rhinitis, bronchospasm, dyspnoea.

Urogenital:

Renal insufficiency.

Dermatologic:

Occasionally allergic and hypersensitivity reactions can occur like rash, pruritus, urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermic necrolysis, psoriasis-like efflorescence, pemphigus and alopecia. This can be accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased ANA-titres. ACE inhibitors have been associated with the onset of angioneurotic oedema in a small subset of patients involving the face and oropharyngeal tissues.

Neurological and psychiatric:

Headache or tiredness may occasionally occur; rarely there may be drowsiness, depression, sleep disturbances, impotence, tingling sensations, numbness or paraesthesia, disturbances of balance, confusion, tinnitus, blurred vision, and alterations of taste or a transient loss of taste.

Other

Sweating, flu syndrome, malaise.

Clinical Laboratory Test Findings:

Decreases in haemoglobin, haematocrit, platelets and white cell count and individual cases of agranulocytosis or pancytopenia, as well as elevation of liver enzymes and serum bilirubin have been reported in a few patients. In patients with congenital deficiency concerning G-6-PDH individual cases of haemolytic anaemia have been reported.

In rare cases, especially in patients with impaired kidney function or collagen disease, or those simultaneously receiving treatment will allopurinol, procainamide or certain drugs which suppress the defence reactions, there may be anaemia, thrombocytopenia, neutropenia, eosinophilia and in isolated cases, even agranulocytosis or pancytopenia.

Creatinine and blood urea nitrogen:

As with other ACE inhibitors, minor increases in blood urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in approximately 1% of patients with essential hypertension who were treated with Perdix. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with compromised renal function.

Potassium:

Since moexipril decreases aldosterone secretion, elevation of serum potassium can occur. Potassium supplements and potassium-sparing diuretics should be given with caution and the patient's serum potassium should be monitored frequently.

Other:

Clinically important changes in standard laboratory tests were rarely associated with Perdix administration. Elevations of liver enzymes and uric acid have been reported. In trials, less than 1% of moexipril-treated patients discontinued Perdix treatment because of laboratory abnormalities.

Symptoms and treatment:

To date, no case of overdosage has been reported.

Symptoms of overdose would be severe hypotension, shock, stupor, bradycardia, electrolyte disturbances and renal failure. Treatment must be symptomatic and supportive.

After ingestion of an overdose, the patients must be kept under close supervision, preferably in an intensive care unit. Serum electrolytes and creatinine must be monitored frequently. Therapeutic measures depend on the nature and severity of the symptoms. Measures to prevent absorption and to hasten elimination, such as administration of absorbents, must be applied if ingestion is recent, within 1 hour after intake. If hypotension occurs, the patient must be placed in a supine position and salt and volume supplementation must be given rapidly. Treatment with angiotensin II infusion and/or intravenous catecholamines must be considered. Bradycardia or extensive vagal reactions must be treated by administering atropine. The use of a pacemaker may be considered. It is not yet known whether Perdix is removed by haemodialysis.

Pharmacotherapeutic class: ACE inhibitor

ATC Code: C09AA13

In animals as well as in humans, interactions between the renin-angiotensin-aldosterone system and the kallikrein-kinin system provide an important biochemical basis for blood pressure homeostasis. In hypertension the normal feedback mechanism formed by the renin-angiotensin system (RAS) may be dysfunctional, resulting in a self-perpetuating hypertensive condition.

Angiotensin converting enzyme (ACE) inhibitors were developed to interrupt this system and thereby to lower blood pressure. Perdix potently inhibits ACE and by this the formation of angiotensin II, the active agent of the RAS, thus blocking its vasoconstrictor and sodium-retaining effects with a consequent reduction in blood pressure.

Since ACE is identical is kininase II, an enzyme that degrades the potent vasodilator bradykinin, inhibition of ACE leads to an additional, non renin-mediated reduction in systemic blood pressure. The antihypertensive effects of ACE inhibitors are accompanied by a reduction in peripheral vascular

The prodrug moexipril is rapidly absorbed and de-esterified to the active metabolite moexiprilate. The pharmacokinetic parameters for moexipril and moexiprilate were similar after both, single and multiple does of moexipril and appear to be dose-proportional.

Moexipril and moexiprilate are moderately bound to plasma proteins, predominately albumin. Therefore, concurrently administered drugs are unlikely to interfere with the binding of moexipril and moexiprilate in any clinically significant way. Metabolites of moexipril present in the diketopiperazine derivatives of moexipril and moexiprilate. Both, moexipril and moexiprilate are eliminated in the urine, and moexiprilate is eliminated in the faeces.

The pharmacokinetic profile of moexipril and moexiprilate should allow the same dosage recommendation in patients with mild to moderate renal dysfunction (Cl_cr> 40 ml/min) as in patients with normal renal function. With severe renal dysfunction, dosage reduction is recommended. In patients with liver cirrhosis, the pharmacokinetics of moexipril and moexiprilate were significantly altered as compared with normal subjects.

There were no apparent pharmacokinetic drug interactions with HCTZ, digoxin, cimetidine, warfarin or nifedipine.

Acute toxicity:

Findings of the acute toxicity studies in animals do not raise questions as to the safety of moexipril HCl as well as the main metabolite moexiprilate under the conditions of proposed clinical usage.

Subacute/chronic toxicity:

Subacute and chronic toxicity studies in rats and dogs with repeated oral administration of moexipril HCl up to 12 months, revealed mainly heart and kidney as target organs. The effects are completely comparable with those of other ACE inhibitors and can be interpreted as results of highly exaggerated pharmacological activity.

First unspecific drug-related side-effects after long-term administration were seen at 75 mg/kg, i.e. a dose which corresponds 150 times the maximum recommended total daily dose in humans when compared on the basis of body weight.

Reproduction studies:

Studies in rats and rabbits including all segments of reproduction revealed no direct effects of moexipril HCl on fertility, reproduction and abnormalities in F₁– or F₂– pups.

Regarding precautions in women of child bearing potential and use during pregnancy and lactation see 4.3 and 4.6.

Mutagenicity:

As conclusion of different 'in vitro' and one 'in vivo' mutagenicity studies, the mutagenic potential of moexipril HCl for human beings should be extremely low.

Carcinogenicity:

Neither the long-term toxicity studies in rats and dogs nor special carcinogenicity studies in mice and rats over 78 and 104 weeks respectively, indicated neoplastigenic properties of moexipril HCl. Therefore, it can be concluded that the carcinogenic risk for human beings will be extremely low.

Lactose monohydrate

Crospovidone

Light magnesium oxide

Gelatin

Magnesium stearate

Hypromellose

Hydroxypropylcellulose

Macrogol 6000

Titanium dioxide [E171]

Ferric oxide [E172].

Not applicable.

5 years.

Store in the original package.

Calendar packs containing 28 tablets, 14 per Al/Al blister pack.

No special requirements.

UCB Pharma Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

United Kingdom

PL 00039/0754

01 April 2009

August 2010