SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Zofenopril / Hydrochlorothiazide Mylan 30 mg / 12.5 mg Film-coated Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 30 mg of zofenopril calcium (equivalent to 28.7 mg zofenopril) and 12.5 mg hydrochlorothiazide.
Excipient with known effect: Each film-coated tablet contains 47.50 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet.
Beige, film-coated, round, biconvex tablet debossed with “M” on one side of the tablet and “Z” over the score and “H” below the score on the other side of the tablet.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of mild to moderate essential hypertension. This fixed dose combination is indicated in patients whose blood pressure is not adequately controlled on zofenopril alone.
4.2 Posology and method of administration
Posology Zofenopril / Hydrochlorothiazide Mylan should be used once daily. Dose titration with the individual components (i.e. zofenopril and hydrochlorothiazide) is recommended before changing to the fixed dose combination.
When clinically appropriate direct change from monotherapy to the fixed combination may be considered.
Adults (18 to 65 years of age)
Patients without volume or salt depletion The usual effective dose is one tablet once daily.
Patients suspected of volume or salt depletion The use of zofenopril / hydrochlorothiazide is not recommended.
Older people (over 65 years) In older people with normal creatinine clearance no dose adjustment is necessary.
In older people with reduced creatinine clearance (less than 45 mL/min) the use of zofenopril / hydrochlorothiazide is not recommended.
Creatinine clearance may be estimated from serum creatinine by the following Cockroft- Gault formula: [(140-age) * weight (Kg)] CrCl (mL/min) 72 *serum Cr (mg/dL)
The above method provides creatinine clearance in males. For females the value obtained should be multiplied by 0.85.
Paediatric population (under 18 years) The safety and efficacy of zofenopril / hydrochlorothiazide in children and adolescents has not been established. Therefore, its use is not recommended.
Patients with renal impairment and dialysis In hypertensive patients with mild impairment (creatinine clearance > 45 mL/min) the same dose level and once-daily regimen of zofenopril / hydrochlorothiazide can be employed as for patients with normal renal function.
In patients with moderate to severe impairment (creatinine clearance < 45 mL/min) its use is not recommended (see section 4.4).
In patients with severe renal impairment (creatinine clearance < 30 ml/min) zofenopril / hydrochlorothiazide is contraindicated (see section 4.3).
In hypertensive patients maintained on dialysis the use of zofenopril / hydrochlorothiazide is not recommended.
Patients with hepatic impairment In hypertensive patients with mild to moderate hepatic impairment, where the 30 mg dose of zofenopril alone has been achieved, the same dose regimen can be employed as for patients with normal hepatic function.
In hypertensive patients with severe liver impairment zofenopril / hydrochlorothiazide is contraindicated.
Method of administration
For oral use.
Zofenopril / Hydrochlorothiazide Mylan can be taken with or without food.
To ease swallowing, tablets may be broken in two parts and swallowed one half after the other, at the prescribed time of administration.
4.3 Contraindications
Second and third trimesters of pregnancy (see sections 4.4 and 4.6). Hypersensitivity to the active substances, other ACE–inhibitors or sulfonamide- derived substances or to any of the excipients listed in section 6.1. History of angioneurotic oedema associated with previous ACE-inhibitor therapy. Hereditary/idiopathic angioneurotic oedema. Severe hepatic impairment. Severe renal impairment (creatinine clearance < 30 mL/min). Bilateral renal artery stenosis or unilateral renal artery stenosis in cases of a solitary single kidney. The concomitant use of zofenopril / hydrochlorothiazide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR ˂ 60 ml/min/1.73 m2) (see sections 4.5 and 5.1). Concomitant use with sacubitril/valsartan therapy. Zofenopril / hydrochlorothiazide must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections 4.4 and 4.5).
4.4 Special warnings and precautions for use
ZOFENOPRIL
Hypotension As with other ACE-inhibitors and diuretics, zofenopril / hydrochlorothiazide may cause a profound fall in blood pressure especially after the first dose, although symptomatic hypotension is seen rarely in uncomplicated hypertensive patients.
It is more likely to occur in patients who have been volume and electrolyte depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension (see sections 4.5 and 4. 8).
In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is more likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment.
In patients at increased risk of symptomatic hypotension, treatment should be started under close medical supervision preferably in the hospital, with low doses and careful dose titration. If possible, diuretic treatment should be discontinued temporarily when therapy with zofenopril / hydrochlorothiazide is initiated.
Such considerations apply also to patients with angina pectoris or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.
If hypotension develops, the patient should be placed in a supine position. Volume repletion with intravenous normal saline may be required. The occurrence of hypotension after the initial dose does not preclude subsequent careful dose titration with each component of the medicinal product after effective management.
Patients with 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 ACE-inhibitors. Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only mild changes in serum creatinine even in patients with unilateral renal artery stenosis.
In these patients, therapy should be initiated under close medical supervision with low dose, careful titration and monitoring of renal function.
Patients with renal insufficiency Close monitoring of renal function during therapy should be performed as deemed appropriate. Renal failure has been reported in association with ACE-inhibitors, mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. Some patients, with no apparent pre-existing renal disease have developed increases in blood urea and creatinine concentrations, particularly when a diuretic is given concomitantly. Dosage reduction of the individual components may be required. It is recommended that the renal function be monitored closely during the first few weeks of therapy.
Patients who are dialysed Patients who are dialysed using high-flux polyacrylonitrile membranes (e.g. AN 69) and treated with ACE-inhibitors are likely to experience anaphylactoid reactions such as facial swelling, flushing, hypotension and dyspnoea within a few minutes of commencing haemodialysis. It is recommended to use an alternative membrane or an alternative antihypertensive medicinal product.
The efficacy and safety of zofenopril in myocardial infarction patients undergoing haemodialysis has not been established. Therefore, it should not be used in these patients.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Patients on LDL apheresis Patients treated with an ACE-inhibitor undergoing LDL apheresis with dextran sulfate may experience anaphylactoid reactions similar to those seen in patients undergoing haemodialysis with high-flux membranes (see above). It is recommended that an agent from another class of antihypertensive products is used in these patients.
Anaphylactic reactions during desensitisation or after insect bites Rarely, patients receiving ACE-inhibitors during desensitisation treatment (e.g. hymenoptera venom) or after insect bites have experienced life-threatening anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE-inhibitors were temporarily withheld but they have reappeared upon inadvertent re-administration of the medicinal product. Therefore, caution should be used in patients treated with ACE-inhibitors undergoing such desensitisation procedures.
Kidney transplantation There is no experience regarding the administration of zofenopril / hydrochlorothiazide in patients with a recent kidney transplantation. Its use in transplant recipients is therefore not recommended.
Primary aldosteronism Patients with primary aldosteronism generally will not respond to antihypertensive products acting through inhibition of the renin-angiotensin system. Therefore the use of zofenopril is not recommended.
Hypersensitivity/angioedema Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx may occur in patients treated with ACE-inhibitors which occurs most frequently during the first weeks of treatment. However in rare cases severe angioedema may develop after long- term treatment with an ACE-inhibitor. Treatment with ACE-inhibitors should promptly be discontinued and replaced by an agent belonging to another class of antihypertensive products.
Angioedema involving the tongue, glottis or larynx may be fatal. Emergency therapy should be given including, but not necessarily limited to, immediate subcutaneous adrenaline solution 1:1,000 (0.3 to 0.5 ml) or slow intravenous adrenaline 1 mg/ml (which should be diluted as instructed) with close monitoring of ECG and blood pressure. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.
Even in such instances where swelling of only the tongue is involved, without respiratory distress, patients may require observation since treatment with antihistamines and corticosteroids may not be sufficient.
ACE-inhibitors cause a higher rate of angioedema in black patients than in non-black patients.
Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving an ACE-inhibitor (see section 4.3).
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of zofenopril / hydrochlorothiazide. Treatment with zofenopril / hydrochlorothiazide must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.
Cough During treatment with ACE-inhibitors a dry and non-productive cough may occur which disappears after discontinuation of therapy. ACE-inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Hepatic failure Rarely, ACE-inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE-inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE-inhibitor and receive appropriate medical follow-up.
Serum potassium ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function, diabetes mellitus and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, heparin, trimethoprim or co-trimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin receptor blockers, hyperkalemia can occur. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors. and serum potassium and renal function should be monitored (see section 4.5).
Surgery/anaesthesia ACE-inhibitors may cause hypotension or even hypotensive shock in patients undergoing major surgery or during anaesthesia, since they may block angiotensin II formation secondary to compensatory renin release. If it is not possible to withhold the ACE-inhibitor, intravascular and plasma volumes should be carefully monitored.
Aortic and mitral valve stenosis/hypertrophic cardiomyopathy ACE-inhibitors should be used with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.
Neutropenia/agranulocytosis Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE-inhibitors. The risk of neutropenia appears to be dose- and type-related and is dependent on patient's clinical status. It is rarely seen in uncomplicated patients but may occur in patients with some degree of renal impairment especially when it is associated with collagen vascular disease e.g. systemic lupus erythematosus, scleroderma and therapy with immunosuppressive agents, treatment with allopurinol or procainamide, or a combination of these complicating factors. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy.
If zofenopril is used in such patients, it is advised that white blood cell count and differential counts should be performed prior to therapy, every 2 weeks during the first 3 months of zofenopril therapy, and periodically thereafter. During treatment all patients should be instructed to report any sign of infection (e.g. sore throat, fever) when a differential white blood cell count should be performed. Zofenopril and other concomitant medication (see section 4.5) should be withdrawn if neutropenia (neutrophils less than 1,000 /mm3) is detected or suspected. It is reversible after discontinuation of the ACE-inhibitor.
Psoriasis ACE-inhibitors should be used with caution in patients with psoriasis.
Proteinuria Proteinuria may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE-inhibitors. Patients with prior renal disease should have urinary protein estimation (dip-stick on first morning urine) prior to treatment, and periodically thereafter.
Diabetic patients The glycaemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic products or insulin, during the first month of treatment with an ACE- inhibitor (see section 4.5).
Lithium The combination of lithium and zofenopril / hydrochlorothiazide is generally not recommended (see section 4.5).
Race As with other ACE-inhibitors, zofenopril may be less effective in lowering blood pressure in black people than in non-blacks.
ACE-inhibitors cause a higher rate of angioedema in black patients than in non-black patients.
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).
HYDROCHLOROTHIAZIDE
Renal impairment In patients with renal disease, thiazides may increase azotaemia. Cumulative effects of this active substance may develop in patients with impaired renal function. If progressive renal impairment becomes evident, as indicated by a rising non-protein nitrogen, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy.
Hepatic impairment Thiazides 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.
Metabolic and endocrine effects Thiazide therapy may impair glucose tolerance. Dosage adjustments of insulin or oral hypoglycaemic agents may be required (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. Thiazide therapy may precipitate hyperuricaemia and/or gout in certain patients.
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 (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with zofenopril may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients with cirrhosis of the 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 ACTH (see section 4.5).
Dilutional hyponatraemia may occur in oedematous patients in hot weather. Chloride deficit is generally mild and usually does not require treatment.
Thiazides may decrease urinary calcium excretion and may 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 test for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.
Lupus erythematosus Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.
Anti-doping test Hydrochlorothiazide contained in this medication could produce a positive analytic result in an anti-doping test.
Other Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If re-administration of the diuretic is deemed necessary, it is recommended to protect the areas exposed to the sun or artificial UVA
Non-melanoma skin cancer An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC. Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).
ZOFENOPRIL/HYDROCHLOROTHIAZIDE COMBINATION
In addition to the warnings related to the monocomponents, the following should be observed:
Pregnancy Zofenopril / Hydrochlorothiazide is not recommended during the first trimester of pregnancy (see section 4.6).
Patients with renal insufficiency Considering the effect of zofenopril and hydrochlorothiazide in patients with impaired renal function, zofenopril / hydrochlorothiazide should not be administered to patients with moderate to severe renal insufficiency (creatinine clearance < 45 ml/min).
Risk of hypokalaemia The combination of an ACE-inhibitor with a thiazide diuretic does not rule out the occurrence of hypokalaemia. Regular monitoring of serum potassium should be performed.
Excipient This product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
ZOFENOPRIL
CONCOMITANT USE CONTRAINDICATED AND NOT RECOMMENDED Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes: Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with zofenopril / hydrochlorothiazide. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when zofenopril / hydrochlorothiazide is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of zofenopril / hydrochlorothiazide with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium and ECG (see section 4.4) .
ACE-inhibitors, angiotensin II receptor blockers or aliskiren: Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Medicines increasing the risk of angioedema Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4).
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4).
CONCOMITANT USE REQUIRING CAUTION Diuretics (thiazide or loop diuretics): Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with zofenopril (see section 4.4). The hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of zofenopril.
Anaesthetic medicinal products: ACE-inhibitors may enhance the hypotensive effects of certain anaesthetic medicinal products.
Narcotic/tricyclic antidepressants/antipsychotics/barbiturates: Postural hypotension may occur.
Other antihypertensive substances (e.g. beta-blockers, alpha-blockers, calcium antagonists): There may be additive hypotensive effect or potentiation. Treatment with nitroglycerine and other nitrates, or other vasodilators, should be used with caution.
Cimetidine: May enhance the risk of hypotensive effect.
Ciclosporin: Concomitant use of ACE inhibitors increases the risk of renal disfunction. Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.
Heparin Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.
Allopurinol, procainamide, cytostatic or immunosuppressive agents: Increased risk of hypersensitivity reactions when ACE-inhibitors are used concurrently. Data from other ACE- inhibitors indicate an increased risk of leucopenia when used concurrently.
Antidiabetics: Rarely ACE-inhibitors can potentiate the blood glucose-reducing effects of insulin and oral antidiabetics like sulfonylurea, in diabetics. In such cases it may be necessary to reduce the dose of the antidiabetic during simultaneous treatment with ACE-inhibitors.
Haemodialysis with high-flux dialysis membranes: Increased risk of anaphylactoid reactions when ACE-inhibitors are used concurrently.
Sympathomimetics: May reduce the antihypertensive effects of ACE-inhibitors; patients should be carefully monitored to confirm that the desired effect is being obtained.
Antacids: Reduce the bioavailability of ACE-inhibitors.
Food: May reduce the rate but not the extent of absorption of zofenopril.
Gold: Nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE-inhibitor therapy.
Co-trimoxazole (trimethoprim/sulfamethoxazole) Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see section 4.4).
Additional information CYP enzymes: direct clinical data on the interaction of zofenopril with other active substances which are metabolised by CYP enzymes are not available. However, in vitro metabolic studies with zofenopril demonstrated no potential interaction with drugs that are metabolised by CYP enzymes.
HYDROCHLOROTHIAZIDE
CONCOMITANT USE REQUIRING CAUTION Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
Sulfonamide diuretics should be taken at least one hour before or four to six hours after these medications.
Corticosteroids, ACTH, amphotericin B (parenteral), carbenoxolone, stimulant laxatives: There may be intensified electrolyte depletion, particularly hypokalaemia when administered concomitantly with Hydrochlorothiazide.
Calcium salts: Increased serum calcium levels due to decreased excretion may occur when administered concurrently with thiazide diuretics.
Cardiac glycosides: Thiazide induced hypokalaemia or hypomagnesaemia favours the occurrence of digitalis induced cardiac arrhythmia.
Medicinal products associated with torsade de pointes: Because of the risk of hypokalaemia, caution should be used when hydrochlorothiazide is co-administered with medicinal products associated with torsade de pointes, e.g. some antiarrhythmics, some antipsychotics, and other medicinal products known to induce torsade de pointes.
Pressor amines (e.g. adrenaline): Possible decreased response to pressor amines, but not sufficient to preclude their use with hydrochlorothiazide.
Skeletal muscle relaxants, non-depolarising (e.g. tubocurarine): Possible increased responsiveness to the muscle relaxant when used with hydrochlorothiazide.
Amantadine: Thiazide may increase the risk of undesirable effects caused by amantadine.
Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone, allopurinol): Dosage adjustment of uricosuric medicinal products may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase of dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.
Additional information Laboratory test interactions: Because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function.
ZOFENOPRIL/HYDROCHLOROTHIAZIDE COMBINATION
In addition to the interactions related to the monocomponents, the following should be observed:
CONCOMITANT USE NOT RECOMMENDED Lithium: Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE-inhibitors. Therefore, zofenopril / hydrochlorothiazide is not recommended in association with lithium and careful monitoring of serum lithium levels should be performed if the combination proves necessary.
Clinical Chemistry: Thiazides may decrease serum PBI (Protein Bound Iodine) levels without signs of thyroid disturbance.
CONCOMITANT USE REQUIRING CAUTION Non-Steroidal Anti-Inflammatory medicinal product (including ASA ≥ 3g/day): The administration of non•steroidal anti-inflammatory agents may reduce the antihypertensive effect of ACE-inhibitors and diuretics. Furthermore, it has been described that NSAIDS and ACE-inhibitors exert an additive effect on the increase in serum potassium whereas renal function may decrease. These effects are in principle reversible, and occur especially in patients with impaired renal function. Rarely, acute renal failure may occur, particularly in patients with compromised renal function such as the elderly or dehydrated.
Alcohol: Enhances the hypotensive effect of ACE-and hydrochlorothiazide.
Trimethoprim: Concomitant administration of ACE-inhibitors and thiazides with trimethoprim increases the risk of hyperkalaemia.
4.6 Fertility, pregnancy and lactation
Pregnancy
Zofenopril and HCTZ Given the effects of the individual components in this combination product on pregnancy, the use of zofenopril / hydrochlorothiazide is not recommended during the first trimester of pregnancy (see section 4.4). The use of zofenopril / hydrochlorothiazide is contraindicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4).
Zofenopril The use of ACE-inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE-inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).
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 trimester 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).
Hydrochlorothiazide There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.
Breast-feeding Zofenopril and HCTZ The use of Zofenopril / Hydrochlorothiazide Mylan during breast-feeding is not recommended.
Zofenopril Because no information is available regarding the use of zofenopril during breastfeeding, zofenopril is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
Hydrochlorothiazide Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of zofenopril / hydrochlorothiazide during breast-feeding is not recommended. If zofenopril / hydrochlorothiazide is used during breast-feeding, doses should be kept as low as possible.
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. When driving vehicles or operating machines it should be remembered that occasionally drowsiness, dizziness or weariness may occur.
4.8 Undesirable effects
In controlled clinical trials involving 597 patients randomised to receive zofenopril plus Hydrochlorothiazide, no adverse reactions peculiar to this combination product have been observed. Adverse reactions have been limited to those that were reported previously with zofenopril calcium or hydrochlorothiazide. The incidence of undesirable effects showed no correlation with gender or age of the patients.
The table below shows all the adverse reactions that have been reported during clinical trials as at least probably• possibly related to treatment with zofenopril / hydrochlorothiazide 30/12.5. They are listed by body-system and ranked under headings of frequency 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) or not known (frequency cannot be estimated from the available data).
Infections and infestations Uncommon: Infection, bronchitis, pharyngitis Metabolism and nutrition disorders Uncommon: Hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hypokalaemia, hyperkalaemia, hyperuricaemia. Psychiatric disorders Uncommon: Insomnia Nervous system disorders Common: Dizziness, headache Uncommon: Somnolence, syncope, hypertonia Cardiac disorders Uncommon: Angina pectoris, atrial fibrillation, myocardial infarction, palpitations Vascular disorders Uncommon: Flushing, hypotension, hypertension Respiratory, thoracic and mediastinal disorders Common: Cough Uncommon: Dyspnoea Gastrointestinal disorders Uncommon: Nausea, dyspepsia, gastritis, gingivitis, dry mouth, abdominal pain Skin and subcutaneous tissue disorders Uncommon: Angioedema, psoriasis, acne, dry skin, pruritus, Urticaria Musculoskeletal and connective tissue disorders Uncommon: Back pain Renal and urinary disorders Uncommon: Polyuria Reproductive system and breast disorders Uncommon Erectile dysfunction General disorders and administration site conditions Uncommon: Asthenia, influenza like illness, oedema peripheral. Investigations Uncommon Creatinine increase, liver function tests abnormal
Additional information on individual component: Adverse reactions known to occur with each component given as monotherapy may occur during treatment with Zofenopril / Hydrochlorothiazide Mylan:
Zofenopril The most common undesirable effects typical of ACE-inhibitors occurred in clinical trials in patients treated with zofenopril were the following:
Nervous system disorders Common Dizziness, headache Respiratory, thoracic and mediastinal disorders Common Cough Gastrointestinal disorders Common Nausea/Vomiting Skin and subcutaneous tissue disorders Uncommon Rash Rare Angioedema Musculoskeletal and connective tissue disorders Uncommon Muscle spasms General disorders and administration site conditions Common Fatigue Uncommon Asthenia
The following adverse reactions have been observed associated with ACE-inhibitors therapy:
Blood and lymphatic system disorders In a few patients agranulocytosis and pancytopenia may occur. There are reports of haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency.
Endocrine disorders Not known, inappropriate antidiuretic hormone secretion.
Metabolism and nutrition disorders Very rare hypoglycaemia.
Psychiatric disorders Rarely, depression, mood altered, sleep disorders, confusional state.
Nervous system disorders Occasionally paraesthesia, dysgeusia, balance disorder.
Eye disorders Rarely, vision blurred.
Ear and labyrinth disorders Rarely, tinnitus.
Cardiac disorders Individual cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction have been reported for ACE-inhibitors in association with hypotension.
Vascular disorders Severe hypotension has occurred after initiation or increase of therapy. This occurs especially in certain risk groups (see section 4.4). In association with hypotension, symptoms like dizziness, feeling of weakness, impaired vision, rarely with disturbance of consciousness (syncope). Rarely flushing occurs.
Respiratory, thoracic and mediastinal disorders Rarely dyspnoea, sinusitis, rhinitis, glossitis, bronchitis and bronchospasm have been reported. ACE-inhibitors have been associated with the onset of angioneurotic oedema in a small subset of patients involving the face and oropharyngeal tissues. In isolated cases angioneurotic oedema involving the upper airways has caused fatal airway obstruction.
Gastrointestinal disorders Occasionally, abdominal pain, diarrhoea, constipation and dry mouth can occur. Individual cases of pancreatitis and ileus have been described in association with ACE- inhibitors. Very rare small bowel angioedema.
Hepatobiliary disorders Individual cases of cholestatic jaundice and hepatitis have been described in association with ACE-inhibitors.
Skin and subcutaneous tissue disorders Occasionally allergic and hypersensitivity reactions can occur like pruritus, urticaria, erythema multiforme, Stevens• Johnson syndrome, toxic epidermic necrolysis, psoriasis-like efflorescences, alopecia. This can be accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased ANA- titers. Rarely hyperhidrosis occurs.
Musculoskeletal and connective tissue disorders Occasionally, myalgia can occur.
Renal and urinary disorders Renal insufficiency may occur or be intensified. Acute renal failure has been reported (see section 4.4). Rarely micturition disorders occur.
Reproductive system and breast disorders Rarely, erectile dysfunction.
General disorders and administration site conditions Very rarely oedema peripheral and chest pain.
Investigations Increases in blood urea and creatinine, reversible on discontinuation may occur, especially in the presence of renal insufficiency, severe heart failure and renovascular hypertension. In a few patients, decreases in haemoglobin, haematocrit, platelets and white-cell count have been reported. Increases in serum levels of hepatic enzymes and bilirubin have also been reported.
Hydrochlorothiazide The adverse events reported that have been reported with the use of hydrochlorothiazide alone include the following:
Blood and lymphatic system disorders Leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow failure.
Immune system disorders Anaphylactic reaction.
Metabolism and nutrition disorders Anorexia, dehydration, gout, diabetes mellitus, metabolic alkalosis, hyperuricaemia, electrolyte imbalance (including hyponatraemia, hypokalaemia, hypomagnesaemia, hypochloraemia, hypercalcaemia), hyperglycaemia, hyperamylasaemia.
Psychiatric disorders Apathy, confusional state, depression, nervousness, restlessness, sleep disorder.
Nervous system disorders Convulsions, depressed level of consciousness, coma, headache, dizziness, paraesthesia, paresis.
Eye disorders Xanthopsia, blurred vision, myopia (aggravated), lacrimation decreased.
Ear and labyrinth disorders Vertigo.
Cardiac disorders Cardiac arrhythmias, palpitations.
Vascular disorders Orthostatic hypotension, thrombosis, embolism, shock.
Respiratory, thoracic and mediastinal disorders Pneumonitis, interstitial lung disease, pulmonary oedema.
Gastrointestinal disorders Dry mouth, nausea, vomiting, stomach discomfort, diarrhoea, constipation, abdominal pain, ileus paralytic, flatulence, sialoadenitis, pancreatitis.
Hepatobiliary disorders Jaundice cholestatic, cholecystitis.
Skin and subcutaneous tissue disorders Pruritus, purpura, urticaria, photosensitivity reactions, rash, cutaneous lupus erythematosus, vasculitis necrotising, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders Muscle spasm, myalgia.
Renal and urinary disorders Renal impairment, renal failure acute, interstitial nephritis, glycosuria.
Reproductive system and breast disorders Erectile dysfunction.
General disorders and administration site conditions Asthenia, pyrexia, fatigue, thirst.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Frequency ‘not known’: Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma) Description of selected adverse reactions Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).
Investigations Electrocardiogram change, blood cholesterol increased, blood triglycerides increased.
Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via [to be completed nationally with the national reporting system listed in Appendix V].
4.9 Overdose
Symptoms of overdosage are severe hypotension, shock, stupor, bradycardia, electrolyte disturbances and renal failure. Treatment is symptomatic and supportive. After ingestion of an overdose, the patients should be kept under close supervision, preferably in an intensive care unit. Serum electrolytes and creatinine should be monitored frequently.
Therapeutic measures depend on the nature and severity of the symptoms. If the ingestion is recent, measures to prevent absorption such as gastric lavage and administration of adsorbents and sodium sulfate may be implemented.
If hypotension occurs, the patient should be placed in shock position and the judicious use of volume expanders and/or treatment with angiotensin II considered. Bradycardia or extensive vagal reactions should be treated by administering atropine. The use of a pacemaker may be considered. ACE-inhibitors may be removed from the circulation by haemodialysis. The use of high-flux polyacrylonitrile membranes should be avoided.
Overdosage with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdosage are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ACE-inhibitors and diuretics, ATC code: C09BA15
Zofenopril / Hydrochlorothiazide Mylan is a fixed dose combination product containing zofenopril, an inhibitor of angiotensin converting enzyme (ACE) and hydrochlorothiazide, a thiazide diuretic. Both components have complementary modes of action and exert an additive antihypertensive effect.
Mechanism of action Zofenopril is a sulfhydryl ACE-inhibitor able to block the enzyme that catalyses the conversion of angiotensin I to the vasoconstrictor peptide angiotensin II, which leads to decreased vasopressor activity and to reduced aldosterone secretion. This latter decrease may result in an increase in serum potassium concentration, along with sodium and fluid loss. The cessation of the negative feedback of angiotensin II on the renin secretion results in an increase of the plasma renin activity.
The mechanism through which zofenopril lowers blood pressure is believed to be primarily suppression of the renin•angiotensin-aldosterone system. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent vasodilatatory peptide, that seems play a role in the therapeutic effect of ACE-inhibitors.
Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects the distal renal tubular mechanism of electrolyte reabsorption.
Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. Presumably through blockade of the renin-angiotensin•aldosterone system, co-administration of zofenopril tends to reverse the potassium lost associated with these diuretics. With hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Clinical efficacy and safety
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE- inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also section 4.4). 5.2 Pharmacokinetic properties
Concomitant administration of zofenopril and hydrochlorothiazide has little or no effect on the bioavailability of either active substance. The combination tablet is bioequivalent to concomitant administration of the separate entities.
ZOFENOPRIL Zofenopril is a prodrug, since the active inhibitor is the free sulfhydryl compound, zofenoprilat, resulting from thioester hydrolysis.
Absorption Zofenopril is rapidly and completely absorbed by the oral route and undergoes nearly complete conversion to zofenoprilat, which reaches peak blood levels after 1.5 h following an oral dose of zofenopril. Single dose kinetics are linear over a dose-range of 10-80 mg of zofenopril and no accumulation occurs after the administration of 15-60 mg of zofenopril for 3 weeks.
The presence of food in the gastrointestinal tract reduces the rate but not the extent of absorption and the AUCs of zofenoprilat are nearly identical in the fasted or fed state.
Distribution Approximately 88% of the circulating radioactivity measured ex-vivo following a radiolabelled dose of zofenopril is bound to plasma protein and the steady state volume of distribution is 96 litres.
Biotransformation Eight metabolites, accounting for 76% of the urinary radioactivity, were identified in human urine following a radiolabelled dose of zofenopril. The main metabolite is zofenoprilat (22%), which is metabolised through several pathways, including glucuronide conjugation (17%), cyclization and glucuronide conjugation (13%), cysteine conjugation (9%) and S- methylation of the thiol group (8%).
Elimination Radiolabelled zofenoprilat administered intravenously is eliminated in urine (76%) and faeces (16%) while following an oral dose of radiolabelled zofenopril, 69% and 26% of the radioactivity is recovered in urine and faeces respectively, indicating a dual route of elimination (kidney and liver). Half-life of zofenoprilat is 5.5 h and its total body clearance is 1,300 ml/min following oral zofenopril.
Pharmacokinetics in older people In older people, no dose adjustment is required when the renal function is normal.
Pharmacokinetics in renal dysfunction Based on comparison of key pharmacokinetic parameters of zofenoprilat measured after oral administration of radiolabelled zofenopril, patients with mild renal impairment (creatinine clearance > 45 and < 90 ml/min) eliminate zofenopril from the body at the same rate as normal subjects (creatinine clearance > 90 ml/min).
In patients with moderate to severe renal impairment (7-44 ml/min), the rate of elimination is reduced to about 50% of normal.
In patients with end stage renal disease on haemodialysis and peritoneal dialysis, the rate of elimination is reduced to 25% of normal.
Pharmacokinetics in hepatic dysfunction In patients with mild to moderate hepatic dysfunction given single doses of radiolabelled zofenopril, the Cmax and Tmax values for zofenoprilat were similar to those in normal subjects. However, AUC values in cirrhotic patients were about twice those obtained for normal subjects, indicating that the initial dose of zofenopril for patients with mild to moderate hepatic dysfunction should be half of that for patients with normal hepatic function.
There are no pharmacokinetic data of zofenopril and zofenoprilat in patients with severe hepatic dysfunction, therefore zofenopril is contraindicated in these patients.
HYDROCHLOROTHIAZIDE
Absorption Hydrochlorothiazide is well absorbed (65 to 75 %) following oral administration. Plasma concentrations are linearly related to the administered dose.
The absorption of hydrochlorothiazide is dependent on intestinal transit time, being increased when the intestinal transit time is slow for example when given with food. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours and peak plasma levels were observed within 1 and 5 h after dosing.
Distribution The thiazides are widely distributed in body fluids and are extensively (92%) bound to plasma proteins, particularly so to albumin, the substituted molecules being the most highly bound. This results in a lower renal clearance than the earlier compounds and in a more prolonged duration of action. No relationship has been demonstrated between hydrochlorothiazide plasma levels and the degree of reduction of blood pressure.
Elimination Hydrochlorothiazide is eliminated primarily by renal pathway. Most of thiazide is excreted in the urine unchanged and more than 95% of hydrochlorothiazide appears unchanged in the urine within 3-6 hours after an oral dose. In patients with renal disease, plasma concentrations of hydrochlorothiazide are increased and elimination half-life is prolonged. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
5.3 Preclinical safety data
The fixed combination zofenopril / hydrochlorothiazide revealed no special risks for human use, based on acute toxicity, repeated dose toxicity and genotoxicity studies.
Reproductive toxicity of the combination has been studied in rats and rabbits and zofenopril and hydrochlorothiazide did not show to be teratogenic. However in pregnant rats and rabbits the combination markedly increased the maternal toxicity induced by zofenopril alone.
Carcinogenicity studies were not performed with the combination zofenopril / hydrochlorothiazide.
Carcinogenicity studies conducted in mice and rats with zofenopril alone revealed no evidence of carcinogenicity.
Preclinical data of hydrochlorothiazide reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core: Cellulose, microcrystalline Lactose monohydrate Maize starch, pregelatinised Silica, colloidal anhydrous Magnesium stearate
Film coat: Lactose monohydrate Hypromellose Titanium dioxide (E171) Macrogol 400 Iron oxide yellow (E172) Iron oxide red (E172) Iron oxide black (E172) Polysorbate 80
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
White opaque PVC/PVdC/Aluminium blister pack sizes: 28
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: [To be completed nationally] Date of latest renewal: [To be completed nationally]
10. DATE OF REVISION OF THE TEXT
[To be completed nationally]
LABELLING
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1. NAME OF THE MEDICINAL PRODUCT
Zofenopril / Hydrochlorothiazide Mylan 30 mg / 12.5 mg Film-coated Tablets zofenopril calcium / hydrochlorothiazide
2. STATEMENT OF ACTIVE SUBSTANCES
Each tablet contains 30 mg zofenopril calcium and 12.5 mg hydrochlorothiazide
3. LIST OF EXCIPIENTS
Also contains lactose. See leaflet for further information.
4. PHARMACEUTICAL FORM AND CONTENTS
Film-coated tablet 28 film-coated tablets
5. METHOD AND ROUTE OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP:
9. SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
[To be completed nationally]
12. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
13. BATCH NUMBER
BATCH:
14. GENERAL CLASSIFICATION FOR SUPPLY
[To be completed nationally]
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Zofenopril / Hydrochlorothiazide Mylan
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA
PC: SN: NN:
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER FOIL
1. NAME OF THE MEDICINAL PRODUCT
Zofenopril / Hydrochlorothiazide Mylan 30 mg / 12.5 mg Film-coated Tablets zofenopril calcium / hydrochlorothiazide
2. NAME OF THE MARKETING AUTHORISATION HOLDER
[To be completed nationally]
3. EXPIRY DATE
EXP:
4. BATCH NUMBER
BATCH:
5. OTHER
PACKAGE LEAFLET
Package leaflet: Information for the patient Zofenopril / Hydrochlorothiazide Mylan 30 mg / 12.5 mg Film-coated Tablets (zofenopril calcium / hydrochlorothiazide)
Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet 1. What Zofenopril / Hydrochlorothiazide Mylan is and what it is used for 2. What you need to know before you take Zofenopril / Hydrochlorothiazide Mylan 3. How to take Zofenopril / Hydrochlorothiazide Mylan 4. Possible side effects 5. How to store Zofenopril / Hydrochlorothiazide Mylan 6. Contents of the pack and other information
1. What Zofenopril /Hydrochlorothiazide Mylan is and what it is used for
Zofenopril / Hydrochlorothiazide Mylan contains zofenopril calcium and hydrochlorothiazide as the active ingredients. Zofenopril calcium belongs to a group of blood pressure lowering medicines called angiotensin converting enzyme (ACE) inhibitors. Hydrochlorothiazide is a diuretic that acts by increasing the amount of urine you produce. Zofenopril / Hydrochlorothiazide Mylan is used to treat mild to moderate high blood pressure (essential hypertension), when this is not adequately controlled by taking zofenopril alone.
2. What you need to know before you take Zofenopril / Hydrochlorothiazide Mylan
Do not take Zofenopril / Hydrochlorothiazide Mylan: if you are more than 3 months pregnant (it is also better to avoid Zofenopril / Hydrochlorothiazide Mylan in early pregnancy - see “pregnancy” section). if you are allergic to zofenopril or hydrochlorothiazide or any of the other ingredients of this medicine (listed in section 6). if you are allergic to any other sulfonamide-derived medicine like hydrochlorothiazide, which is a sulfonamide-derived medicine) if you are allergic to any other ACE-inhibitors such as captopril or enalapril. if you have a history of severe swelling and itching of the hands, face, tongue or throat (angioedema) after using an ACE-inhibitor. if you or a member of your family suffer from swelling or itching of the hands, face, lips, tongue or throat (hereditary/idiopathic angioedema). if you suffer from severe liver or kidney problems. if you suffer from narrowing of the arteries that carry blood to the kidneys (renal artery stenosis). if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren. if you have taken or are currently taking sacubitril/valsartan, a medicine used to treat a type of long-term (chronic) heart failure in adults, as the risk of angioedema (rapid swelling under the skin in an area such as the throat) is increased.
Warnings and precautions Talk to your doctor or pharmacist before taking Zofenopril / Hydrochlorothiazide Mylan: if you have any other heart, liver or kidney problems if you have low levels of sodium in the blood, are on a salt restricted diet, have suffered from excessive vomiting or diarrhoea recently or are dehydrated if you have high blood pressure that is caused by a kidney problem (renovascular hypertension) if you have recently had a kidney transplant if you are undergoing dialysis if you are on LDL apheresis (a procedure similar to kidney dialysis that clears your blood of harmful cholesterol) if you have abnormally high levels of the hormone aldosterone in your blood (primary aldosteronism) if you have a narrowing of the heart valve (aortic stenosis), thickening of the heart walls (hypertrophic cardiomyopathy) or a condition called ‘left ventricular outflow tract obstruction’ if you suffer or have suffered from psoriasis (skin disease characterised by scaly pink patches) if you are receiving desensitisation treatment (‘allergy injections’) if you have an insect bite or sting if you have lupus erythematosus (a disorder of the immune system, your body’s defence system) if you have diabetes if you are black as you are more likely to develop angioedema and zofenopril / hydrochlorothiazide may be less effective in lowering your blood pressure than non- black patients if you have angina or problems with the blood flow to your brain, since low blood pressure can lead to a heart attack or stroke. if you think you are (or might become) pregnant. Zofenopril / Hydrochlorothiazide Mylan is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section) if you are taking any of the following medicines, the risk of angioedema (rapid swelling under the skin in area such as the throat) may be increased: - racecadotril, a medicine used to treat diarrhoea; - medicines used to prevent organ transplant rejection and for cancer (e.g., temsirolimus, sirolimus, everolimus); - vildagliptin, a medicine used to treat diabetes. if you have had skin cancer or if you develop an unexpected skin lesion during the treatment. Treatment with hydrochlorothiazide, particularly long-term use with high doses, may increase the risk of some types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from sun exposure and UV rays while taking Zofenopril / Hydrochlorothiazide if you are taking any of the following medicines used to treat high blood pressure: • an angiotensin II receptor blocker (ARBs)(also known as sartans – for example valsartan, telmisartan, irbesartan), in particular if you have diabetes- related kidney problems. • aliskiren.
Your doctor may check your kidney function, blood pressure, the amount of electrolytes (e.g. potassium) in your blood and your blood cell count at regular intervals.
See also information under the heading “Do not take Zofenopril / Hydrochlorothiazide Mylan”.
During treatment The hydrochlorothiazide in Zofenopril / Hydrochlorothiazide Mylan may cause your skin to be oversensitive to sunlight or artificial UV light. Stop taking Zofenopril / Hydrochlorothiazide Mylan and tell your doctor if you get a rash, itchy spots or sensitive skin during treatment (see section 4).
You may get a dry, persistent cough which is common for this type of medicine but this should go away when you stop taking this medicine.
If you have a test to check your parathyroid function tell the doctor before the test that you are taking Zofenopril / Hydrochlorothiazide Mylan as this may affect the test results.
If you get an insect bite or sting while taking Zofenopril / Hydrochlorothiazide Mylan, contact your doctor immediately, if you start to get signs of an allergic reaction (see section 4) go to the nearest hospital emergency department.
Anti-dope test: Zofenopril / Hydrochlorothiazide Mylan could cause a positive anti-dope test.
Your blood pressure may get too low with Zofenopril / Hydrochlorothiazide Mylan, especially after the first dose (see “Warnings and precautions”). If this happens, tell your doctor immediately and then lie down on your back (see section 4).
If you are having an operation or receiving anaesthesia, tell your anaesthetist, doctor or dentist that you are taking Zofenopril / Hydrochlorothiazide Mylan before being anaesthetised. This will help them to control your blood pressure and heart rate during the procedure.
Children and adolescents Do not give this medicine to children and adolescents under the age of 18 years because it is unlikely to be safe.
Other medicines and Zofenopril / Hydrochlorothiazide Mylan Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor may need to change your dose and/or to take other precautions. In particular, tell your doctor if you are taking: • potassium supplements (including salt substitutes), potassium-sparing diuretics (such as spironolactone, triamterene, amiloride), and other medicines that can increase the amount of potassium in your blood (e.g. trimethoprim and co-trimoxazole also known as trimethoprim/sulfamethoxazole for infections caused by bacteria; ciclosporin, an immunosuppressant medicine used to prevent organ transplant rejection; and heparin, a medicine used to thin blood to prevent clots) • other medicines that affect the levels of blood chemicals (corticosteroids such as prednisolone, AdrenoCorticoTropic Hormone - ACTH - used to stimulate the production of some hormones by the body, amphotericin B injections, carbenoxolone, stimulant laxatives) • lithium (used to treat mood disorders) • anaesthetics (see “During treatment”) • narcotic medicines (such as morphine) • antipsychotic medicines (used to treat schizophrenia and similar illnesses) • antidepressants of the tricyclic type, e.g. amitriptyline and clomipramine • sedatives called barbiturates (also used for epilepsy) • other high blood pressure medicines and vasodilators (including, beta-blockers, alpha- blockers, calcium channel blockers) • diuretics, such as bendroflumethiazide, furosemide, torasemide, angiotensin II receptor blockers (ARB) or aliskiren (see also information under the headings “Do not take Zofenopril / Hydrochlorothiazide Mylan” and “Warnings and precautions”) • medicines which are most often used to avoid rejection of transplanted organs (sirolimus, everolimus, temsirolimus and other medicines belonging to the class of mTOR inhibitors). See section “Warnings and precauions”. • nitroglycerine and other nitrates (used for angina) • antacids including cimetidine (used to treat heartburn and stomach ulcers) • immunosuppressants (medicines that suppress your body’s immune defences) • medicines for gout (e.g. probenecid, sulfinpyrazone and allopurinol) • insulin or oral anti-diabetic medicines (e.g. sulfonylurea) • cytostatic agents (used to treat cancer or diseases which affect the body’s immune defences) • procainamide (used to control an irregular heart beat) • nonsteroidal anti-inflammatory drugs (NSAIDs, such as acetylsalicylic acid or ibuprofen) • sympathomimetics (medicines that act on the nervous system, including some used to treat asthma or hay fever and pressor amines, e.g. epinephrine) • calcium salts • cardiac glycosides such as digitalis (used to help the heart pump) • cholestyramine and colestipol resins (used to lower cholesterol) • medicines used to relax muscles (e.g. tubocurarine) • amantadine (an antiviral medicine) • gold (e.g. sodium aurothiomalate, used to treat rheumatoid arthritis) • sacubitril/valsartan, a medicine used to treat a type of long-term (chronic) heart failure in adults. See section “Do not take Zofenopril / Hydrochlorothiazide Mylan” • racecadotril, a medicine used to treat diarrhoea. See section “Warnings and precautions” • vildagliptin, a medicine used to treat diabetes. See section “Warnings and precautions”
Zofenopril / Hydrochlorothiazide Mylan with alcohol Alcohol increases the hypotensive (lowering of blood pressure) effect of Zofenopril / Hydrochlorothiazide Mylan; ask your doctor for further advice on drinking alcohol whilst on this medication.
Pregnancy and breast-feeding Pregnancy If you are pregnant, if you think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Your doctor will normally advise you to stop taking Zofenopril / Hydrochlorothiazide Mylan before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of zofenopril / hydrochlorothiazide.
Zofenopril / hydrochlorothiazide is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy (see “Do not take Zofenopril / Hydrochlorothiazide Mylan”).
Breast-feeding If you are breast-feeding or about to start breast-feeding ask your doctor for advice before taking this medicine. Zofenopril / hydrochlorothiazide is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.
Driving and using machines This medicine may cause dizziness or tiredness. If this happens to you, do not drive or operate machinery.
Zofenopril / Hydrochlorothiazide Mylan contains lactose If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
3. How to take Zofenopril / Hydrochlorothiazide Mylan Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.
Use in adults The recommended dose of Zofenopril / Hydrochlorothiazide Mylan is one tablet per day.
Use in older people If you are over 65 and suffer from an impaired kidney function, Zofenopril / Hydrochlorothiazide Mylan may not be suitable for you (see section 2 – ’warnings and precautions’)
Use in children and adolescents This medicine is not recommended for use in children and adolescents under the age of 18 years.
Zofenopril / Hydrochlorothiazide Mylan may be taken with food or on an empty stomach. Swallow the tablet with water.
The score line is only there to help you break the tablet if you have difficulty swallowing it whole.
If you take more Zofenopril / Hydrochlorothiazide Mylan than you should If you accidentally take too many tablets, contact your doctor or go to the nearest hospital emergency department immediately taking any remaining tablets, the carton or this leaflet with you if possible.
You may have very low blood pressure with fainting (hypotension), cold clammy skin with a rapid heart beat, weakness and dizziness (shock), very slow heart beat (bradycardia), changes in blood chemicals (electrolytes), kidney problems, excessive urination with consequent dehydration, reduced consciousness, feeling sick (nausea), drowsiness, muscle spasms or heart rhythm disturbances (especially if you are also taking digitalis or medicines for heart rhythm problems).
If you forget to take Zofenopril / Hydrochlorothiazide Mylan If you miss a dose, take the next dose as soon as you remember. However if your next dose is nearly due, skip the forgotten dose and take the next scheduled normal dose at the usual time. Do not take a double dose to make up for a forgotten tablet.
If you stop taking Zofenopril / Hydrochlorothiazide Mylan Always consult your doctor before stopping Zofenopril / Hydrochlorothiazide Mylan treatment.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop taking Zofenopril / Hydrochlorothiazide Mylan and immediately contact your doctor or go straight to the nearest hospital emergency department if you get any of the following:
Uncommon (may affect up to 1 in 100 people) heavy or pressing sensation on your chest with chest pain and an increased shortness of breath on exercise (these may be signs of problems with your heart such as angina) sudden chest pain which may spread to the neck or arm, with a shortness of breath and a clammy feeling (these may be signs of a heart attack or other problems with your heart) an irregular heartbeat often abnormally fast with chest pain allergic reactions such as a rash, itching, hives or swelling of the hands, face, lips, tongue or throat that may cause difficulty swallowing or breathing
Not known (frequency cannot be estimated from the available data) an increase in the number of infections you get resulting in fever, severe chills, sore throat or mouth ulcers or tiredness, shortness of breath, coldness in your hands and feet and pale skin, unexplained bruising or difficulty in healing after a cut (this may indicate you have a low number of blood cells or platelets in your body, especially if you suffer from G6PD (glucose-6-phosphate dehydrogenase) deficiency) a lower than normal level of sodium in the blood, which may make you feel weak and confused with aching of muscles or fluid retention. This may be due to inappropriate ADH secretion, a hormone that causes the body to retain water and dilute the blood, reducing the amount of sodium severe stomach pain which may radiate to your back (this may be signs of problems with your pancreas) stomach pain with feeling sick (nausea) or being sick (vomiting) may indicate you have swelling in your gut. If you have these and persistent constipation, these may be signs of a blockage in your intestine yellowing of your skin or whites of your eyes, dark urine, pale stools, tiredness, fever, nausea, weakness, drowsiness and abdominal pain or an increase in liver enzymes which would be seen in a blood test (these may be signs of problems with your liver or bile duct) serious skin reactions such as red, blistering or peeling skin and bleeding of the lips, eyes or mouth (these may indicate you have Stevens-Johnson syndrome or toxic epidermal necrolysis) an auto immune disease affecting the skin, joints and kidneys (systemic lupus erythematosus) inflammation of blood vessels with consequent death of tissue (vasculitis necrotising) producing little or no urine, cloudy urine or blood in the urine, pain when passing urine or lower back pain (these may be signs of serious problems with your kidneys) excessive thirst, increased appetite with weight loss, feeling tired, weak, depressed, irritable and generally unwell, and passing large amounts of urine (these may indicate you have diabetes) fits (convulsions) loss of consciousness, coma rapid, shallow breathing, cold, clammy skin, rapid weak pulse, dizziness and fainting (these may suggest you are in circulatory shock) a blood clot in a vein or artery in your body. This can cause pain, tenderness, change in skin colour and may lead to difficulty breathing, blurred or loss of vision, heart attack or stroke, depending where the clot is. Signs of a stroke include weakness or numbness down one side of the body, confusion, trouble speaking or loss of coordination shortness of breath which is relieved in the upright position, coughing up pink, frothy sputum dry mouth, painful swelling in your mouth or neck, difficulty opening you mouth (these may be signs of inflamed salivary glands) skin rashes when exposed to sunlight skin and lip cancer (Non-melanoma skin cancer)
Other possible side effects:
Common (may affect up to 1 in 10 people) dizziness headache cough
Uncommon (may affect up to 1 in 100 people) inflammation of the bronchi (bronchitis) with symptoms including coughing, wheezing, chest discomfort sore throat high levels of fat, such as cholesterol which would be seen in a blood test (this may increase the risk of blood clots) increased blood glucose, potassium, uric acid, creatinine or a decrease in liver enzyme levels which would be seen in a blood test decrease in blood potassium levels which would be seen in a blood test difficulty getting to sleep (insomnia) drowsiness, fainting, muscle tightness (hypertonia) fast heartbeats you may feel as a thumping in your chest (palpitations) flushing, low blood pressure or high blood pressure indigestion, inflammation of the stomach (gastritis), inflammation of the gums, dry mouth, stomach pain skin disease characterised by scaly pink patches (psoriasis), acne, dry skin back pain increased urine (polyuria) general weakness (asthenia), flu like symptoms, peripheral swelling (usually around the ankles) inability to get or maintain an erection (impotence)
The following side effects have been seen with the individual components of this medicine or similar medicines, either more commonly or in addition to those seen with this medicine:
Common (may affect up to 1 in 10 people) tiredness (fatigue) feeling sick (nausea) being sick (vomiting)
Uncommon (may affect up to 1 in 100 people) muscle spams
Rare (may affect up to 1 in 1,000 people) changes in your mood, depression, other sleeping problems, confusion ringing in your ears (tinnitus), blurred vision runny, stuffy or blocked nose, possibly with facial pain or inflammation of the tongue excessive sweating
Very rare (may affect up to 1 in 10,000 people) decreased blood glucose levels which would be seen in a blood test
Not known (frequency cannot be estimated from the available data) severe low blood pressure at the start of treatment or when the dosage is increased, with dizziness, impaired vision, fainting; low blood pressure on standing diarrhoea, constipation hair loss (alopecia) skin sensations such as burning, prickling, or tingling (paraesthesia) problems with your balance, changes to your sense of taste changes to your blood such as increased blood levels of bilirubin, urea, calcium, an excessive loss of body fluids (dehydration) and blood chemicals (sodium, magnesium or chloride electrolytes) or a high level of blood pH (metabolic alkalosis) or blood amylase (hyperamylasaemia) which would be seen in a blood test severe pain, redness and swelling of a joint (gout) a feeling of indifference (apathy), nervousness or restlessness difficulty moving (paresis) yellow vision (xanthopsia), worsening of short sightedness (myopia), reduced amount of tears produced vertigo (spinning sensation) other heart rhythm disturbances (arrhythmias) which would be seen in an electrocardiogram (ECG) thirst, loss of appetite (anorexia) wind purple spots/blotches on the skin (purpura) muscle or joint pain glucose in your urine
Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via [to be completed nationally with the national reporting system listed in Appendix V]. By reporting side effects you can help provide more information on the safety of this medicine.
5. How to store Zofenopril / Hydrochlorothiazide Mylan Keep this medicine out of the sight and reach of children. This medicine does not require any special storage conditions. Do not use this medicine after the expiry date which is stated on the box and blister pack after “EXP”. The expiry date refers to the last day of that month. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other infomation What Zofenopril / Hydrochlorothiazide Mylan contains The active substances are zofenopril calcium 30 mg and hydrochlorothiazide 12.5 mg. The other ingredients are: -Tablet core: microcrystalline cellulose, lactose monohydrate (see section 2 “Zofenopril / Hydrochlorothiazide Mylan contains lactose”), maize starch, pre-gelatinised, colloidal anhydrous silica, magnesium stearate -Film coat: lactose monohydrate (see section 2 “Zofenopril / Hydrochlorothiazide Mylan contains lactose”), hypromellose, titanium dioxide (E171), macrogol, iron oxide yellow (E172), iron oxide red (E172), iron oxide black (E172), polysorbate 80
What Zofenopril / Hydrochlorothiazide Mylan looks like and contents of the pack Your medicine comes as beige, film-coated, round, tablets with two side that curve out, marked with “M” on one side of the tablet and “Z” over the score and “H” below the score on the other side of the tablet. Zofenopril / Hydrochlrothiazide Mylan is available in blisters of 28 film-coated tablets.
Marketing Authorisation Holder [To be completed nationally]
Manufacturer
Mylan Hungary Kft., H-2900 Komarom, Mylan utca 1, Hungary.
This medicinal product is authorised in the Member States of the EEA under the following names:
Italy Zofenopril e Idroclorotiazide Mylan
This leaflet was last revised in