Regoval Co 12,5 mg/25 mg Film-Coated Tablets

• Treatment of mild to moderate hypertension.
• REGOVAL CO is indicated for the treatment of hypertension in patients whose blood pressure has been stabilised at the same dosages of the individual components given together.

The recommended dose of REGOVAL CO is 1 tablet per day. When clinically appropriate either REGOVAL CO 80/12,5 mg or REGOVAL CO 160/12,5 mg may be used. If necessary, REGOVAL CO 160/25 mg may be used. The maximum antihypertensive effect is seen within 2 - 4 weeks. For initial therapy, the usual starting dose is 160/12,5 mg once daily, the dosage can be increased after 1-2 weeks of therapy to a maximum of 320/25 mg once daily as needed to control blood pressure.

REGOVAL-CO is not recommended as initial therapy in patients with intravascular volume depletion (see section 4.4). The maximum daily dose is 320/25 mg.

Special populations

Hepatic insufficiency: No dosage adjustment is required in patients with mild to moderate hepatic insufficiency of non-biliary origin and without cholestasis. REGOVAL CO is contraindicated in patients with severe hepatic impairment or with biliary cirrhosis and cholestasis (see section 4.3).

Renal impairment: No dose adjustment is required for patients with mild to moderate renal impairment (Glomerular Filtration Rate (GFR) u2265 30 mL/min). Due to the hydrochlorothiazide component, REGOVAL CO is contraindicated in patients with severe renal impairment and those with anuria (see section 4.3).

Paediatric population: The safety and efficacy of REGOVAL CO have not been established in children.

Method of administration: Oral use. REGOVAL CO can be taken with or without food and should be administered with water.

Missed dose: Doctors should advise patients who forget to take REGOVAL CO to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.

• Hypersensitivity to valsartan, sulphonamide-derived substances (as hydrochlorothiazide) or to any of the ingredients of REGOVAL CO.
• Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip.
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs). Such patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance less than 30 mL/min) or anuria.
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis.
• Concomitant use of fluoroquinolones with ACE inhibitors/ARBs is contraindicated in patients with moderate to severe renal function impairment (creatinine clearance less than 30 mL/min) and in elderly patients.
• Concomitant therapy with potassium-sparing diuretics such as spironolactone, triamterene, amiloride.
• Lithium therapy: Concomitant administration with REGOVAL CO may lead to toxic blood concentrations of lithium.
• Pregnancy and lactation (see sections 4.4 and 4.6).
• The concomitant use of REGOVAL CO with renin inhibitors such as aliskiren is contraindicated (see sections 4.4 and 4.5).
• Severe hepatic impairment, biliary cirrhosis and cholestasis.
• Refractory hypokalaemia, hyponatraemia, hypercalcaemia and symptomatic hyperuricaemia.
• REGOVAL CO is contraindicated in patients with Addisonu2019s disease due to the hydrochlorothiazide component.
• Patients with primary hyperaldosteronism should not be treated with REGOVAL CO as their renin-angiotensin system is not activated (see section 4.4).
• Porphyria.

Should a woman become pregnant while taking REGOVAL CO, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see sections 4.3 and 4.6).

Sodium and/or volume - depleted patients:

• In sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, and/or patients with moderate to severe renal impairment, symptomatic hypotension may occur after initiation of therapy with REGOVAL CO. Sodium and/or volume-depletion should be corrected before starting treatment with REGOVAL CO, for example, by reducing the diuretic dose (see section 4.2).
• Symptomatic hypotension may occur after initiation of REGOVAL CO. If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Treatment with REGOVAL CO may be continued once blood pressure has stabilised.

Serum electrolyte changes:

• Concomitant use with potassium supplements, salt substitutes containing potassium or other medicines that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium. Frequent monitoring of serum potassium is recommended (see section 4.5).
• Concomitant use with potassium-sparing diuretics is contraindicated (see section 4.3).
• Hydrochlorothiazide, as contained in REGOVAL CO, has been linked to hypochloraemic alkalosis and hyponatraemia, or the exacerbation of pre-existing hyponatraemia.
• Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed in isolated cases. Regular monitoring of serum sodium concentrations is recommended.
• The urinary excretion of magnesium may be increased by hydrochlorothiazide, as contained in REGOVAL CO, which could result in hypomagnesaemia (see section 4.5).
• Hypomagnesaemia or hypokalaemia, induced by hydrochlorothiazide, as contained in REGOVAL CO, may occur as unwanted effects, favouring the onset of digoxin-induced cardiac dysrhythmias. If hypokalaemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations), REGOVAL CO should be discontinued. Correction of hypokalaemia and any hypomagnesemia is recommended prior to the initiation of thiazides. Frequent monitoring is recommended.
• Decreased urinary calcium excretion caused by hydrochlorothiazide, as contained in REGOVAL CO, may result in an intermittent and slightly raised serum calcium concentration. Should marked hypercalcaemia occur, it may be evidence of underlying hyperparathyroidism. REGOVAL CO therapy should be discontinued before carrying out tests for parathyroid function (see section 4.5).

Other metabolic disturbances:

• Hydrochlorothiazide, as contained in REGOVAL CO, may increase serum levels of uric acid (either causing or exacerbating hyperuricemia and precipitating gout in susceptible patients), triglyceride and cholesterol, as well as changes in glucose tolerance. In diabetic patients, dosage adjustments of insulin or oral hypoglycaemic medicines may be required (see section 4.5).

Impaired renal function:

• Concomitant use of fluoroquinolones with ACE inhibitors/ ARBs may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment and monitored during treatment with fluoroquinolones or ACE inhibitors /ARBs, whether used separately and/or in combination.
• No dosage adjustment is required for patients with mild renal impairment (creatinine clearance > 70 mL/min). However, in moderate to severe cases (creatinine clearance < 70 mL/min) insufficient data are available. REGOVAL CO should not be used because of increased side effects (see section 4.3).
• REGOVAL CO is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section 4.3).

Hepatic impairment:

• Reduced doses must be considered in patients with hepatic impairment.
• Valsartan is mostly eliminated unchanged in the bile, and patients with biliary obstructive disorders showed lower valsartan clearance (see section 5.2).
• REGOVAL CO should not be used in patients with biliary obstructive disorders.

Post - myocardial infarction/heart failure:

• Use of REGOVAL CO in patients with post-myocardial infarction or heart failure, commonly results in some reduction in blood pressure, but discontinuation of REGOVAL CO therapy because of continuing symptomatic hypotension is not usually necessary provided dosing instructions are followed. Caution should be observed when initiating therapy in patients with heart failure or post-myocardial infarction.
• As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the RAAS, treatment with ACE inhibitors such as valsartan or angiotensin receptor antagonists has been associated with oliguria and/or progressive uraemia and with acute renal failure and/or death. Evaluation of patients with post-myocardial infarction and heart failure should always include assessment of renal function.
• In patients with heart failure, caution should be observed with concurrent administration of ACE inhibitors, beta-blockers and REGOVAL CO, as an increase in mortality has been reported on this triple therapy.

Dehydration:

• A reduction in salt or fluid volume may increase the risk of symptomatic hypotension. Sodium and or volume-depletion may be caused by excessive perspiration, vomiting, diarrhoea, prolonged diuretic therapy, dialysis or dietary salt restriction. Caution is advised when exercising or during hot weather, because of the risk of dehydration (due to excessive sweating) which may result in hypotension.

Systemic lupus erythematosus:

• Exacerbation or activation of systemic lupus erythematosus has been reported with the use of hydrochlorothiazide, as contained in REGOVAL CO.

Dual blockade of the renin - angiotensin - aldosterone system (RAAS):

• There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers (ARBs) or renin inhibitors such as aliskiren may increase the risk of hypotension, hyperkalaemia and decrease renal function (including acute renal failure). Dual blockade of RAAS through the combined use of REGOVAL CO and renin inhibitors such as aliskiren is therefore contraindicated (see section 4.3). REGOVAL CO should not be used concomitantly with aliskiren (see section 4.3).

Primary hyperaldosteronism:

• Patients with primary hyperaldosteronism should not be treated with REGOVAL CO as their renin-angiotensin system is not activated (see section 4.3).

History of angioedema:

• Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported in patients treated with valsartan; some of these patients previously experienced angioedema with other medicines including ACE inhibitors. REGOVAL CO should be discontinued immediately in patients who develop angioedema and should not be re-administered (see sections 4.3 and 4.8).

Photosensitivity:

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

Acute angle - closure glaucoma:

• Hydrochlorothiazide, a sulfonamide, as contained in REGOVAL CO has been associated with an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to a week of initiation.
• Untreated acute-angle closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue REGOVAL CO as rapidly as possible. Prompt medical or surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Renal artery stenosis:

• REGOVAL CO should not be used to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, since blood urea and serum creatinine may increase in such patients (see section 4.3).

Kidney transplantation:

• There is currently no experience on the safe use of REGOVAL CO in patients who have recently undergone kidney transplantation (see section 4.3).

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. Photosensitising actions of HCTZ could act as a possible mechanism for NMSC. Patients taking REGOVAL CO 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 minimise the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies.
• REGOVAL CO should not be used by patients who have had previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and/or lip (see section 4.3).

General:

• Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.

Information on excipients of REGOVAL CO

• Lactose: REGOVAL CO contains lactose. Patients with the rare hereditary conditions of galactose intolerance e.g., galactosaemia, Lapp lactase deficiency or glucose-galactose malabsorption should not take REGOVAL CO.
• Sorbitol: Patients with the rare hereditary condition of sorbitol intolerance should not take REGOVAL CO. Sorbitol is a source of fructose. Patients with hereditary fructose intolerance (HFI) must not receive this medicine. Patients with HFI cannot break down fructose, which may cause serious side effects.

Contraindication of concomitant use (see section 4.3):

• Lithium: Increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors and hydrochlorothiazide (see section 4.3).
• Fluoroquinolones and ACE inhibitors/Angiotensin receptor blockers (ARBs): Concomitant use of fluoroquinolones and ACE inhibitors/ARBs may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).
• Potassium-sparing diuretics: Concomitant use with potassium-sparing diuretics (e.g., spironolactone, triamterene and amiloride), potassium supplements, salt substitutes containing potassium or other medicines that may alter potassium levels (e.g., heparin) may lead to increases in serum potassium. REGOVAL CO and potassium-sparing diuretics should not be given together (see sections 4.3 and 4.4).

Concomitant use not recommended (see section 4.4):

Transporters: In vitro data indicates that valsartan is a substrate of the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of this finding is unknown. Co-administration of inhibitors of the uptake transporter (e.g., rifampicin, ciclosporin) or efflux transporter (e.g., ritonavir) may increase the systemic exposure to REGOVAL CO. Exercise appropriate care when initiating or ending concomitant treatment with such medicines.

Concomitant use requiring caution:

Other antihypertensive medicines: The antihypertensive effects of REGOVAL CO may be potentiated by other medicines that lower blood pressure (e.g., guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, ARBs and Direct Renin Inhibitors (DRIs)).

Pressor amines: Pressor amines [e.g., epinephrine (adrenaline)] u2013 hydrochlorothiazide, as contained in REGOVAL CO, may decrease response to pressor amines. This decrease in response is not sufficient to preclude the use of pressor amines.

(NSAIDs) including selective COX - 2 inhibitors, aspirin (acetylsalicylic acid) (> 3 g/day), and non-selective NSAIDs: The diuretic and anti-hypertensive activity of the hydrochlorothiazide component of REGOVAL CO may weaken with concomitant administration of non-steroidal anti-inflammatory drugs (NSAIDs) including selective COX-2 inhibitors, aspirin (acetylsalicylic acid) (> 3 g/day), and non-selective NSAIDs (e.g., indomethacin, salicylic acid derivative). Acute renal failure may be induced by concurrent hypovolaemia. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.

Interactions related to valsartan:

Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren: Clinical trial data have 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 (see sections 4.3 and 4.4).

No interaction: Under monotherapy with valsartan, no drug interactions of clinical significance have been found with the following drugs: cimetidine, warfarin, furosemide, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

Interactions related to hydrochlorothiazide:

Medicines affecting serum potassium levels: Concomitant use of corticosteroids, kaliuretic diuretics, carbenoxolone, amphotericin, ACTH, salicylic acid derivatives, laxatives, or penicillin G, with hydrochlorothiazide, as contained in REGOVAL CO, may intensify electrolyte depletion and hypokalaemia.

If these medicines are to be prescribed with REGOVAL CO, monitoring of potassium plasma levels is advised (see section 4.4).

Medicines that could induce torsadeu2019s de pointes: Due to the risk of hypokalaemia, REGOVAL CO should be administered with caution when associated with medicines that could induce torsadeu2019s de pointes, in particular Class Ia and Class III antidysrhythmics (disopyramide, procainamide, quinidine and sotalol) and some antipsychotics (haloperidol, thioridazine and pimozide).

Medicines affecting serum sodium levels: The hyponatremic effect of diuretics may be intensified by concomitant administration of medicines such as anti-depressant, antipsychotics, antiepileptics, etc. Caution is advised in long term administration of these medicines (see section 4.4).

Digitalis glycosides: Thiazide-induced hypokalaemia or hypomagnesaemia may occur as unwanted effects, favouring the onset of digitalis-induced cardiac arrhythmias.

Calcium salts and Vitamin D: Administration of hydrochlorothiazide, as contained in REGOVAL CO, with calcium salts or Vitamin D may lead to a rise in serum calcium.

Antidiabetic medicine (oral medicines and insulin): Hydrochlorothiazide may alter glucose tolerance. Dosage adjustment of the antidiabetic medicine may be required with the concomitant use of REGOVAL CO (see section 4.4).

Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Beta blockers and diazoxide: Concomitant use of hydrochlorothiazide with beta blockers may increase the risk of hyperglycaemia. REGOVAL CO may enhance the hyperglycaemic effect of diazoxide.

Anticholinergic medicines and other medicines affecting gastric motility: Anticholinergic medicines (e.g., biperiden, atropine) may increase the bioavailability of hydrochlorothiazide, as contained in REGOVAL CO, apparently due to a decrease in gastrointestinal motility and the stomach-emptying rate. Conversely prokinetic drugs, such as cisapride, may decrease bioavailability of thiazide-type diuretics.

Methyldopa: Haemolytic anaemia occurring with concurrent use of methyldopa and hydrochlorothiazide, as contained in REGOVAL CO, has been reported.

Cholestyramine and colestipol: Cholestyramine and colestipol decreases the absorption of hydrochlorothiazide, as contained in REGOVAL CO. This could result in sub-therapeutic effects of hydrochlorothiazide. However, staggering the dosage of REGOVAL CO and resin such that hydrochlorothiazide is administered at least 4 hours before or 4 - 6 hours after the administration of resins would potentially minimise the interaction.

Ciclosporin: Concurrent therapy with ciclosporin may increase the risk of gout-type complications and hyperuricaemia.

Iodine contrast media: In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of the iodine product. Patients should be rehydrated before the administration.

Co-administration of hydrochlorothiazide, as contained in REGOVAL CO, may:

• increase the risk of side effects caused by amantadine
• increase the incidence of hypersensitivity reactions to allopurinol
• add to the hyperglycaemic effect of diazoxide
• potentiate the action of skeletal muscle relaxants such as curare derivatives
• decrease the renal excretion of cytotoxic medicines (e.g., methotrexate, cyclophosamide) and cause their myelosuppressive effects.

Alcohol, barbiturates or narcotics: Potentiation of orthostatic hypotension caused by hydrochlorothiazide, as contained in REGOVAL CO, may occur.

Non depolarising muscle relaxants (e.g., tubocurarine): Hydrochlorothiazide, as contained in REGOVAL CO, may increase the responsiveness to the muscle relaxant.

Since REGOVAL CO is not metabolised to a significant extent, clinically relevant interactions in the form of metabolic induction or inhibition of the cytochrome P450 system are not expected with REGOVAL CO.

REGOVAL CO is contraindicated in pregnancy and lactation. Safety in pregnancy and lactation has not been established (see section 4.3).

Women of childbearing potential / Contraception in males and females: Women of childbearing potential should ensure effective contraception (see section 4.3).

Pregnancy: When pregnancy is planned or confirmed, REGOVAL CO should be discontinued. Medicines affecting the renin-angiotensin system, such as REGOVAL CO, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women. 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. There have been reports of spontaneous abortion, oligohydramnios and new born renal dysfunction, when pregnant women have inadvertently taken valsartan. Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, is associated with foetal or neonatal jaundice or thrombocytopenia, and may be associated with other adverse reactions that have occurred in adults.

Breastfeeding: Hydrochlorothiazide is excreted in breastmilk. Mothers on REGOVAL CO should not breastfeed their infants.

REGOVAL CO may affect the ability to drive and use machines. When driving vehicles or operating machines, patients should take into account that visual disorders, dizziness or weariness may occur during treatment of hypertension.

Tabulated summary of adverse reactions

Valsartan:

Hydrochlorothiazide:

Valsartan and Hydrochlorothiazide:

The following additional adverse reactions have been reported with valsartan - hydrochlorothiazide combination:

The following events have also been observed during clinical trials: Abdominal pain, upper abdominal pain, anxiety, arthritis, asthenia, back pain, bronchitis, acute bronchitis, chest pain, postural dizziness, dyspepsia, dyspnoea, dry mouth, epistaxis, erectile dysfunction, gastroenteritis, headache, hyperhidrosis, hypoesthesis, influenza, insomnia, ligament sprain, muscle spasms, muscle strain, nasal congestion, nasopharyngitis, nausea, neck pain, oedema, peripheral oedema, otitis media, pain in extremity, palpitations, pharyngolaryngal pain, pollakiuria, pyrexia, rash, sinusitis, situs congestion, somnolence tachycardia, upper respiratory tract infections, urinary tract infections, vertigo, viral infections, vision disturbance.

Post-marketing data revealed angioneurotic oedema, rash, pruritus, and other hypersensitivity/ allergic reactions including serum sickness, and vasculitis. Cases of renal impairment and myalgia have also been reported. There have also been reported cases of hydrochlorothiazide-induced pulmonary oedema with granulocytic infiltration and lgG deposition in alveolar membranes. Non-cardiogenic pulmonary oedema may be an immunologically mediated idiosyncratic reaction to hydrochlorothiazide.

Description of selected adverse reactions:

Non-melanoma skin cancer: based on available data from epidemiological studies, cumulative dose dependent association between hydrochlorothiazide and NMSC has been observed (see also sections 4.4 and 5.1).

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the online service for adverse drug reaction reporting by following the link: https://www.sahpra.org.za/Publications/Index/8. An email can be sent directly to the company, [email protected], to ensure safety of the product.

In overdose, side effects will be exacerbated and exaggerated (see section 4.8).

Signs and symptoms:

Valsartan: Overdose with valsartan, as contained in REGOVAL CO, may result in marked hypotension, which could lead to a depressed level of consciousness, circulatory collapse and/or shock. Bradycardia or tachycardia may also occur with REGOVAL CO overdose.

Hydrochlorothiazide: The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digoxin has also been administered, hypokalaemia may accentuate cardiac dysrhythmias.

Management of overdose:

Valsartan: If the ingestion is recent, vomiting should be induced. Otherwise, the usual treatment would be intravenous infusion of normal saline solution.

Hydrochlorothiazide: Treatment is symptomatic and supportive.