The black triangle has been removed.
Section 4.1
The information has changed from:
Treatment of essential hypertension.
To read:
To treatment of essential hypertension in adults.
Section 4.2
The following section has changed from:
The recommended dose of Co-Diovan® is one coated tablet per day. When clinically appropriate, either 80 mg valsartan and 12.5 mg hydrochlorothiazide or 160 mg valsartan and 12.5 mg hydrochlorothiazide may be used. When necessary, 160 mg valsartan and 25 mg hydrochlorothiazide may be used. The maximum antihypertensive effect is seen within 2-4 weeks.
Doses higher than valsartan 160 mg/hydrochlorothiazide 25 mg once daily have not been investigated and are therefore not recommended.
To read:
Posology
The recommended dose of Co-Diovan 80/12.5mg is one film-coated tablet once daily. Dose titration with the individual components is recommended. In each case, up- titration of individual components to the next dose should be followed in order to reduce the risk of hypotension and other adverse events.
When clinically appropriate direct change from monotherapy to the fixed combination may be considered in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy, provided the recommended dose titration sequence for the individual components is followed.
The clinical response to Co-Diovan should be evaluated after initiating therapy and if blood pressure remains uncontrolled, the dose may be increased by increasing either one of the components to a maximum dose of Co-Diovan 320 mg/25 mg.
The antihypertensive effect is substantially present within 2 weeks.
In most patients, maximal effects are observed within 4 weeks. However, in some patients, 4-8 weeks treatment may be required. This should be taken into account during dose-titration.
Method of administration
Co-Diovan can be taken with or without food and should be administered with water.
The following section has been changed from:
Renal Impairment:
Due to the HCTZ component, Co-Diovan® is not recommended for use in patients with significant renal impairment (creatinine clearance < 30 mL/min). No dosage adjustment is required for patients with mild to moderate renal impairment (creatinine clearance >30mL/min).
To read:
Special populations
Renal Impairment
No dose adjustment is required for patients with mild to moderate renal impairment (creatinine clearance >30ml/min). Due to the hydrochlorothiazide component, Co-Diovan is contraindicated in patients with severe renal impairment (see sections 4.3, 4.4 and 5.2).
The following section has been changed from:
Hepatic Impairment:
Patients with severe hepatic impairment, cirrhosis or biliary obstruction should not use Co-Diovan® (see Section 4.3 Contra-indications). No dosage adjustment is required in patients with mild to moderate hepatic insufficiency of non biliary origin and without cholestasis (see Section 4.4 Special Warnings and Precautions for use).
To read:
Hepatic Impairment
In patients with mild to moderate hepatic impairment without cholestasis the dose of valsartan should not exceed 80 mg (see section 4.4). Co-Diovan is contraindicated in patients with severe hepatic impairment (see sections 4.3, 4.4 and 5.2).
The following section has been changed from:
Elderly:
Use in patients over 65 years: The exposure to valsartan may be increased by over 50% in the elderly. However, no dose adjustment is required in the elderly patients.
To read:
Elderly
No dose adjustment is required in elderly patients.
Section 4.3
The following section has been changed from:
Hypersensitivity to any of the components of Co-Diovan® or other sulphonamide-derived products.
To read:
- Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived medicinal products or to any of the excipients.
The following section has been changed from:
Pregnancy and lactation (See section 4.6 Pregnancy and lactation).
To read:
- Second and third trimester of pregnancy (section 4.4 and 4.6).
The following section has been changed from:
In addition, there are contraindications to the use of the individual components of Co-Diovan®. These are as follows:
Valsartan is contraindicated in the following conditions - severe hepatic impairment, cirrhosis and biliary obstruction.
Hydrochlorothiazide is contraindicated in the following conditions - anuria, creatinine clearance < 30 mL/min, conditions involving enhanced potassium loss e.g. salt losing nephropathies and pre-renal (cardiogenic) impairment of kidney function, hepatic failure, refractory hypokalaemia, hyponatraemia, hypercalcaemia, hyperuricaemia, history of gout and uric acid calculi, hypertension during pregnancy, untreated Addison's disease and concomitant lithium therapy.
To read:
- Severe hepatic impairment, biliary cirrhosis and cholestasis.
- Severe renal impairment (creatinine clearance <30 ml/min), anuria.
- Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.
Section 4.4
The following section has been changed from:
Serum electrolyte changes:
Concomitant use with potassium supplements, potassium sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (heparin, etc.) should be used with caution. Hypokalaemia has been reported under treatment with thiazide diuretics. Frequent monitoring of serum potassium is recommended.
Treatment with thiazide diuretics, including hydrochlorothiazide has been associated with hyponatraemia and hypochloroaemic alkalosis. Thiazides, including hydrochlorothiazide increase the urinary excretion of magnesium, which may result in hypomagnesaemia. Calcium excretion is decreased by thiazide diuretics. This may result in hypercalcaemia. Thiazides should be discontinued before carrying out tests for parathyroid function.
To read:
Serum electrolyte changes
Valsartan
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other agents that may increase potassium levels (heparin, etc.) is not recommended. Monitoring of potassium should be undertaken as appropriate.
Hydrochlorothiazide
Hypokalaemia has been reported under treatment with thiazide diuretics, including hydrochlorothiazide. Frequent monitoring of serum potassium is recommended.
Treatment with thiazide diuretics, including hydrochlorothiazide has been associated with hyponatraemia and hypochloraemic alkalosis. Thiazides, including hydrochlorothiazide increase the urinary excretion of magnesium, which may result in hypomagnesaemia. Calcium excretion is decreased by thiazide diuretics. This may result in hypercalcaemia.
As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
The following section has been changed:
Sodium, and/or volume-depleted patients:
Patients should be observed for clinical signs of fluid or electrolyte imbalance e.g. when the patient is vomiting excessively or receiving parenteral fluids as this may precipitate sudden worsening of hepatic function. Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restless muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, gastrointestinal disturbances such as nausea or vomiting.
In severely sodium-depleted and/or volume-depleted patients such as those receiving high doses of diuretics, there is a risk symptomatic hypotension may occur in rare cases after initiation of therapy with Co-Diovan®. Sodium and/or volume depletion should be corrected before starting treatment with Co-Diovan®.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued once the blood pressure has stabilised.
To read:
Sodium, and/or volume-depleted patients
Patients receiving thiazide diuretics, including hydrochlorothiazide, should be observed for clinical signs of fluid or electrolyte imbalance.
In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with Co-Diovan. Sodium and/or volume depletion should be corrected before starting treatment with Co-Diovan.
The following paragraph has been added:
Patients with severe chronic heart failure or other conditions with stimulation of the renin-angiotensin-aldosterone-system
In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotaemia, and in rare cases with acute renal failure. The use of Co-Diovan in patients with severe chronic heart failure has not been established.
Hence it cannot be excluded that because of the inhibition of the renin-angiotensin-aldosterone system the application of Co-Diovan as well may be associated with impairment of the renal function. Co-Diovan should not be used in these patients.
The following section has been changed:
Renal impairment:
No dosage adjustment is required for patients with renal impairment (creatinine clearance >30 mL/min).
To read:
Renal impairment
No dosage adjustment is required for patients with renal impairment with a creatinine clearance >30 ml/min (see section 4.2). Periodic monitoring of serum potassium, creatinine and uric acid levels is recommended when Co-Diovan is used in patients with renal impairment.
The following section has been changed:
Renal artery stenosis:
In patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney, the safe use of Co-Diovan® has not been established. Thus Co-Diovan® should not be used to treat hypertension in these patients.
To read:
Renal artery stenosis
Co-Diovan 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.
The following sections have been added:
Kidney transplantation
There is currently no experience on the safe use of Co-Diovan in patients who have recently undergone kidney transplantation.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with Co-Diovan as their renin-angiotensin system is not activated.
Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy
As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).
The following section has been changed:
Hepatic impairment:
In patients with mild to moderate hepatic impairment without cholestasis, no dosage adjustment is required. However, Co-Diovan® should be used with caution. Liver disease does not significantly alter the pharmacokinetics of hydrochlorothiazide (see section 4.3 Contraindications).
To read:
Hepatic impairment
In patients with mild to moderate hepatic impairment without cholestasis, Co-Diovan should be used with caution (see sections 4.2 and 5.2).
The following section has been changed:
Other metabolic disturbances:
Thiazide diuretics, including hydrochlorothiazide may alter glucose tolerance (see section 4.5 Interaction with other medicinal products and other forms of interaction) and raise serum levels of cholesterol, triglycerides and uric acid.
Thiazides may decrease serum Protein Bound Iodine Levels without signs of thyroid disturbance.
Sensitivity reactions may occur in patients receiving thiazides with or without any previous history of allergy or bronchial asthma.
To read:
Other metabolic disturbances
Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol, triglycerides and uric acid. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required.
Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of underlying hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
The following sections have been added:
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.
Pregnancy
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
General
Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
Section 4.5
The following section has been added:
Interactions related to both valsartan and hydrochlorothiazide
Concomitant use not recommended
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors and thiazide, including hydrochlorothiazide. Due to the lack of experience with concomitant use of valsartan and lithium, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
The following section has been changed from:
Potential drug interactions due to the combination of valsartan and hydrochlorothiazide:
The antihypertensive effect may be increased with concomitant use of other antihypertensive drugs.
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may alter potassium levels (heparin, etc.) should be used with caution and with frequent monitoring of potassium.
To read:
Interactions related to both valsartan and hydrochlorothiazide
Concomitant use requiring caution
Other antihypertensive agents
Co-Diovan ay increase the effects of other agents with antihypertensive properties (e.g ACEI, beta-blockers, calcium channel blockers).
The following sections have been added to this section:
Pressor amines (e.g. noradrenaline, adrenaline)
Possible decreased response to pressor amines but not sufficient to preclude their use.
Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid >3 g/day), and non-selective NSAIDs
NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of Co-Diovan and NSAIDs may lead to worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.
The following section has been changed from:
Potential drug interactions due to valsartan:
In monotherapy with valsartan, no drug interactions of clinical significance have been found with cimetidine, warfarin, furosemide, digoxin, atenolol, hydrochlorothiazide, amlodipine and glibenclamide.
Combination with NSAIDs: When Angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (>3g/day) and non-selective NSAIDs), attenuation of the anti-hypertensive effect may occur.
As with ACE inhibitors, concomitant use of Angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
As valsartan is not metabolised to a significant extent, clinically relevant drug-drug interactions in the form of metabolic induction or inhibition of the cytochrome P450 system are not expected with valsartan. Although valsartan is highly bound to plasma proteins, in vitro studies have not shown any interaction at this level with a range of molecules which are also highly protein-bound, such as diclofenac, furosemide, and warfarin.
To read:
Interactions related to valsartan
Concomitant use not recommended
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels
If a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium plasma levels is advised.
No interaction
In drug interaction studies with valsartan, no interactions of clinical significance have been found with valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin could interact with the hydrochlorothiazide component of Co-Diovan (see interactions related to hydrochlorothiazide).
The following section has been changed from:
Potential drug interactions due to hydrochlorothiazide:
Concomitant administration of NSAIDs (e.g. salicylic acid derivative, indometacin) may weaken the diuretic and antihypertensive activity of the thiazide component of Co-Diovan®. Concurrent hypovolemia may induce acute renal failure.
The hypokalaemic effect of diuretics may be increased by kaliuretic diuretics, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G and salicylic acid derivatives.
To read:
Interactions related to hydrochlorothiazide
Concomitant use requiring caution
Medicinal products associated with potassium loss and hypokalaemia (e.g. kaliuretic diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid and derivatives).
If these medicinal products are to be prescribed with the hydrochlorothiazide-valsartan combination, monitoring of potassium plasma levels is advised. These medicinal products may potentiate the effect of hydrochlorothiazide on serum potassium (see section 4.4).
The following section has been added to this section:
Medicinal products that could induce torsades de pointes
· Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide)
· Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)
· Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)
· Others (e.g. bepridil, cisapride, diphemanil, erythromycin i.v., halofantrin, ketanserin, mizolastin, pentamidine, sparfloxacine, terfenadine, vincamine i.v.)
Due to the risk of hypokalemia, hydrochlorothiazide should be administered with caution when associated with medicinal products that could induce torsades de pointes.
The following section has been changed:
It may prove necessary to readjust the dosage of insulin and of oral antidiabetic agents.
To read:
Antidiabetic agents (oral agents and insulin)
The treatment with a thiazide may influence the glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be necessary.
Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.
The following section has been reworded:
Co-administration of thiazide diuretics, including hydrochlorothiazide may increase the incidence of hypersensitivity reactions to allopurinol, may increase the risk of adverse effects caused by amantadine, may enhance the hyperglycaemic effect of diazoxide, and may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide and methotrexate) and potentiate their myelosuppressive effects.
To read:
Beta blockers and diazoxide
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycaemic effect of diazoxide.
And:
Cytotoxic agents (e.g. cyclophosamide, methotrexate)
Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents and potentiate their myelosuppressive effects.
The following sections have been added:
Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol)
Dose adjustment of uricosuric medications 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, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.
Amantadine
Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine
Carbamazepine
Patients receiving hydrochlorothiazide concomitantly with carbamazepine may develop hyponatremia. Such patients should therefore be advised about the possibility of hyponatraemic reactions, and should be monitored accordingly.
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.
Section 4.6
The following information has been updated:
Pregnancy:
Due to the mechanism of action of angiotensin II antagonists, a risk factor for the foetus cannot be excluded. In-utero exposure to angiotensin converting enzyme (ACE) inhibitors (a specific class of drugs acting on the renin-angiotensin-aldosterone system – RAAS) given to pregnant women during the second and third trimesters has been reported to cause injury and death to the developing foetus.
There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken valsartan.
Intrauterine exposure to thiazide diuretics is associated with foetal or neonatal thrombocytopenia, and may be associated with other adverse reactions that have occurred in adults.
As for any drug that also acts directly on the RAAS, Co-Diovan should not be used during pregnancy (see section 4.3 Contraindications) or in women planning to become pregnant. Healthcare professionals prescribing Co-Diovan should counsel women of childbearing potential about the potential risk of this product during pregnancy. If pregnancy is detected during therapy, Co-Diovan should be discontinued as soon as possible.
Lactation:
It is not known whether valsartan is excreted in human milk. Valsartan was excreted in the milk of lactating rats.
Hydrochlorothiazide crossed the placenta and is excreted in human milk. Thus, it is not advisable to use Co-Diovan in lactating mothers.
To read:
Pregnancy
Valsartan
The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during first trimester of pregnancy (see section 4.4). The use of AIIRAs is contra-indicated during the second and third trimester 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. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.
AIIRAs therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see also section 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.
Lactation
No information is available regarding the use of valsartan during breastfeeding. Hydrochlorothiazide is excreted in human milk. Therefore the use of Co-Diovan during breast feeding is not recommended. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Section 4.7
The following information has been updated:
As with other antihypertensive agents, it is advisable to exercise caution when driving or operating machinery.
To read:
No studies on the effect of Co-Diovan, on the ability to drive and use machines have been performed. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur.
Section 4.8
Has been completely reworded and updated to read:
Adverse reactions reported in clinical trials and laboratory findings occurring more frequently with valsartan plus hydrochlorothiazide versus placebo and individual postmarketing reports are presented below according to system organ class. Adverse reactions known to occur with each component given individually but which have not been seen in clinical trials may occur during treatment with valsartan/ hydrochlorothiazide.
Adverse drug reactions are ranked by frequency, the most frequent first, 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Table 1. Frequency of adverse reactions with valsartan/hydrochlorothiazide
|
Metabolism and nutrition disorders
|
|
Uncommon
|
Dehydration
|
|
Nervous system disorders
|
|
Very rare
|
Dizziness
|
|
Uncommon
|
Paraesthesia
|
|
Not known
|
Syncope
|
|
Eye disorders
|
|
Uncommon
|
Vision blurred
|
|
Ear and labyrinth disorders
|
|
|
Uncommon
|
Tinnitus
|
|
Vascular disorders
|
|
Uncommon
|
Hypotension
|
|
Respiratory, thoracic and mediastinal disorders
|
|
Uncommon
|
Cough
|
|
Not known
|
Non cardiogenic pulmonary oedema
|
|
Gastrointestinal disorders
|
|
Very rare
|
Diarrhoea
|
|
Musculoskeletal and connective tissue disorders
|
|
Uncommon
|
Myalgia
|
|
Very rare
|
Arthralgia
|
|
Renal and urinary disorders
|
|
Not known
|
Impaired renal function
|
|
General disorders and administration site conditions
|
|
Uncommon
|
Fatigue
|
|
Investigations
|
|
Not known
|
Serum uric acid increased, Serum bilirubin and Serum creatinine increased, Hypokalaemia, Hyponatraemia, Elevation of Blood Urea Nitrogen, Neutropenia
|
Additional information on the individual components
Adverse reactions previously reported with one of the individual components may be potential undesirable effects with Co-Diovan as well, even if not observed in clinical trials or during postmarketing period.
Table 2. Frequency of adverse reactions with valsartan
|
Blood and lymphatic system disorders
|
|
|
Not known
|
Decrease in haemoglobin, decrease in haematocrit, thrombocytopenia
|
|
|
Immune system disorders
|
|
|
Not known
|
Other hypersensitivity/allergic reactions including serum sickness
|
|
|
Metabolism and nutrition disorders
|
|
|
Not known
|
Increase of serum potassium
|
|
|
Ear and labyrinth disorders
|
|
|
Uncommon
|
Vertigo
|
|
|
Vascular disorders
|
|
|
Not known
|
Vasculitis
|
|
|
Gastrointestinal disorders
|
|
|
Uncommon
|
Abdominal pain
|
|
|
Hepatobiliary disorders
|
|
|
Not known
|
Elevation of liver function values
|
|
|
Skin and subcutaneous tissue disorders
|
|
|
Not known
|
Angioedema, rash, pruritus
|
|
|
Renal and urinary disorders
|
|
|
|
Not known
|
Renal failure
|
|
|
|
|
|
|
|
Table 3. Frequency of adverse reactions with hydrocholothiazide
Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those administered with Co-Diovan. The following adverse reactions have been reported in patients treated with monotherapy of thiazide diuretics, including hydrochlorothiazide:
|
Blood and lymphatic system disorders
|
|
Rare
|
Thrombocytopenia sometimes with purpura
|
|
Very rare
|
Agranulocytosis, leucopenia, haemolytic anaemia, bone marrow depression
|
|
Immune system disorders
|
|
Very rare
|
Hypersenstivity reactions
|
|
Psychiatric disorders
|
|
Rare
|
Depression, sleep disturbances
|
|
Nervous system disorders
|
|
Rare
|
Headache
|
|
Cardiac disorders
|
|
Rare
|
Cardiac arrhythmias
|
|
Vascular disorders
|
|
Common
|
Postural hypotension
|
|
Respiratory, thoracic and mediastinal disorders
|
|
Very rare
|
Respiratory distress including pneumonitis and pulmonary oedema
|
|
Gastrointestinal disorders
|
|
Common
|
Loss of appetite, mild nausea and vomiting
|
|
Rare
|
Constipation, gastrointestinal discomfort
|
|
Very rare
|
Pancreatitis
|
|
Hepatobiliary disorders
|
|
Rare
|
Intrahepatic cholestasis or jaundice
|
|
Skin and subcutaneous tissue disorders
|
|
Common
|
Urticaria and other forms of rash
|
|
Rare
|
Photosensitisation
|
|
Very rare
|
Necrotising vasculitis and toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus
|
|
Reproductive system and breast disorders
|
|
Common
|
Impotence
|
Section 4.9
Has been reworded and updated from:
The major sign that might be expected is marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock. If the ingestion is recent, vomiting should be induced or consider activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. Otherwise, the usual treatment would be intravenous infusion of normal saline solution.
Valsartan cannot be eliminated by means of haemodialysis because of its strong plasma binding behaviour whereas clearance of hydrochlorothiazide will be achieved by dialysis.
To read:
Symptoms
Overdose with valsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock. In addition, the following signs and symptoms may occur due to an overdose of the hydrochlorothiazide component: nausea, somnolence, hypovolaemia, and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.
Treatment
The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms, stabilisation of the circulatory condition being of prime importance.
If hypotension occurs, the patient should be placed in the supine position and salt and volume supplementation should be given rapidly.
Valsartan cannot be eliminated by means of haemodialysis because of its strong plasma binding behaviour whereas clearance of hydrochlorothiazide will be achieved by dialysis.
Section 5.1
Has been extensively updated. The following information has been removed:
The active hormone of the RAAS is angiotensin II, which is formed from angiotensin I through ACE. Angiotensin II binds to specific receptors located in the cell membranes of various tissues. It has a wide variety of physiological effects, including in particular both direct and indirect involvement in the regulation of blood pressure. As a potent vasoconstrictor angiotensin II exerts a direct pressor response. In addition, it promotes sodium retention and stimulation of aldosterone secretion.
Valsartan is an orally active and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of Ang II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20,000 fold) greater affinity for the AT1 receptor than for the AT2 receptor.
The following information had been added to this section:
Valsartan/hydrochlorothiazide
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (14.9/11.3 mmHg) compared to hydrochlorothiazide 12.5 mg (5.2/2.9 mmHg) and hydrochlorothiazide 25 mg (6.8/5.7 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (60%) compared to hydrochlorothiazide 12.5 mg (25%) and hydrochlorothiazide 25 mg (27%).
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 80 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (9.8/8.2 mmHg) compared to valsartan 80 mg (3.9/5.1 mmHg) and valsartan 160 mg (6.5/6.2 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (51%) compared to valsartan 80 mg (36%) and valsartan 160 mg (37%).
In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (16.5/11.8 mmHg) compared to placebo (1.9/4.1 mmHg) and both hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg) and valsartan 80 mg (8.8/8.6 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (64%) compared to placebo (29%) and hydrochlorothiazide (41%).
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/ hydrochlorothiazide 160/12.5 mg (12.4/7.5 mmHg) compared to hydrochlorothiazide 25 mg (5.6/2.1 mmHg). In addition, a significantly greater percentage of patients responded (BP <140/90 mmHg or SBP reduction ≥20 mmHg or DBP reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 160/12.5 mg (50%) compared to hydrochlorothiazide 25 mg (25%).
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 160 mg, significantly greater mean systolic/diastolic BP reductions were observed with both the combination of valsartan/hydrochlorothiazide 160/25 mg (14.6/11.9 mmHg) and valsartan/hydrochlorothiazide 160/12.5 mg (12.4/10.4 mmHg) compared to valsartan 160 mg (8.7/8.8 mmHg). The difference in BP reductions between the 160/25 mg and 160/12.5 mg doses also reached statistical significance. In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 160/25 mg (68%) and 160/12.5 mg (62%) compared to valsartan 160 mg (49%).
In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 160/12.5 mg (17.8/13.5 mmHg) and 160/25 mg (22.5/15.3 mmHg) compared to placebo (1.9/4.1 mmHg) and the respective monotherapies, i.e., hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg), hydrochlorothiazide 25 mg (12.7/9.3 mmHg) and valsartan 160 mg (12.1/9.4 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 160/25 mg (81%) and valsartan/hydrochlorothiazide 160/12.5 mg (76%) compared to placebo (29%) and the respective monotherapies, i.e., hydrochlorothiazide 12.5 mg (41%), hydrochlorothiazide 25 mg (54%), and valsartan 160 mg (59%).
Dose-dependent decreases in serum potassium occurred in controlled clinical studies with valsartan + hydrochlorothiazide. Reduction in serum potassium occurred more frequently in patients given 25 mg hydrochlorothiazide than in those given 12.5 mg hydrochlorothiazide. In controlled clinical trials with valsartan/hydrochlorothiazide the potassium lowering effect of hydrochlorothiazide was attenuated by the potassium-sparing effect of valsartan.
Beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and morbidity are currently unknown.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with Valsartan) study assessed the reduction in urinary albumin excretion (UAE) with valsartan (80‑160 mg/od) versus amlodipine (5‑10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years; 265 men) with microalbuminuria (valsartan: 58 µg/min; amlodipine: 55.4 µg/min), normal or high blood pressure and with preserved renal function (blood creatinine <120 µmol/l). At 24 weeks, UAE was reduced (p <0.001) by 42% (–24.2 µg/min; 95% CI: –40.4 to –19.1) with valsartan and approximately 3% (–1.7 µg/min; 95% CI: –5.6 to 14.9) with amlodipine despite similar rates of blood pressure reduction in both groups. The Diovan Reduction of Proteinuria (DROP) study further examined the efficacy of valsartan in reducing UAE in 391 hypertensive patients (BP=150/88 mmHg) with type 2 diabetes, albuminuria (mean=102 µg/min; 20–700 µg/min) and preserved renal function (mean serum creatinine = 80 µmol/l). Patients were randomised to one of 3 doses of valsartan (160, 320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal dose of valsartan for reducing UAE in hypertensive patients with type 2 diabetes. At 30 weeks, the percentage change in UAE was significantly reduced by 36% from baseline with valsartan 160 mg (95%CI: 22 to 47%), and by 44% with valsartan 320 mg (95%CI: 31 to 54%). It was concluded that 160‑320 mg of valsartan produced clinically relevant reductions in UAE in hypertensive patients with type 2 diabetes.
Section 5.2
This section has been substantially reworded and some additional information has been added:
To the section on absorption of valsartan:
Food decreases exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups.
To the section on biotransformation of valsartan:
Valsartan is not biotransformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.
To the section on elimination of valsartan:
Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.
To the section on distribution of hydrochlorothiazide:
The apparent volume of distribution is 4–8 l/kg.
The following paragraph has also been added to section 5.2:
Circulating hydrochlorothiazide is bound to serum proteins (40–70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 1.8 times the level in plasma.
The following information has been added to the section on elimination of hydrochlorothiazide:
The renal clearance is composed of passive filtration and active secretion into the renal tubule.
Section 5.3
The following information has been removed from section 5.3:
Preclinical safety data reveal no special hazard for humans based on conventional studies of repeated dose toxicity and toxicity to reproduction (fetotoxicity at maternal toxic doses). Preclinical effects were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
And replaced with:
The potential toxicity of the valsartan - hydrochlorothiazide combination after oral administration was investigated in rats and marmosets in studies lasting up to six months. No findings emerged that would exclude the use of therapeutic doses in man.
The changes produced by the combination in the chronic toxicity studies are most likely to have been caused by the valsartan component. The toxicological target organ was the kidney, the reaction being more marked in the marmoset than the rat. The combination led to kidney damage (nephropathy with tubular basophilia, rises in plasma urea, plasma creatinine and serum potassium, increases in urine volume and urinary electrolytes from 30 mg/kg/day valsartan + 9 mg/kg/day hydrochlorothiazide in rats and 10 + 3 mg/kg/d in marmosets), probably by way of altered renal haemodynamics. These doses in rat, respectively, represent 0.9 and 3.5–times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. These doses in marmoset, respectively, represent 0.3 and 1.2–times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)
High doses of the valsartan - hydrochlorothiazide combination caused falls in red blood cell indices (red cell count, haemoglobin, haematocrit, from 100 + 31 mg/kg/d in rats and 30 + 9 mg/kg/d in marmosets). These doses in rat, respectively, represent 3.0 and 12 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient).
In marmosets, damage was observed in the gastric mucosa (from 30 + 9 mg/kg/d). The combination also led in the kidney to hyperplasia of the afferent aterioles (at 600 + 188 mg/kg/d in rats and from 30 + 9 mg/kg/d in marmosets). These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. These doses in rat, respectively, represent 18 and 73 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient).
The above mentioned effects appear to be due to the pharmacological effects of high valsartan doses (blockade of angiotensin II-induced inhibition of renin release, with stimulation of the renin-producing cells) and also occur with ACE inhibitors. These findings appear to have no relevance to the use of therapeutic doses of valsartan in humans.
In rats, maternally toxic doses of valsartan (600 mg/kg/day) during the last days of gestation and lactation led to lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). Similar findings were seen with valsartan/hydrochlorothiazide in rats and rabbits. In embryo-fetal development (Segment II) studies with valsartan/hydrochlorothiazide in rat and rabbit, there was no evidence of teratogenicity; however, fetotoxicity associated with maternal toxicity was observed.
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