Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2022 Publisher: Novartis Pharmaceuticals Australia Pty Limited, ABN 18 004 244 160, 54 Waterloo Road, Macquarie Park NSW 2113
Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived medicinal products or to any of the excipients of Co-Diovan; pregnancy; severe hepatic impairment; biliary cirrhosis and cholestasis; anuria; severe renal impairment (creatinine clearance <30 mL/min); refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia; concomitant use with aliskiren in patients with Type 2 diabetes mellitus (see Section 4.5 Interactions with other medicines and other forms of interactions).
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (heparin, trimethoprim containing medicines etc.) should be used with caution. Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate pre-existing hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced potassium loss, for example salt losing nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalaemia is accompanied by clinical signs (e.g. muscular weakness, paresis, or ECG alterations), Co-Diovan should be discontinued. Correction of hypokalaemia and any coexisting hypomagnesaemia is recommended prior to the initiation of thiazides. Potassium and magnesium serum concentrations should be checked periodically. All patients receiving thiazide diuretics should be monitored for imbalances in electrolytes, particularly potassium.
Regular monitoring of serum sodium concentrations is recommended. Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with hyponatraemia and hypochloraemic alkalosis. Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed in isolated cases. 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.
Periodic determination of serum electrolytes should be performed at appropriate intervals.
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.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued once the blood pressure has stabilised.
In patients whose renal function may depend on the activity of the renin-angiotensin aldosterone system (e.g. patients with severe 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 heart failure has not been established. Hence it cannot be excluded that because of the inhibition of the renin-angiotensin-aldosterone system the use of Co-Diovan may as well be associated with impairment of the renal function. Co-Diovan should not be used in these patients.
There is an increased risk of severe hypotension and renal insufficiency when patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney are treated with agents that affect the renin-angiotensin-aldosterone system. Co-Diovan should be used with caution, since blood urea and serum creatinine may increase in such patients.
Patients with primary hyperaldosteronism will not generally respond to antihypertensive drugs acting through the renin-angiotensin aldosterone system therefore use of co-Diovan in these patients is not recommended.
As with all other vasodilators, special caution is indicated when using Co-Diovan in patients with haemodynamically relevant aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).
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 drugs including ACE inhibitors. Co-Diovan should be immediately discontinued in patients who develop angioedema, and should not be re-administered.
Caution is required while co-administering angiotensin receptor antagonists (ARBs), including valsartan, with other agents blocking the RAS such as ACE inhibitors or aliskiren (see Section 4.5 Interactions with other medicines and other forms of interactions).
Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.
Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol, triglycerides, and uric acid. Like other diuretics, hydrochlorothiazide, may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricaemia and precipitate gout in susceptible patients.
Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium in the absence of known disorders of calcium metabolism. Since hydrochlorothiazide can increase serum calcium concentrations, it should be used with caution in patients with hypercalcaemia. Marked hypercalcaemia unresponsive to thiazide withdrawal or ≥12 mg/dL may be evidence of an underlying thiazide independent hypercalcaemic process.
Pathological changes in the parathyroid gland of patients with hypercalcaemia and hypophosphataemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcaemia occurs, further diagnostic clarification is necessary.
Hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction resulting in choroidal effusion with visual field defect, 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 week of a drug initiation. Untreated acute-angle closure glaucoma can lead to permanent vision loss.
The primary treatment is to discontinue hydrochlorothiazide 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.
Cases of photosensitivity reactions have been reported with thiazide diuretics. 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 exposed areas to the sun or to artificial UVA.
Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
An increased risk of non-melanoma skin cancer [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. The risk for non-melanoma skin cancer appears to increase with long-term use (see Section 5.1 Pharmacodynamic properties). Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for non-melanoma skin cancer.
Patients taking hydrochlorothiazide should be informed of the risk of non-melanoma skin cancer 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 examination of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have previously experienced non-melanoma skin cancer (see Section 4.8 Adverse effects (undesirable effects)).
Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, Co-Diovan should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.
In patients with mild to moderate hepatic impairment without cholestasis Co-Diovan should be used with caution (see Section 5.2 Pharmacokinetic properties – Hepatic Impairment). Patients with severe hepatic impairment, biliary cirrhosis or cholestasis should not take Co-Diovan (see Section 4.3 Contraindications).
Thiazides, like other diuretics, may precipitate electrolyte imbalance, hepatic encephalopathy and hepato-renal syndrome when used to treat cirrhotic ascites.
Renal function has a marked effect on the kinetics of hydrochlorothiazide (see Section 5.2 Pharmacokinetic properties – Renal Impairment). Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. Co-Diovan should be used with caution in patients with moderate renal impairment (creatinine clearance >30 mL/min). Periodic checks of serum potassium, creatinine and uric acid levels are advisable.
Patients with severe renal impairment (creatinine clearance <30 mL/min) should not take Co-Diovan (see Section 4.3 Contraindications).
See Sections 4.5 Interactions with other medicines and other forms of interactions, and 5.2 Pharmacokinetic properties.
The safety and efficacy of Co-Diovan have not been established in children.
See sub-sections Serum electrolyte changes, and Other metabolic disturbances of Section 4.4 Special warnings and precautions for use.
The following drug interactions may occur due to both components (valsartan and/or hydrochlorothiazide) of Co-Diovan:
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, angiotensin II receptor antagonists or thiazides. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with Co-Diovan. Therefore, careful monitoring of serum lithium concentrations is recommended during concomitant use.
In monotherapy with valsartan, no drug interactions of clinical significance have been found with the following drugs: cimetidine, warfarin, frusemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
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, frusemide, and warfarin.
When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur.
Furthermore, the use of an ACE inhibiting drug (ACE-inhibitors) or angiotensin receptor antagonist, a thiazide diuretic (including hydrochlorothiazide), and an anti-inflammatory drug (NSAID or COX-2 inhibitor) at the same time increases the risk of renal impairment. Concomitant use of angiotensin II antagonists and NSAIDs in patients who are elderly, volume-depleted (including those on diuretic therapy) or have compromised renal function may lead to an increased risk of worsening renal function, including possible acute renal failure. This includes use in fixed combination products containing more that one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly when initiating or modifying treatment.
The concomitant use of ARBs, including valsartan, with other agents acting on the RAS is associated with an increased incidence of hypotension, hyperkalaemia, and changes in renal function compared to monotherapy. It is recommended to monitor blood pressure, renal function and electrolytes in patients on Co-Diovan and other agents that affect the RAS (see Section 4.4 Special warnings and precautions for use).
The concomitant use of ARBs including valsartan, or ACEIs, with aliskiren is contraindicated in patients with Type 2 diabetes mellitus (see Section 4.3 Contraindications).
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may alter potassium levels (heparin, trimethoprim containing medicines etc.) should be used with caution and with frequent monitoring of potassium (see Section 4.4 Special warnings and precautions for use – Serum electrolyte changes).
Co-administration with inhibitors of the hepatic uptake transporter OATP1B1 (such as rifampicin, cyclosporin) or hepatic efflux transporter MRP2 (e.g. ritonavir) may increase the systemic exposure to valsartan.
The antihypertensive effect may be increased with concomitant use of other antihypertensive drugs (e.g. guanethidine, methyldopa, beta-blockers, vasodilators, calcium chanel blockers). The thiazide component of Co-Diovan may enhance the hyperglycemic effect of beta-blockers and diazoxide.
Thiazides, including hydrochlorothiazide, potentiate the action of non-depolarising muscle relaxants (e.g. curare derivatives).
Concomitant administration of NSAIDs (e.g. salicylic acid derivatives indomethacin) including Selective Cyclooxegase-2 Inhibitors (COX-2 Inhibitors) may weaken the diuretic and antihypertensive activity of the thiazide component of Co-Diovan. Concurrent hypovolaemia may induce acute renal failure. In patients who are elderly, volume-depleted (including those on diuretic therapy), or have compromised renal function, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on valsartan who are taking NSAIDs concomitantly.
Thiazide diuretics, including hydrochlorothiazide, may increase blood glucose. It may prove necessary to readjust the dosage of insulin and of oral antidiabetic agents.
Thiazide-induced hypokalaemia or hypomagnesaemia may occur as unwanted effects, favoring the onset of digitalis-induced cardiac arrhythmias.
The hypokalaemic effect of diuretics may be increased by concomitant administration of kaliuretic diuretics, amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives or antiarrhythmics. 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 Special warnings and precautions for use, Serum electrolyte changes).
Periodic monitoring of serum potassium and ECG is recommended when Co-Diovan is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics) and the torsades de pointes inducing medicinal products (which include some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes.
The hyponatraemic effect of diuretics may be intensified by concomitant administration of drugs such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in long-term administration of these drugs.
Coadministration of thiazide diuretics (including hydrochlorothiazide) may increase the incidence of hypersensitivity reactions to allopurinol.
The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, prokinetic drugs such as cisapride may decrease the bioavailability of thiazide-type diuretics.
The effect of pressor amines (e.g. noradrenaline) may be decreased.
Single doses of cholestyramine or colestipol resins reduced the absorption of hydrochlorothiazide by up to 85 and 43 percent respectively.
Electrolyte depletion, particularly hypokalaemia, may be increased.
Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol. Thiazides may also increase serum uric acid levels, and the dose of uricosuric agents such as probenacid or sulfinpyrazone may need to be increased.
Concomitant administration of tetracyclines and thiazide diuretics increases the risk for tetracycline induced increase in urea. This interaction is probably not applicable to doxycycline.
Potentiation of orthostatic hypotension may occur.
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 thiazide diuretics, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine, and may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
There have been reports in the literature of hemolytic anemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium.
Concomitant treatment with cyclosporin may increase the risk of hyperuricemia and gout-type complications.
Patients receiving hydrochlorothiazide concomitantly with carbamazepine may develop hyponatremia. Such patients should therefore be advised about the possibility of hyponatremic reactions, and should be monitored accordingly.
The effects of valsartan and hydrochlorothiazide in combination and hydrochlorothiazide alone on fertility have not been investigated.
Fertility of male and female rats was not affected at oral doses of valsartan up to 200 mg/kg/day, with plasma concentrations approximately 2 times the concentrations achieved in humans (based on AUC) at the maximum recommended dose.
Pregnancy Category D.
Co-Diovan should not be used during pregnancy (see Section 4.3 Contraindications) or in women planning to become pregnant. Physicians prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Co-Diovan should be discontinued as soon as possible.
Drugs that act on the renin-angiotensin-aldosterone system (RAAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors (a specific class of drugs acting on the RAAS).
Due to the mechanism of action of angiotensin II antagonists, a risk to the fetus cannot be excluded. The use of drugs that act directly on the renin-angiotensin-aldosterone system (RAAS) during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. In addition, in retrospective data, first trimester use of ACE inhibitors has been associated with a potential risk of birth defects. Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, is associated with fetal or neonatal thrombocytopenia, and may be associated with other adverse reactions that have occurred in adults. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken valsartan. In case of accidental exposure to ARB therapy, appropriate foetal monitoring should be considered. Infants whose mothers have taken ARB therapy should be closely observed for hypotension.
There was no evidence of teratogenicity in mice, rats and rabbits dose with the valsartan/hydrochlorothiazide combination during organogenesis at up to 600/187.5, 200/62.5 and 100/3.125 mg/kg/day PO, respectively. Fetotoxicity was observed in association with maternal toxicity in rats and rabbits at valsartan/hydrochlorothiazide doses of 200/62.5 mg/kg/day and 100/3.125 mg/kg/day. Decreased fetal weights, absent renal papillae and delayed ossification were observed in rats and increased late resorptions in rabbits.
No teratogenic effects were observed when valsartan alone was administered orally to mice and rats at a dose of 600 mg/kg/day and to rabbits at a dose of 10 mg/kg/day during the period of organogenesis. However, foetal losses were observed at the highest dose level in rabbits, and foetal weight was reduced at 600 mg/kg/day in rats and at 5 mg/kg/day in rabbits.
Administration of 600 mg/kg/day valsartan to rats prior to parturition and during lactation caused a decrease in birth weight, a reduction in post-natal growth and survival, and a slight delay in physical development of the offspring. A reduction of red blood cell parameters and evidence of changes in renal haemodynamics were observed at 200-600 mg/kg/day.
It is not known whether valsartan is excreted in human milk. Valsartan was excreted in the milk of lactating rats. Hydrochlorothiazide crosses the placenta and is excreted in human milk. Thus, it is not advisable to use Co-Diovan in breast-feeding mothers.
There are no studies with the valsartan/hydrochlorothiazide combination in lactating animals. A peri/postnatal study in rats with valsartan showed reductions in post-natal growth and survival, and a slight delay in physical development of the offspring when valsartan was administered to rats prior to parturition and during lactation at 600 mg/kg/day. No effects were observed at 200 mg/kg/day.
When driving vehicles or operating machinery, it should be taken into account that occasionally dizziness may occur during treatment of hypertension.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reportingproblems.
Co-Diovan has been evaluated for safety in more than 5700 patients. Adverse experiences have generally been mild and transient in nature.
The following table of adverse experiences is based on five controlled trials involving a total of 7616 patients (study Protocols 201, 301, 19, C2301 and C2302). Of the 7616 patients receiving valsartan in combination with hydrochlorothiazide, 4372 received one of the marketed doses. All adverse experiences showing an incidence of 1% or more in the Co-Diovan group are included in the following table, irrespective of their causal association with the study drug.
| Co-Diovan† n=4372 % | Placebo n=262 % | |
|---|---|---|
| Infections and infestations | ||
| Nasopharyngitis‡ | 2.4 | 1.9 |
| Upper respiratory tract infection | 1.2 | 3.4 |
| Nervous system disorders | ||
| Headache NOS | 3.7 | 14.5 |
| Dizziness (excl. vertigo) | 3.5 | 3.8 |
| Musculoskeletal & connective tissue disorders | ||
| Back pain | 1.2 | 2.7 |
| Arthralgia | 1.0 | 1.1 |
| Gastrointestinal disorders | ||
| Diarrhoea NOS | 1.1 | 1.1 |
| General disorders & administration site conditions | ||
| Fatigue | 1.6 | 1.5 |
| Respiratory, thoracic & mediastinal disorders | ||
| Cough | 1.2 | 0.8 |
† Includes combinations of valsartan 80 mg / hydrochlorothiazide 12.5 mg , valsartan 160 mg /hydrochlorothiazide 12.5 mg, valsartan 160mg / hydrochlorothiazide 25 mg, 320 mg/12.5 mg and 320 mg/25 mg.
‡ Nasopharyngitis including pharyngitis + rhinitis NOS = Not otherwise specified.
Other adverse experiences with a frequency below 1% included abdominal pain, abdominal pain upper, alopecia, anaemia, anxiety, arrhythmia, arthritis, asthenia, bilirubin increase, bronchitis, bronchitis acute, chest pain, dehydration, dizziness postural, dyspepsia, dyspnoea, dry mouth, epistaxis, erectile dysfunction, gastroenteritis, haemorrhage, hyperhidrosis, hypoaesthesia, hypokalaemia, hyponatraemia, hypotension, influenza, insomnia, muscle spasms, muscle strain, muscular weakness, nausea, nasal congestion, neck pain, oedema, oedema peripheral, otitis media, pain in extremity, palpitations, paraesthesia, pharyngolaryngeal pain, pollakiuria, pyrexia, serum uric acid increased, sinus congestion, sinusitis, somnolence, ligament sprain, syncope, tachycardia, tinnitus, urinary tract infection, vertigo, viral infection, vision blurred, vision disturbance. It is unknown whether these effects were causally related to the therapy.
Very rare cases of angioedema, rash, pruritus, and other hypersensitivity/allergic reactions including serum sickness, and vasculitis have been reported. Very rare cases of impaired renal function, and myalgia have also been reported. Several cases of hydrochlorothiazide-induced pulmonary oedema with granulocytic infiltration and IgG deposition in alveolar membranes have been reported. Noncardiogenic pulmonary oedema may be an immunologically mediated rare idiosyncratic reaction to hydrochlorothiazide. Very rare cases of thrombocytopenia have been reported.
A greater than 20% decrease in serum potassium was observed in 3.7% of patients receiving CoDiovan as compared to placebo (3.1%) (see Section 4.4 Special warnings and precautions for use, Serum electrolyte changes).
Elevations in creatinine and blood urea nitrogen (BUN) occurred in 1.9% and 14.7% respectively, of patients taking Co-Diovan and 0.4% and 6.3% respectively, given placebo in controlled clinical trials.
Neutropenia was observed in 0.1% of patients treated with Co-Diovan versus 0.4% of patients treated with placebo.
Other adverse experiences that occurred in controlled clinical trials of patients treated with valsartan (>0.2% of valsartan patients) are listed below. It cannot be determined whether these events were causally related to valsartan.
Blood and lymphatic system: decrease in haemoglobin, decrease in haematocrit
Body as a whole: oedema, allergic reactions and asthenia
Cardiovascular: palpitations
Dermatologic: pruritus and rash
Gastrointestinal: abdominal pain, constipation, diarrhoea, dry mouth, dyspepsia and flatulence
Infections and infestations: viral infections, pharyngitis, sinusitis, upper respiratory tract infection
Metabolism and nutrition: increase of serum potassium
Musculoskeletal: back pain, muscle cramps, arthralgia and myalgia
Neurologic and psychiatric: anxiety, insomnia, paraesthesia and somnolence, neuralgia, libido decrease
Respiratory: dyspnoea
Special Senses: vertigo
Urogenital: impotence
Other reported events seen less frequently in clinical trials included other hypersensitivity reactions including serum sickness, vasculitis, thrombocytopenia, acute renal failure, chest pain, syncope, anorexia, vomiting, dizziness, headache, nausea, rhinitis and angioedema.
During the post-marketing period of valsartan there have been reports of dermatitis bullous, elevated liver enzymes and very rare reports of hepatitis. There have also been very rare cases of bleeding. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those contained in Co-Diovan. The following adverse reactions have been reported in patients treated with thiazide diuretics alone, including hydrochlorothiazide:
Very common: Mainly at higher doses, hypokalaemia, blood lipids increased.
Common: Hyponatraemia, hypomagnesaemia, hyperuricaemia, urticaria and other forms of rash, loss of appetite, mild nausea and vomiting, postural hypotension, which may be aggravated by alcohol, anesthetics or sedatives, impotence, electrolyte and metabolic disorders (see Section 4.4 Special warnings and precautions for use).
Rare: Hypercalcaemia, hyperglycaemia, glycosuria and worsening of diabetic metabolic state, photosensitisation, abdominal distress, constipation, diarrhoea, and gastrointestinal discomfort, intrahepatic cholestasis or jaundice, cardiac arrhythmias, headache, dizziness or lightheadedness, sleep disturbances, depression, paraesthesia, disturbances of vision, and thrombocytopenia, sometimes with purpura.
Very rare: Hypochloraemic alkalosis, necrotising vasculitis and toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, pancreatitis, leukopenia, agranulocytosis, bone marrow depression, haemolytic anaemia, hypersensitivity reactions, respiratory distress including pneumonitis and pulmonary oedema. Acute respiratory distress syndrome (see Section 4.4 Special warnings and precautions for use).
The following adverse drug reactions have been identified based on post-marketing experiences. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequencies. Therefore, the frequency assigned is “not known”.
Frequency not known: Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma.
With hydrochlorothiazide: Frequency not known: Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma). Based on available data from epidemiological studies, cumulative dose dependent association between hydrochlorothiazide and non-melanoma skin cancer has been observed (see Section 4.4 Special warnings and precautions for use, and Section 5.1 Pharmacodynamic properties).
Eye disorders: Choroidal effusion, acute myopia (frequency not known). Cases of choroidal effusion with visual field defect have been reported after the use of thiazide diuretics.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
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