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Diovan
Angiotensin II antagonist
COMPOSITION AND PHARMACEUTICAL FORM
Active substance: (S)-N-valeryl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-valine (INN = valsartan).
One tablet contains 40 mg,
80 mg, 160 mg or 320 mg valsartan.
For excipients, see section EXCIPIENTS.
Diovan 40 mg: Yellow, ovaloid film-coated tablet, with bevelled edges,
slightly convex, scored on one side with debossing "D" on one side of the
score and "0" on the other side of the score and "NVR" on the reverse side
of the tablet.
Length: approximately 9.1 mm.
Width: approximately 3.5mm.
Diovan 80 mg: Pale-red, round film-coated tablet with bevelled edges, scored
on one side with debossing "D" on one side of the score and "V" on the other
side of the score and "NVR" on the reverse side of the tablet. Diameter:
approximately 8.2mm.
Diovan 160 mg: Grey-orange, ovaloid film-coated tablet, slightly convex,
scored on one side with debossing "DX" on one side of the score and "DX" on
the other side of the score and "NVR" on the reverse side of the tablet.
Length: approximately 14.2mm.
Width: approximately 5.7mm.
Diovan 320 mg: Dark grey-violet, ovaloid with bevelled edges, slightly
convex, one side with recessing "DXL' and "NVR" on the other side.
Length: approximately 17.6mm.
Width: approximately 8.1mm.
Appearance of tablets may differ between countries. Certain dosage strengths
may not be available in all countries.
INDICATIONS
Hypertension
Treatment of hypertension.
Heart failure
Treatment of heart failure (NYHA class II-IV) in patients receiving usual
therapy (such as diuretics, digitalis) who are intolerant to ACE inhibitors.
Diovan improves morbidity in these patients, primarily via reduction in
hospitalisation for heart failure. Diovan also slows the progression of
heart failure, improves NYHA functional class, ejection fraction and signs
and symptoms of heart failure and improves quality of life versus placebo
(see section PHARMACODYNAMICS).
Post-myocardial infarction
Diovan is indicated to improve survival following myocardial infarction in
clinically stable patients with signs, symptoms or radiological evidence of
left ventricular failure and/or with left ventricular systolic dysfunction
(see section PHARMACODYNAMICS).
DOSAGE AND ADMINISTRATION
Hypertension
The recommended dose of Diovan is 80 mg or 160 mg once daily, irrespective
of race, age, or gender. The anti hypertensive effect is substantially
present within 2 weeks and maximal effects are seen after 4 weeks. In
patients whose blood pressure is not adequately controlled, the daily dose
may be increased to 320 mg, or a diuretic may be added. Diovan may also be
administered with other anti hypertensive agents.
Heart failure
The recommended starting dose of Diovan is 40 mg twice daily. Uptitration to
80 mg and 160 mg twice daily should be done to the highest dose tolerated by
the patient. Consideration should be given to reducing the dose of
concomitant diuretics. The maximum daily dose administered in clinical
trials is 320 mg in divided doses. Evaluation of patients with heart failure
should always include assessment of renal function.
Post-myocardial infarction
Therapy may be initiated as early as 12 hours after a myocardial infarction.
After an initial dose of 20 mg twice daily, valsartan therapy should be
titrated to
40 mg, 80 mg, and 160 mg twice daily over the next few weeks. The starting
dose is provided by the 40 mg divisible tablet.
The target maximum dose is 160 mg twice daily. In general, it is recommended
that patients achieve a dose level of 80 mg twice daily by two weeks after
treatment initiation and that the target maximum dose be achieved by three
months, based on the patient's tolerability to valsartan during titration.
If symptomatic hypotension or
renal dysfunction occur, consideration should be given to a dosage
reduction.
Valsartan may be used in patients treated with other post-myocardial
infarction therapies, e.g. thrombolytics, acetylsalicylic acid, beta
blockers or statins.
Evaluation of post-myocardial infarction patients should always include
assessment of renal function.
NOTE for all indications: No dosage adjustment
is required for patients with renal impairment or for patients with hepatic
insufficiency of non-biliary origin and without cholestasis.
Use in children and adolescents
The safety and efficacy of Diovan have not been established in children and
adolescents (below the age of 18 years).
CONTRAINDICATIONS
Hypersensitivity to valsartan or to any of the excipients of Diovan.
Pregnancy (see section PREGNANCY AND LACTATION).
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Sodium- and/or volume-depleted
patients 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 Diovan. Sodium and/or
volume depletion should be corrected before starting treatment with Diovan,
for example by reducing the diuretic dose.
If hypotension occurs, the patient should be placed in the supine position
and, if necessary, given an i.v. infusion of normal saline. Treatment can be
continued once blood pressure has been, stabilised.
Renal artery stenosis
Short-term administration of Diovan to twelve patients with renovascular
hypertension secondary to unilateral renal artery stenosis did not induce
any significant changes in renal haemodynamics, serum creatinine, or blood
urea nitrogen (BUN). However, since other drugs that affect the
renin-angiotensin-aldosterone system (RAAS) may increase blood urea and
serum creatinine in patients with bilateral or unilateral renal artery
stenosis, monitoring of both parameters is recommended as a safety measure.
Impaired renal function
No dosage adjustment is required for patients with renal
impairment. However, no data is available for severe cases (creatinine
clearance < 10 mL/min.), and caution is therefore advised.
Hepatic impairment
No dosage adjustment is required for patients with hepatic insufficiency.
Valsartan is mostly eliminated unchanged in the bile, and patients with
biliary obstructive disorders showed lower valsartan clearance (see section
PHARMACOKINETICS). Particular caution should be exercised when administering
valsartan to patients with biliary obstructive disorders.
Heart failure/ Post-myocardial infarction
Use of Diovan in patients with heart failure or post-myocardial infarction
commonly results in some reduction in blood pressure, but discontinuation of
Diovan 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 (see section DOSAGE AND
ADMINISTRATION).
As a consequence of the inhibition of the 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 or angiotensin receptor antagonists has been
associated with oliguria and/or progressive azotaemia and (rarely) with
acute renal failure and/or death. Evaluation of patients with heart failure
or post-myocardial infarction should always include assessment of renal
function.
In patients with heart failure, caution should be observed with
the triple combination of an ACE inhibitor, a beta blocker and valsartan
(see section PHARMACODYNAMICS).
INTERACTIONS
No drug interactions of clinical significance have been found. Compounds
which have been studied in clinical trials include cimetidine, warfarin,
furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine
and glibenclamide.
As Diovan 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.
Concomitant use of potassium-sparing diuretics
(e.g. spironolactone, triamterene, amiloride), potassium supplements, or
salt substitutes containing potassium may lead to increases in serum
potassium and in heart failure patients to increases in serum creatinine. If
comedication is considered necessary, caution is advisable.
PREGNANCY AND LACTATION
Pregnancy
Due to the mechanism of action of angiotensin II antagonists, a risk for the
fetus cannot be excluded.
In utero exposure to ACE inhibitors (a specific class of drugs acting on the
RAAS) during the second and third trimesters has been reported to cause
injury and death to the developing fetus. In addition, in retrospective
data, first trimester use of ACE inhibitors has been associated with a
potential risk of birth defects. There have been reports of spontaneous
abortion, oligohydramnios and newborn renal dysfunction, when pregnant women
have inadvertently taken valsartan. As for any drug that also acts directly
on the RAAS, Diovan should not be used during pregnancy (see section
CONTRAINDICATIONS) or in women planning to become pregnant. Healthcare
professionals 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, 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. Thus, it is not advisable to use
Diovan in lactating mothers.
EFFECTS ON ABILITY TO DRIVE AND USE
MACHINES
As with other anti hypertensive agents, it is advisable to exercise caution
when driving or operating machinery.
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