ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Copalia 5 mg/80 mg film-coated tablets
2.
Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate) and 80 mg of valsartan.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Dark yellow, round film-coated tablet with bevelled edges, imprinted with “NVR” on one side and
“NV” on the other side.
4.
Treatment of essential hypertension.
Copalia is indicated in patients whose blood pressure is not adequately controlled on amlodipine or
valsartan monotherapy.
The recommended dose of Copalia is one tablet per day.
Copalia 5 mg/80 mg may be administered in patients whose blood pressure is not adequately
controlled with amlodipine 5 mg or valsartan 80 mg alone.
Copalia can be used with or without food. It is recommended to take Copalia with some water.
Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended before
changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy
to the fixed-dose combination may be considered.
For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may be
switched to Copalia containing the same component doses.
Renal impairment
No dosage adjustment is required for patients with mild to moderate renal impairment. Monitoring of
potassium levels and creatinine is advised in moderate renal impairment.
Hepatic impairment
Caution should be exercised when administering Copalia to patients with hepatic impairment or biliary
obstructive disorders (see section 4.4). In patients with mild to moderate hepatic impairment without
cholestasis, the maximum recommended dose is 80 mg valsartan.
Elderly (age 65 years or over)
In elderly patients, caution is required when increasing the dosage.
2
Children and adolescents
Copalia is not recommended for use in patients aged below 18 years due to a lack of data on safety and
efficacy.
Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the excipients.
Severe hepatic impairment, biliary cirrhosis or cholestasis.
Severe renal impairment (GFR <30 ml/min/1.73 m
2
) and patients undergoing dialysis.
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Pregnancy
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless
continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to
alternative antihypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if
appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Sodium- and/or volume-depleted patients
Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with
Copalia in placebo-controlled studies. In patients with an activated renin-angiotensin system (such as
volume- and/or salt-depleted patients receiving high doses of diuretics) who are receiving angiotensin
receptor blockers, symptomatic hypotension may occur. Correction of this condition prior to
administration of Copalia or close medical supervision at the start of treatment is recommended.
If hypotension occurs with Copalia, the patient should be placed in the supine position and, if
necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood
pressure has been stabilised.
Hyperkalaemia
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing
potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be
undertaken with caution and with frequent monitoring of potassium levels.
Renal artery stenosis
No data are available on the use of Copalia in patients with bilateral renal artery stenosis or stenosis to
a solitary kidney.
Kidney transplantation
To date there is no experience of the safe use of Copalia in patients who have had a recent kidney
transplantation.
Hepatic impairment
Valsartan is mostly eliminated unchanged via the bile, whereas amlodipine is extensively metabolised
by the liver. Particular caution should be exercised when administering Copalia to patients with mild
to moderate hepatic impairment or biliary obstructive disorders.
In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended
dose is 80 mg valsartan.
Renal impairment
No dosage adjustment of Copalia is required for patients with mild to moderate renal impairment
(GFR >30 ml/min/1.73 m
2
). Monitoring of potassium levels and creatinine is advised in moderate
renal impairment.
3
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist
valsartan as their renin-angiotensin system is affected by the primary disease.
Heart failure
As a consequence of the inhibition of the renin-angiotensin-aldosterone system, 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 renin-angiotensin-aldosterone system, treatment with
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been
associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or
death. Similar outcomes have been reported with valsartan.
In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New
York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine
was associated with increased reports of pulmonary oedema despite no significant difference in the
incidence of worsening heart failure as compared to placebo.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral
stenosis, or obstructive hypertrophic cardiomyopathy.
Copalia has not been studied in any patient population other than hypertension.
Interactions linked to amlodipine
Caution required with concomitant use
CYP3A4 inhibitors
A study in elderly patients has shown that diltiazem inhibits the metabolism of amlodipine, probably
via CYP3A4 (plasma concentration increases by approximately 50% and the effect of amlodipine is
increased). The possibility that more potent inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole,
ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem
cannot be excluded.
CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin,
fosphenytoin, primidone], rifampicin, Hypericum perforatum)
Co-administration may lead to reduced plasma concentrations of amlodipine. Clinical monitoring is
indicated, with possible dosage adjustment of amlodipine during the treatment with the inducer and
after its withdrawal.
To be taken into account with concomitant use
Others
In monotherapy, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE
inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil,
anti-acid medicines (aluminium hydroxide gel, magnesium hydroxide, simeticone), cimetidine, non-
steroidal anti-inflammatory medicines, antibiotics and oral hypoglycaemic medicines.
Interactions linked to valsartan
Concomitant use not recommended
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during
concurrent use of ACE inhibitors. Despite 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 (see section 4.4).
4
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 to be prescribed in combination with valsartan,
monitoring of potassium plasma levels is advised.
Caution required with concomitant use
Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors,
acetylsalicylic acid (>3 g/day), and non-selective NSAIDs
When angiotensin II antagonists are administered simultaneously with NSAIDs attenuation of the
antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and
NSAIDs may lead to an increased risk of 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.
Others
In monotherapy with valsartan, no interactions of clinical significance have been found with the
following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin,
hydrochlorothiazide, amlodipine, glibenclamide.
Interactions common to the combination
No drug interaction studies were performed with Copalia and other medicinal products.
To be taken into account with concomitant use
Other antihypertensive agents
Commonly used antihypertensive agents (e.g. alpha blockers, diuretics) and other medicinal products
which may cause hypotensive adverse effects (e.g. tricyclic antidepressants, alpha blockers for
treatment of benign prostate hyperplasia) may increase the antihypertensive effect of the combination.
Pregnancy
The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first
trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and
third trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors
during the first trimester of pregnancy has not been conclusive; however a small increase in risk
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative
antihypertensive treatments which have an established safety profile for use in pregnancy. When
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,
alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal
toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).
Should exposure to 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 sections
4.3 and 4.4).
5
Lactation
Because no information is available regarding the use of Copalia during breast-feeding, Copalia is not
recommended and alternative treatments with better established safety profiles during breast-feeding
are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. When driving
vehicles or using machines it should be taken into account that occasionally dizziness or weariness
may occur.
The safety of Copalia has been evaluated in five controlled clinical studies with 5,175 patients, 2,613
of whom received valsartan in combination with amlodipine.
Adverse reactions have been ranked under headings of frequency using the following convention: very
common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000,
<1/1,000); very rare (<1/10,000), including isolated reports.
6
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Cardiac disorders
Tachycardia, palpitations
Rare:
Syncope
Nervous system disorders
Uncommon:
Dizziness, somnolence, dizziness postural, paraesthesia
Eye disorders
Rare: Visual disturbance
Ear and labyrinth disorders
Uncommon: Vertigo
Rare: Tinnitus
Respiratory, thoracic and mediastinal disorders
Uncommon:
Cough, pharyngolaryngeal pain
Gastrointestinal disorders
Uncommon: Diarrhoea, nausea, abdominal pain, constipation, dry mouth
Renal and urinary disorders
Rare: Pollakisuria, polyuria
Skin and subcutaneous tissue disorders
Uncommon: Rash, erythema
Rare: Hyperhidrosis, exanthema, pruritus
Musculoskeletal and connective tissue disorders
Uncommon:
Joint swelling, back pain, arthralgia
Rare:
Muscle spasm, sensation of heaviness
Infections and infestations
Common:
Nasopharyngitis, influenza
Vascular disorders
Uncommon: Orthostatic hypotension
Rare: Hypotension
General disorders and administration site conditions
Common:
Oedema, pitting oedema, facial oedema, oedema peripheral, fatigue, flushing,
asthenia, hot flush
Immune system disorders
Rare: Hypersensitivity
Reproductive system and breast disorders
Rare:
Erectile dysfunction
Psychiatric disorders
Rare:
Anxiety
Additional information on the combination
Peripheral oedema, a recognised side effect of amlodipine, was generally observed at a lower
incidence in patients who received the amlodipine/valsartan combination than in those who received
amlodipine alone. In double-blind, controlled clinical trials, the incidence of peripheral oedema by
dose was as follows:
% of patients who experienced peripheral
oedema
Valsartan (mg)
0
40
80
160
320
0
3.0
5.5
2.4
1.6
0.9
2.5
8.0
2.3
5.4
2.4
3.9
Amlodipine
(mg)
5
3.1
4.8
2.3
2.1
2.4
10
10.3
NA
NA
9.0
9.5
7
Uncommon:
Common:
Headache
The mean incidence of peripheral oedema evenly weighted across all doses was 5.1% with the
amlodipine/valsartan combination.
Additional information on the individual components
Adverse drug reactions previously reported with one of the individual components (amlodipine or
valsartan) may be potential undesirable effects with Copalia as well, even if not observed in clinical
trials or during the post-marketing period.
Amlodipine
Common
Vomiting.
Uncommon
Alopecia, altered bowel habits, dyspepsia, dyspnoea, rhinitis, gastritis, gingival
hyperplasia, gynaecomastia, hyperglycaemia, impotence, increased urinary
frequency, leucopenia, malaise, mood changes, myalgia, peripheral neuropathy,
pancreatitis, hepatitis, thrombocytopenia, vasculitis, angioedema and erythema
multiforme.
Rare
Arrhythmia, myocardial infarction.
Rarely, patients, particularly those with severe
obstructive coronary artery disease, have developed increased frequency, duration or
severity of angina or acute myocardial infarction on starting calcium channel blocker
therapy or at the time of dosage increase. Arrhythmia (including ventricular
tachycardia and atrial fibrillation) has also been reported. These adverse events may
not be distinguishable from the natural history of the underlying disease.
Very rare
Cholestatic jaundice, AST and ALT increase, purpura, rash and pruritus. Exceptional
cases of extrapyramidal syndrome have been reported.
Valsartan
Not known
Decrease in haemoglobin, decrease in haematocrit, neutropenia, thrombocytopenia,
increase of serum potassium, elevation of liver function values including increase of
serum bilirubin, renal failure and impairment, elevation of serum creatinine,
angioedema, myalgia, vasculitis, hypersensitivity including serum sickness.
Symptoms
There is no experience of overdose with Copalia. The major symptom of overdose with valsartan is
peripheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged systemic
hypotension up to and including shock with fatal outcome have been reported.
Treatment
If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of
activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine
has been shown to significantly decrease amlodipine absorption. Clinically significant hypotension
due to Copalia overdose calls for active cardiovascular support, including frequent monitoring of
cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and
urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided
that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in
reversing the effects of calcium channel blockade.
Both valsartan and amlodipine are unlikely to be removed by haemodialysis.
8
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: angiotensin II antagonists, plain (valsartan), combinations with
dihydropyridine derivatives (amlodipine), ATC code:
C09DB01
Copalia combines two antihypertensive compounds with complementary mechanisms to control blood
pressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist class
and valsartan to the angiotensin II antagonist class of medicines. The combination of these substances
has an additive antihypertensive effect, reducing blood pressure to a greater degree than either
component alone.
Amlodipine
The amlodipine component of Copalia inhibits the transmembrane entry of calcium ions into cardiac
and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a
direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance
and in blood pressure. Experimental data suggest that amlodipine binds to both dihydropyridine and
non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth
muscle are dependent upon the movement of extracellular calcium ions into these cells through
specific ion channels.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces
vasodilation, resulting in a reduction of supine and standing blood pressures. These decreases in blood
pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with
chronic dosing.
Plasma concentrations correlate with effect in both young and elderly patients.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a
decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal
plasma flow, without change in filtration fraction or proteinuria.
As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and
during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have
generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on
left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been
associated with a negative inotropic effect when administered in the therapeutic dose range to intact
animals and humans, even when co-administered with beta blockers to humans.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals
or humans. In clinical studies in which amlodipine was administered in combination with beta
blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic
parameters were observed.
Valsartan
Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively
on the receptor subtype AT
1
, which is responsible for the known actions of angiotensin II. The
increased plasma levels of angiotensin II following AT
1
receptor blockade with valsartan may
stimulate the unblocked receptor subtype AT
2
, which appears to counterbalance the effect of the AT
1
receptor. Valsartan does not exhibit any partial agonist activity at the AT
1
receptor and has much
(about 20,000-fold) greater affinity for the AT
1
receptor than for the AT
2
receptor.
Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin
II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or
substance P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials
where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (p
9
<0.05) lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6%
versus 7.9%, respectively). In a clinical trial of patients with a history of dry cough during ACE
inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide
diuretic experienced coughing, compared to 68.5% of those treated with an ACE inhibitor (p <0.05).
Valsartan does not bind to or block other hormone receptors or ion channels known to be important in
cardiovascular regulation.
Administration of valsartan to patients with hypertension results in a drop in blood pressure without
affecting pulse rate.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs
within 2 hours, and the peak drop in blood pressure is achieved within 4–6 hours. The
antihypertensive effect persists over 24 hours after administration. During repeated administration, the
maximum reduction in blood pressure with any dose is generally attained within 2–4 weeks and is
sustained during long-term therapy. Abrupt withdrawal of valsartan has not been associated with
rebound hypertension or other adverse clinical events.
Amlodipine/Valsartan
Over 1,400 hypertensive patients received Copalia once daily in two placebo-controlled trials. Adults
with mild to moderate uncomplicated essential hypertension (mean sitting diastolic blood pressure
≥95 and <110 mmHg) were enrolled. Patients with high cardiovascular risks – heart failure, type I and
poorly controlled type II diabetes and history of myocardial infarction or stroke within one year –
were excluded.
The combination of amlodipine and valsartan produces dose-related additive reduction in blood
pressure across its therapeutic dose range. The antihypertensive effect of a single dose of the
combination persisted for 24 hours.
A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation
of blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients
not adequately controlled on valsartan 160 mg in 75% of patients treated with amlodipine/valsartan
10 mg/160 mg and 62% of patients treated with amlodipine/valsartan 5 mg/160 mg, compared to 53%
of patients remaining on valsartan 160 mg. The addition of amlodipine 10 mg and 5 mg produced an
additional reduction in systolic/diastolic blood pressure of 6.0/4.8 mmHg and 3.9/2.9 mmHg,
respectively, compared to patients who remained on valsartan 160 mg only.
A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation
of blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients
not adequately controlled on amlodipine 10 mg in 78% of patients treated with amlodipine/valsartan
10 mg/160 mg, compared to 67% of patients remaining on amlodipine 10 mg. The addition of
valsartan 160 mg produced an additional reduction in systolic/diastolic blood pressure of
2.9/2.1 mmHg compared to patients who remained on amlodipine 10 mg only.
Copalia was also studied in an active-controlled study of 130 hypertensive patients with diastolic
blood pressure ≥110 mmHg and <120 mmHg. In this study (baseline blood pressure 171/113 mmHg),
an Copalia regimen of 5 mg/160 mg titrated to 10 mg/160 mg reduced sitting blood pressure by
36/29 mmHg as compared to 32/28 mmHg with a regimen of lisinopril/hydrochlorothiazide
10 mg/12.5 mg titrated to 20 mg/12.5 mg.
In two long-term follow-up studies the effect of Copalia was maintained for over one year. Abrupt
withdrawal of Copalia has not been associated with a rapid increase in blood pressure.
In patients not adequately controlled on amlodipine 5 mg, amlodipine/valsartan 5 mg/80 mg may
achieve blood pressure control similar to amlodipine 10 mg with less oedema. In patients adequately
controlled on amlodipine 10 mg but who experience unacceptable oedema, amlodipine/valsartan
5 mg/80 mg may achieve similar blood pressure control with less oedema. Age, gender and race did
not influence the response to Copalia.
10
Copalia has not been studied in any patient population other than hypertension. Valsartan has been
studied in patients with post myocardial infarction and heart failure. Amlodipine has been studied in
patients with chronic stable angina, vasospastic angina and angiographically documented coronary
artery disease.
5.2 Pharmacokinetic properties
Linearity
Amlodipine and valsartan exhibit linear pharmacokinetics.
Amlodipine
Absorption:
After oral administration of therapeutic doses of amlodipine alone, peak plasma
concentrations of amlodipine are reached in 6–12 hours. Absolute bioavailability has been calculated as
between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.
Distribution:
Volume of distribution is approximately 21 l/kg.
In vitro
studies with amlodipine have
shown that approximately 97.5% of circulating drug is bound to plasma proteins in hypertensive
patients.
Biotransformation:
Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive
metabolites.
Excretion:
Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of
approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for
7–8 days. Ten per cent of original amlodipine and 60% of amlodipine metabolites are excreted in urine.
Valsartan
Absorption:
Following oral administration of valsartan alone, peak plasma concentrations of valsartan
are reached in 2–4 hours. Mean absolute bioavailability is 23%. Valsartan shows multiexponential
decay kinetics (t
½α
<1 h and t
½ß
about 9 h). Food decreases exposure (as measured by AUC) to
valsartan by about 40% and peak plasma concentration (C
max
) by about 50%, although from about 8 h
post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in
AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and
valsartan can therefore be given either with or without food.
Distribution:
The steady-state volume of distribution of valsartan after intravenous administration is
about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly
bound to serum proteins (94–97%), mainly serum albumin.
Biotransformation:
Valsartan is not transformed 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.
Excretion:
Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of
dose), mainly as unchanged drug. 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.
Amlodipine/Valsartan
Following oral administration of Copalia, peak plasma concentrations of valsartan and amlodipine are
reached in 3 and 6–8 hours, respectively. The rate and extent of absorption of Copalia are equivalent
to the bioavailability of valsartan and amlodipine when administered as individual tablets.
Special populations
Paediatric patients (age below 18 years)
No pharmacokinetic data are available in the paediatric population.
11
Elderly (age 65 years or over)
Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly
patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC)
and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in the
young therefore caution is required when increasing the dosage.
Renal impairment
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expected
for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation
was seen between renal function and systemic exposure to valsartan.
Hepatic impairment
Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase of
approximately 40–60% in AUC. On average, in patients with mild to moderate chronic liver disease
exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers (matched by
age, sex and weight). Caution should be exercised in patients with liver disease (see section 4.2).
5.3 Preclinical safety data
Adverse reactions observed in animal studies with possible clinical relevance were as follows:
Histopathological signs of inflammation of the glandular stomach was seen in male rats at an exposure
of about 1.9 (valsartan) and 2.6 (amlodipine) times the clinical doses of 160 mg valsartan and 10 mg
amlodipine. At higher exposures, there were ulceration and erosion of the stomach mucosa in both
females and males. Similar changes were also seen in the valsartan alone group (exposure 8.5–
11.0 times the clinical dose of 160 mg valsartan).
An increased incidence and severity of renal tubular basophilia/hyalinisation, dilation and casts, as
well as interstitial lymphocyte inflammation and arteriolar medial hypertrophy were found at an
exposure of 8–13 (valsartan) and 7–8 (amlodipine) times the clinical doses of 160 mg valsartan and
10 mg amlodipine. Similar changes were found in the valsartan alone group (exposure 8.5–11.0 times
the clinical dose of 160 mg valsartan).
In an embryo-foetal development study in the rat, increased incidences of dilated ureters, malformed
sternebrae, and unossified forepaw phalanges were noticed at exposures of about 12 (valsartan) and 10
(amlodipine) times the clinical doses of 160 mg valsartan and 10 mg amlodipine. Dilated ureters were
also found in the valsartan alone group (exposure 12 times the clinical dose of 160 mg valsartan).
There were only modest signs of maternal toxicity (moderate reduction of body weight) in this study.
The no-observed-effect-level for developmental effects was observed at 3- (valsartan) and 4-
(amlodipine) fold the clinical exposure (based on AUC).
For the single compounds there was no evidence of mutagenicity, clastogenicity or carcinogenicity.
12
6.
6.1 List of excipients
Tablet core:
Cellulose microcrystalline
Crospovidone Type A
Silica, colloidal anhydrous
Magnesium stearate
Coating:
Hypromellose
Titanium dioxide (E171)
Iron oxide, yellow (E172)
Macrogol 4000
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PVC/PVDC blisters. One blister contains 7, 10 or 14 film-coated tablets.
Pack sizes: 7, 14, 28, 30, 56, 90, 98 or 280 film-coated tablets.
PVC/PVDC perforated unit dose blisters. One blister contains 7, 10 or 14 film-coated tablets.
Pack sizes: 56, 98 or 280 film-coated tablets and multipacks containing 280 (4x70 or 20x14) film-
coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
13
8.
EU/1/06/372/001
EU/1/06/372/002
EU/1/06/372/003
EU/1/06/372/004
EU/1/06/372/005
EU/1/06/372/006
EU/1/06/372/007
EU/1/06/372/008
EU/1/06/372/025
EU/1/06/372/026
EU/1/06/372/027
EU/1/06/372/034
EU/1/06/372/037
9.
16.01.2007
14
1.
Copalia 5 mg/160 mg film-coated tablets
2.
Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate) and 160 mg of valsartan.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Dark yellow, oval film-coated tablet, imprinted with “NVR” on one side and “ECE” on the other side.
4.
Treatment of essential hypertension.
Copalia is indicated in patients whose blood pressure is not adequately controlled on amlodipine or
valsartan monotherapy.
The recommended dose of Copalia is one tablet per day.
Copalia 5 mg/160 mg may be administered in patients whose blood pressure is not adequately
controlled with amlodipine 5 mg or valsartan 160 mg alone.
Copalia can be used with or without food. It is recommended to take Copalia with some water.
Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended before
changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy
to the fixed-dose combination may be considered.
For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may be
switched to Copalia containing the same component doses.
Renal impairment
No dosage adjustment is required for patients with mild to moderate renal impairment. Monitoring of
potassium levels and creatinine is advised in moderate renal impairment.
Hepatic impairment
Caution should be exercised when administering Copalia to patients with hepatic impairment or biliary
obstructive disorders (see section 4.4). In patients with mild to moderate hepatic impairment without
cholestasis, the maximum recommended dose is 80 mg valsartan.
Elderly (age 65 years or over)
In elderly patients, caution is required when increasing the dosage.
15
Children and adolescents
Copalia is not recommended for use in patients aged below 18 years due to a lack of data on safety and
efficacy.
Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the excipients.
Severe hepatic impairment, biliary cirrhosis or cholestasis.
Severe renal impairment (GFR <30 ml/min/1.73 m
2
) and patients undergoing dialysis.
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Pregnancy
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless
continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to
alternative antihypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if
appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Sodium- and/or volume-depleted patients
Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with
Copalia in placebo-controlled studies. In patients with an activated renin-angiotensin system (such as
volume- and/or salt-depleted patients receiving high doses of diuretics) who are receiving angiotensin
receptor blockers, symptomatic hypotension may occur. Correction of this condition prior to
administration of Copalia or close medical supervision at the start of treatment is recommended.
If hypotension occurs with Copalia, the patient should be placed in the supine position and, if
necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood
pressure has been stabilised.
Hyperkalaemia
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing
potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be
undertaken with caution and with frequent monitoring of potassium levels.
Renal artery stenosis
No data are available on the use of Copalia in patients with bilateral renal artery stenosis or stenosis to
a solitary kidney.
Kidney transplantation
To date there is no experience of the safe use of Copalia in patients who have had a recent kidney
transplantation.
Hepatic impairment
Valsartan is mostly eliminated unchanged via the bile, whereas amlodipine is extensively metabolised
by the liver. Particular caution should be exercised when administering Copalia to patients with mild
to moderate hepatic impairment or biliary obstructive disorders.
In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended
dose is 80 mg valsartan.
Renal impairment
No dosage adjustment of Copalia is required for patients with mild to moderate renal impairment
(GFR >30 ml/min/1.73 m
2
). Monitoring of potassium levels and creatinine is advised in moderate
renal impairment.
16
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist
valsartan as their renin-angiotensin system is affected by the primary disease.
Heart failure
As a consequence of the inhibition of the renin-angiotensin-aldosterone system, 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 renin-angiotensin-aldosterone system, treatment with
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been
associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or
death. Similar outcomes have been reported with valsartan.
In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New
York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine
was associated with increased reports of pulmonary oedema despite no significant difference in the
incidence of worsening heart failure as compared to placebo.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral
stenosis, or obstructive hypertrophic cardiomyopathy.
Copalia has not been studied in any patient population other than hypertension.
Interactions linked to amlodipine
Caution required with concomitant use
CYP3A4 inhibitors
A study in elderly patients has shown that diltiazem inhibits the metabolism of amlodipine, probably
via CYP3A4 (plasma concentration increases by approximately 50% and the effect of amlodipine is
increased). The possibility that more potent inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole,
ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem
cannot be excluded.
CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin,
fosphenytoin, primidone], rifampicin, Hypericum perforatum)
Co-administration may lead to reduced plasma concentrations of amlodipine. Clinical monitoring is
indicated, with possible dosage adjustment of amlodipine during the treatment with the inducer and
after its withdrawal.
To be taken into account with concomitant use
Others
In monotherapy, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE
inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil,
anti-acid medicines (aluminium hydroxide gel, magnesium hydroxide, simeticone), cimetidine, non-
steroidal anti-inflammatory medicines, antibiotics and oral hypoglycaemic medicines.
Interactions linked to valsartan
Concomitant use not recommended
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during
concurrent use of ACE inhibitors. Despite 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 (see section 4.4).
17
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 to be prescribed in combination with valsartan,
monitoring of potassium plasma levels is advised.
Caution required with concomitant use
Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors,
acetylsalicylic acid (>3 g/day), and non-selective NSAIDs
When angiotensin II antagonists are administered simultaneously with NSAIDs attenuation of the
antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and
NSAIDs may lead to an increased risk of 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.
Others
In monotherapy with valsartan, no interactions of clinical significance have been found with the
following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin,
hydrochlorothiazide, amlodipine, glibenclamide.
Interactions common to the combination
No drug interaction studies were performed with Copalia and other medicinal products.
To be taken into account with concomitant use
Other antihypertensive agents
Commonly used antihypertensive agents (e.g. alpha blockers, diuretics) and other medicinal products
which may cause hypotensive adverse effects (e.g. tricyclic antidepressants, alpha blockers for
treatment of benign prostate hyperplasia) may increase the antihypertensive effect of the combination.
Pregnancy
The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first
trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and
third trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors
during the first trimester of pregnancy has not been conclusive; however a small increase in risk
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative
antihypertensive treatments which have an established safety profile for use in pregnancy. When
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,
alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal
toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).
Should exposure to 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 sections
4.3 and 4.4).
18
Lactation
Because no information is available regarding the use of Copalia during breast-feeding, Copalia is not
recommended and alternative treatments with better established safety profiles during breast-feeding
are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. When driving
vehicles or using machines it should be taken into account that occasionally dizziness or weariness
may occur.
The safety of Copalia has been evaluated in five controlled clinical studies with 5,175 patients, 2,613
of whom received valsartan in combination with amlodipine.
Adverse reactions have been ranked under headings of frequency using the following convention: very
common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000,
<1/1,000); very rare (<1/10,000), including isolated reports.
19
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Cardiac disorders
Tachycardia, palpitations
Rare:
Syncope
Nervous system disorders
Uncommon:
Dizziness, somnolence, dizziness postural, paraesthesia
Eye disorders
Rare: Visual disturbance
Ear and labyrinth disorders
Uncommon: Vertigo
Rare: Tinnitus
Respiratory, thoracic and mediastinal disorders
Uncommon:
Cough, pharyngolaryngeal pain
Gastrointestinal disorders
Uncommon: Diarrhoea, nausea, abdominal pain, constipation, dry mouth
Renal and urinary disorders
Rare: Pollakisuria, polyuria
Skin and subcutaneous tissue disorders
Uncommon: Rash, erythema
Rare: Hyperhidrosis, exanthema, pruritus
Musculoskeletal and connective tissue disorders
Uncommon:
Joint swelling, back pain, arthralgia
Rare:
Muscle spasm, sensation of heaviness
Infections and infestations
Common:
Nasopharyngitis, influenza
Vascular disorders
Uncommon: Orthostatic hypotension
Rare: Hypotension
General disorders and administration site conditions
Common:
Oedema, pitting oedema, facial oedema, oedema peripheral, fatigue, flushing,
asthenia, hot flush
Immune system disorders
Rare: Hypersensitivity
Reproductive system and breast disorders
Rare:
Erectile dysfunction
Psychiatric disorders
Rare:
Anxiety
Additional information on the combination
Peripheral oedema, a recognised side effect of amlodipine, was generally observed at a lower
incidence in patients who received the amlodipine/valsartan combination than in those who received
amlodipine alone. In double-blind, controlled clinical trials, the incidence of peripheral oedema by
dose was as follows:
% of patients who experienced peripheral
oedema
Valsartan (mg)
0
40
80
160
320
0
3.0
5.5
2.4
1.6
0.9
2.5
8.0
2.3
5.4
2.4
3.9
Amlodipine
(mg)
5
3.1
4.8
2.3
2.1
2.4
10
10.3
NA
NA
9.0
9.5
20
Uncommon:
Common:
Headache
The mean incidence of peripheral oedema evenly weighted across all doses was 5.1% with the
amlodipine/valsartan combination.
Additional information on the individual components
Adverse drug reactions previously reported with one of the individual components (amlodipine or
valsartan) may be potential undesirable effects with Copalia as well, even if not observed in clinical
trials or during the post-marketing period.
Amlodipine
Common
Vomiting.
Uncommon
Alopecia, altered bowel habits, dyspepsia, dyspnoea, rhinitis, gastritis, gingival
hyperplasia, gynaecomastia, hyperglycaemia, impotence, increased urinary
frequency, leucopenia, malaise, mood changes, myalgia, peripheral neuropathy,
pancreatitis, hepatitis, thrombocytopenia, vasculitis, angioedema and erythema
multiforme.
Rare
Arrhythmia, myocardial infarction.
Rarely, patients, particularly those with severe
obstructive coronary artery disease, have developed increased frequency, duration or
severity of angina or acute myocardial infarction on starting calcium channel blocker
therapy or at the time of dosage increase. Arrhythmia (including ventricular
tachycardia and atrial fibrillation) has also been reported. These adverse events may
not be distinguishable from the natural history of the underlying disease.
Very rare
Cholestatic jaundice, AST and ALT increase, purpura, rash and pruritus. Exceptional
cases of extrapyramidal syndrome have been reported.
Valsartan
Not known
Decrease in haemoglobin, decrease in haematocrit, neutropenia, thrombocytopenia,
increase of serum potassium, elevation of liver function values including increase of
serum bilirubin, renal failure and impairment, elevation of serum creatinine,
angioedema, myalgia, vasculitis, hypersensitivity including serum sickness.
Symptoms
There is no experience of overdose with Copalia. The major symptom of overdose with valsartan is
peripheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged systemic
hypotension up to and including shock with fatal outcome have been reported.
Treatment
If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of
activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine
has been shown to significantly decrease amlodipine absorption. Clinically significant hypotension
due to Copalia overdose calls for active cardiovascular support, including frequent monitoring of
cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and
urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided
that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in
reversing the effects of calcium channel blockade.
Both valsartan and amlodipine are unlikely to be removed by haemodialysis.
21
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: angiotensin II antagonists, plain (valsartan), combinations with
dihydropyridine derivatives (amlodipine), ATC code:
C09DB01
Copalia combines two antihypertensive compounds with complementary mechanisms to control blood
pressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist class
and valsartan to the angiotensin II antagonist class of medicines. The combination of these substances
has an additive antihypertensive effect, reducing blood pressure to a greater degree than either
component alone.
Amlodipine
The amlodipine component of Copalia inhibits the transmembrane entry of calcium ions into cardiac
and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a
direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance
and in blood pressure. Experimental data suggest that amlodipine binds to both dihydropyridine and
non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth
muscle are dependent upon the movement of extracellular calcium ions into these cells through
specific ion channels.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces
vasodilation, resulting in a reduction of supine and standing blood pressures. These decreases in blood
pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with
chronic dosing.
Plasma concentrations correlate with effect in both young and elderly patients.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a
decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal
plasma flow, without change in filtration fraction or proteinuria.
As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and
during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have
generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on
left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been
associated with a negative inotropic effect when administered in the therapeutic dose range to intact
animals and humans, even when co-administered with beta blockers to humans.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals
or humans. In clinical studies in which amlodipine was administered in combination with beta
blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic
parameters were observed.
Valsartan
Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively
on the receptor subtype AT
1
, which is responsible for the known actions of angiotensin II. The
increased plasma levels of angiotensin II following AT
1
receptor blockade with valsartan may
stimulate the unblocked receptor subtype AT
2
, which appears to counterbalance the effect of the AT
1
receptor. Valsartan does not exhibit any partial agonist activity at the AT
1
receptor and has much
(about 20,000-fold) greater affinity for the AT
1
receptor than for the AT
2
receptor.
Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin
II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or
substance P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials
where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (p
22
<0.05) lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6%
versus 7.9%, respectively). In a clinical trial of patients with a history of dry cough during ACE
inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide
diuretic experienced coughing, compared to 68.5% of those treated with an ACE inhibitor (p <0.05).
Valsartan does not bind to or block other hormone receptors or ion channels known to be important in
cardiovascular regulation.
Administration of valsartan to patients with hypertension results in a drop in blood pressure without
affecting pulse rate.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs
within 2 hours, and the peak drop in blood pressure is achieved within 4–6 hours. The
antihypertensive effect persists over 24 hours after administration. During repeated administration, the
maximum reduction in blood pressure with any dose is generally attained within 2–4 weeks and is
sustained during long-term therapy. Abrupt withdrawal of valsartan has not been associated with
rebound hypertension or other adverse clinical events.
Amlodipine/Valsartan
Over 1,400 hypertensive patients received Copalia once daily in two placebo-controlled trials. Adults
with mild to moderate uncomplicated essential hypertension (mean sitting diastolic blood pressure
≥95 and <110 mmHg) were enrolled. Patients with high cardiovascular risks – heart failure, type I and
poorly controlled type II diabetes and history of myocardial infarction or stroke within one year –
were excluded.
The combination of amlodipine and valsartan produces dose-related additive reduction in blood
pressure across its therapeutic dose range. The antihypertensive effect of a single dose of the
combination persisted for 24 hours.
A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation
of blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients
not adequately controlled on valsartan 160 mg in 75% of patients treated with amlodipine/valsartan
10 mg/160 mg and 62% of patients treated with amlodipine/valsartan 5 mg/160 mg, compared to 53%
of patients remaining on valsartan 160 mg. The addition of amlodipine 10 mg and 5 mg produced an
additional reduction in systolic/diastolic blood pressure of 6.0/4.8 mmHg and 3.9/2.9 mmHg,
respectively, compared to patients who remained on valsartan 160 mg only.
A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation
of blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients
not adequately controlled on amlodipine 10 mg in 78% of patients treated with amlodipine/valsartan
10 mg/160 mg, compared to 67% of patients remaining on amlodipine 10 mg. The addition of
valsartan 160 mg produced an additional reduction in systolic/diastolic blood pressure of
2.9/2.1 mmHg compared to patients who remained on amlodipine 10 mg only.
Copalia was also studied in an active-controlled study of 130 hypertensive patients with diastolic
blood pressure ≥110 mmHg and <120 mmHg. In this study (baseline blood pressure 171/113 mmHg),
an Copalia regimen of 5 mg/160 mg titrated to 10 mg/160 mg reduced sitting blood pressure by
36/29 mmHg as compared to 32/28 mmHg with a regimen of lisinopril/hydrochlorothiazide
10 mg/12.5 mg titrated to 20 mg/12.5 mg.
In two long-term follow-up studies the effect of Copalia was maintained for over one year. Abrupt
withdrawal of Copalia has not been associated with a rapid increase in blood pressure.
In patients not adequately controlled on amlodipine 5 mg, amlodipine/valsartan 5 mg/80 mg may
achieve blood pressure control similar to amlodipine 10 mg with less oedema. In patients adequately
controlled on amlodipine 10 mg but who experience unacceptable oedema, amlodipine/valsartan
5 mg/80 mg may achieve similar blood pressure control with less oedema. Age, gender and race did
not influence the response to Copalia.
23
Copalia has not been studied in any patient population other than hypertension. Valsartan has been
studied in patients with post myocardial infarction and heart failure. Amlodipine has been studied in
patients with chronic stable angina, vasospastic angina and angiographically documented coronary
artery disease.
5.2 Pharmacokinetic properties
Linearity
Amlodipine and valsartan exhibit linear pharmacokinetics.
Amlodipine
Absorption:
After oral administration of therapeutic doses of amlodipine alone, peak plasma
concentrations of amlodipine are reached in 6–12 hours. Absolute bioavailability has been calculated as
between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.
Distribution:
Volume of distribution is approximately 21 l/kg.
In vitro
studies with amlodipine have
shown that approximately 97.5% of circulating drug is bound to plasma proteins in hypertensive
patients.
Biotransformation:
Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive
metabolites.
Excretion:
Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of
approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for
7–8 days. Ten per cent of original amlodipine and 60% of amlodipine metabolites are excreted in urine.
Valsartan
Absorption:
Following oral administration of valsartan alone, peak plasma concentrations of valsartan
are reached in 2–4 hours. Mean absolute bioavailability is 23%. Valsartan shows multiexponential
decay kinetics (t
½α
<1 h and t
½ß
about 9 h). Food decreases exposure (as measured by AUC) to
valsartan by about 40% and peak plasma concentration (C
max
) by about 50%, although from about 8 h
post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in
AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and
valsartan can therefore be given either with or without food.
Distribution:
The steady-state volume of distribution of valsartan after intravenous administration is
about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly
bound to serum proteins (94–97%), mainly serum albumin.
Biotransformation:
Valsartan is not transformed 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.
Excretion:
Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of
dose), mainly as unchanged drug. 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.
Amlodipine/Valsartan
Following oral administration of Copalia, peak plasma concentrations of valsartan and amlodipine are
reached in 3 and 6–8 hours, respectively. The rate and extent of absorption of Copalia are equivalent
to the bioavailability of valsartan and amlodipine when administered as individual tablets.
Special populations
Paediatric patients (age below 18 years)
No pharmacokinetic data are available in the paediatric population.
24
Elderly (age 65 years or over)
Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly
patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC)
and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in the
young therefore caution is required when increasing the dosage.
Renal impairment
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expected
for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation
was seen between renal function and systemic exposure to valsartan.
Hepatic impairment
Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase of
approximately 40–60% in AUC. On average, in patients with mild to moderate chronic liver disease
exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers (matched by
age, sex and weight). Caution should be exercised in patients with liver disease (see section 4.2).
5.3 Preclinical safety data
Adverse reactions observed in animal studies with possible clinical relevance were as follows:
Histopathological signs of inflammation of the glandular stomach was seen in male rats at an exposure
of about 1.9 (valsartan) and 2.6 (amlodipine) times the clinical doses of 160 mg valsartan and 10 mg
amlodipine. At higher exposures, there were ulceration and erosion of the stomach mucosa in both
females and males. Similar changes were also seen in the valsartan alone group (exposure 8.5–
11.0 times the clinical dose of 160 mg valsartan).
An increased incidence and severity of renal tubular basophilia/hyalinisation, dilation and casts, as
well as interstitial lymphocyte inflammation and arteriolar medial hypertrophy were found at an
exposure of 8–13 (valsartan) and 7–8 (amlodipine) times the clinical doses of 160 mg valsartan and
10 mg amlodipine. Similar changes were found in the valsartan alone group (exposure 8.5–11.0 times
the clinical dose of 160 mg valsartan).
In an embryo-foetal development study in the rat, increased incidences of dilated ureters, malformed
sternebrae, and unossified forepaw phalanges were noticed at exposures of about 12 (valsartan) and 10
(amlodipine) times the clinical doses of 160 mg valsartan and 10 mg amlodipine. Dilated ureters were
also found in the valsartan alone group (exposure 12 times the clinical dose of 160 mg valsartan).
There were only modest signs of maternal toxicity (moderate reduction of body weight) in this study.
The no-observed-effect-level for developmental effects was observed at 3- (valsartan) and 4-
(amlodipine) fold the clinical exposure (based on AUC).
For the single compounds there was no evidence of mutagenicity, clastogenicity or carcinogenicity.
25
6.
6.1 List of excipients
Tablet core:
Cellulose microcrystalline
Crospovidone Type A
Silica, colloidal anhydrous
Magnesium stearate
Coating:
Hypromellose
Titanium dioxide (E171)
Iron oxide, yellow (E172)
Macrogol 4000
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PVC/PVDC blisters. One blister contains 7, 10 or 14 film-coated tablets.
Pack sizes: 7, 14, 28, 30, 56, 90, 98 or 280 film-coated tablets.
PVC/PVDC perforated unit dose blisters. One blister contains 7, 10 or 14 film-coated tablets.
Pack sizes: 56, 98 or 280 film-coated tablets and multipacks containing 280 (4x70 or 20x14) film-
coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
26
8.
EU/1/06/372/009
EU/1/06/372/010
EU/1/06/372/011
EU/1/06/372/012
EU/1/06/372/013
EU/1/06/372/014
EU/1/06/372/015
EU/1/06/372/016
EU/1/06/372/028
EU/1/06/372/029
EU/1/06/372/030
EU/1/06/372/035
EU/1/06/372/038
9.
16.01.2007
27
1.
Copalia 10 mg/160 mg film-coated tablets
2.
Each film-coated tablet contains 10 mg of amlodipine (as amlodipine besylate) and 160 mg of
valsartan.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Light yellow, oval film-coated tablet, imprinted with “NVR” on one side and “UIC” on the other side.
4.
Treatment of essential hypertension.
Copalia is indicated in patients whose blood pressure is not adequately controlled on amlodipine or
valsartan monotherapy.
The recommended dose of Copalia is one tablet per day.
Copalia 10 mg/160 mg may be administered in patients whose blood pressure is not adequately
controlled with amlodipine 10 mg or valsartan 160 mg alone or with Copalia 5 mg/160 mg.
Copalia can be used with or without food. It is recommended to take Copalia with some water.
Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended before
changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy
to the fixed-dose combination may be considered.
For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may be
switched to Copalia containing the same component doses.
Renal impairment
No dosage adjustment is required for patients with mild to moderate renal impairment. Monitoring of
potassium levels and creatinine is advised in moderate renal impairment.
Hepatic impairment
Caution should be exercised when administering Copalia to patients with hepatic impairment or biliary
obstructive disorders (see section 4.4). In patients with mild to moderate hepatic impairment without
cholestasis, the maximum recommended dose is 80 mg valsartan.
Elderly (age 65 years or over)
In elderly patients, caution is required when increasing the dosage.
28
Children and adolescents
Copalia is not recommended for use in patients aged below 18 years due to a lack of data on safety and
efficacy.
Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the excipients.
Severe hepatic impairment, biliary cirrhosis or cholestasis.
Severe renal impairment (GFR <30 ml/min/1.73 m
2
) and patients undergoing dialysis.
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Pregnancy
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless
continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to
alternative antihypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if
appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Sodium- and/or volume-depleted patients
Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with
Copalia in placebo-controlled studies. In patients with an activated renin-angiotensin system (such as
volume- and/or salt-depleted patients receiving high doses of diuretics) who are receiving angiotensin
receptor blockers, symptomatic hypotension may occur. Correction of this condition prior to
administration of Copalia or close medical supervision at the start of treatment is recommended.
If hypotension occurs with Copalia, the patient should be placed in the supine position and, if
necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood
pressure has been stabilised.
Hyperkalaemia
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing
potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be
undertaken with caution and with frequent monitoring of potassium levels.
Renal artery stenosis
No data are available on the use of Copalia in patients with bilateral renal artery stenosis or stenosis to
a solitary kidney.
Kidney transplantation
To date there is no experience of the safe use of Copalia in patients who have had a recent kidney
transplantation.
Hepatic impairment
Valsartan is mostly eliminated unchanged via the bile, whereas amlodipine is extensively metabolised
by the liver. Particular caution should be exercised when administering Copalia to patients with mild
to moderate hepatic impairment or biliary obstructive disorders.
In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended
dose is 80 mg valsartan.
Renal impairment
No dosage adjustment of Copalia is required for patients with mild to moderate renal impairment
(GFR >30 ml/min/1.73 m
2
). Monitoring of potassium levels and creatinine is advised in moderate
renal impairment.
29
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist
valsartan as their renin-angiotensin system is affected by the primary disease.
Heart failure
As a consequence of the inhibition of the renin-angiotensin-aldosterone system, 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 renin-angiotensin-aldosterone system, treatment with
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been
associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or
death. Similar outcomes have been reported with valsartan.
In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New
York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine
was associated with increased reports of pulmonary oedema despite no significant difference in the
incidence of worsening heart failure as compared to placebo.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral
stenosis, or obstructive hypertrophic cardiomyopathy.
Copalia has not been studied in any patient population other than hypertension.
Interactions linked to amlodipine
Caution required with concomitant use
CYP3A4 inhibitors
A study in elderly patients has shown that diltiazem inhibits the metabolism of amlodipine, probably
via CYP3A4 (plasma concentration increases by approximately 50% and the effect of amlodipine is
increased). The possibility that more potent inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole,
ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem
cannot be excluded.
CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin,
fosphenytoin, primidone], rifampicin, Hypericum perforatum)
Co-administration may lead to reduced plasma concentrations of amlodipine. Clinical monitoring is
indicated, with possible dosage adjustment of amlodipine during the treatment with the inducer and
after its withdrawal.
To be taken into account with concomitant use
Others
In monotherapy, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE
inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil,
anti-acid medicines (aluminium hydroxide gel, magnesium hydroxide, simeticone), cimetidine, non-
steroidal anti-inflammatory medicines, antibiotics and oral hypoglycaemic medicines.
Interactions linked to valsartan
Concomitant use not recommended
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during
concurrent use of ACE inhibitors. Despite 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 (see section 4.4).
30
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 to be prescribed in combination with valsartan,
monitoring of potassium plasma levels is advised.
Caution required with concomitant use
Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors,
acetylsalicylic acid (>3 g/day), and non-selective NSAIDs
When angiotensin II antagonists are administered simultaneously with NSAIDs attenuation of the
antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and
NSAIDs may lead to an increased risk of 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.
Others
In monotherapy with valsartan, no interactions of clinical significance have been found with the
following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin,
hydrochlorothiazide, amlodipine, glibenclamide.
Interactions common to the combination
No drug interaction studies were performed with Copalia and other medicinal products.
To be taken into account with concomitant use
Other antihypertensive agents
Commonly used antihypertensive agents (e.g. alpha blockers, diuretics) and other medicinal products
which may cause hypotensive adverse effects (e.g. tricyclic antidepressants, alpha blockers for
treatment of benign prostate hyperplasia) may increase the antihypertensive effect of the combination.
Pregnancy
The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first
trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and
third trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors
during the first trimester of pregnancy has not been conclusive; however a small increase in risk
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative
antihypertensive treatments which have an established safety profile for use in pregnancy. When
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,
alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal
toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).
Should exposure to 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 sections
4.3 and 4.4).
31
Lactation
Because no information is available regarding the use of Copalia during breast-feeding, Copalia is not
recommended and alternative treatments with better established safety profiles during breast-feeding
are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. When driving
vehicles or using machines it should be taken into account that occasionally dizziness or weariness
may occur.
The safety of Copalia has been evaluated in five controlled clinical studies with 5,175 patients, 2,613
of whom received valsartan in combination with amlodipine.
Adverse reactions have been ranked under headings of frequency using the following convention: very
common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000,
<1/1,000); very rare (<1/10,000), including isolated reports.
32
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Cardiac disorders
Tachycardia, palpitations
Rare:
Syncope
Nervous system disorders
Uncommon:
Dizziness, somnolence, dizziness postural, paraesthesia
Eye disorders
Rare: Visual disturbance
Ear and labyrinth disorders
Uncommon: Vertigo
Rare: Tinnitus
Respiratory, thoracic and mediastinal disorders
Uncommon:
Cough, pharyngolaryngeal pain
Gastrointestinal disorders
Uncommon: Diarrhoea, nausea, abdominal pain, constipation, dry mouth
Renal and urinary disorders
Rare: Pollakisuria, polyuria
Skin and subcutaneous tissue disorders
Uncommon: Rash, erythema
Rare: Hyperhidrosis, exanthema, pruritus
Musculoskeletal and connective tissue disorders
Uncommon:
Joint swelling, back pain, arthralgia
Rare:
Muscle spasm, sensation of heaviness
Infections and infestations
Common:
Nasopharyngitis, influenza
Vascular disorders
Uncommon: Orthostatic hypotension
Rare: Hypotension
General disorders and administration site conditions
Common:
Oedema, pitting oedema, facial oedema, oedema peripheral, fatigue, flushing,
asthenia, hot flush
Immune system disorders
Rare: Hypersensitivity
Reproductive system and breast disorders
Rare:
Erectile dysfunction
Psychiatric disorders
Rare:
Anxiety
Additional information on the combination
Peripheral oedema, a recognised side effect of amlodipine, was generally observed at a lower
incidence in patients who received the amlodipine/valsartan combination than in those who received
amlodipine alone. In double-blind, controlled clinical trials, the incidence of peripheral oedema by
dose was as follows:
% of patients who experienced peripheral
oedema
Valsartan (mg)
0
40
80
160
320
0
3.0
5.5
2.4
1.6
0.9
2.5
8.0
2.3
5.4
2.4
3.9
Amlodipine
(mg)
5
3.1
4.8
2.3
2.1
2.4
10
10.3
NA
NA
9.0
9.5
33
Uncommon:
Common:
Headache
The mean incidence of peripheral oedema evenly weighted across all doses was 5.1% with the
amlodipine/valsartan combination.
Additional information on the individual components
Adverse drug reactions previously reported with one of the individual components (amlodipine or
valsartan) may be potential undesirable effects with Copalia as well, even if not observed in clinical
trials or during the post-marketing period.
Amlodipine
Common
Vomiting.
Uncommon
Alopecia, altered bowel habits, dyspepsia, dyspnoea, rhinitis, gastritis, gingival
hyperplasia, gynaecomastia, hyperglycaemia, impotence, increased urinary
frequency, leucopenia, malaise, mood changes, myalgia, peripheral neuropathy,
pancreatitis, hepatitis, thrombocytopenia, vasculitis, angioedema and erythema
multiforme.
Rare
Arrhythmia, myocardial infarction.
Rarely, patients, particularly those with severe
obstructive coronary artery disease, have developed increased frequency, duration or
severity of angina or acute myocardial infarction on starting calcium channel blocker
therapy or at the time of dosage increase. Arrhythmia (including ventricular
tachycardia and atrial fibrillation) has also been reported. These adverse events may
not be distinguishable from the natural history of the underlying disease.
Very rare
Cholestatic jaundice, AST and ALT increase, purpura, rash and pruritus. Exceptional
cases of extrapyramidal syndrome have been reported.
Valsartan
Not known
Decrease in haemoglobin, decrease in haematocrit, neutropenia, thrombocytopenia,
increase of serum potassium, elevation of liver function values including increase of
serum bilirubin, renal failure and impairment, elevation of serum creatinine,
angioedema, myalgia, vasculitis, hypersensitivity including serum sickness.
Symptoms
There is no experience of overdose with Copalia. The major symptom of overdose with valsartan is
peripheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged systemic
hypotension up to and including shock with fatal outcome have been reported.
Treatment
If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of
activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine
has been shown to significantly decrease amlodipine absorption. Clinically significant hypotension
due to Copalia overdose calls for active cardiovascular support, including frequent monitoring of
cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and
urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided
that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in
reversing the effects of calcium channel blockade.
Both valsartan and amlodipine are unlikely to be removed by haemodialysis.
34
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: angiotensin II antagonists, plain (valsartan), combinations with
dihydropyridine derivatives (amlodipine), ATC code:
C09DB01
Copalia combines two antihypertensive compounds with complementary mechanisms to control blood
pressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist class
and valsartan to the angiotensin II antagonist class of medicines. The combination of these substances
has an additive antihypertensive effect, reducing blood pressure to a greater degree than either
component alone.
Amlodipine
The amlodipine component of Copalia inhibits the transmembrane entry of calcium ions into cardiac
and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a
direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance
and in blood pressure. Experimental data suggest that amlodipine binds to both dihydropyridine and
non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth
muscle are dependent upon the movement of extracellular calcium ions into these cells through
specific ion channels.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces
vasodilation, resulting in a reduction of supine and standing blood pressures. These decreases in blood
pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with
chronic dosing.
Plasma concentrations correlate with effect in both young and elderly patients.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a
decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal
plasma flow, without change in filtration fraction or proteinuria.
As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and
during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have
generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on
left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been
associated with a negative inotropic effect when administered in the therapeutic dose range to intact
animals and humans, even when co-administered with beta blockers to humans.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals
or humans. In clinical studies in which amlodipine was administered in combination with beta
blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic
parameters were observed.
Valsartan
Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively
on the receptor subtype AT
1
, which is responsible for the known actions of angiotensin II. The
increased plasma levels of angiotensin II following AT
1
receptor blockade with valsartan may
stimulate the unblocked receptor subtype AT
2
, which appears to counterbalance the effect of the AT
1
receptor. Valsartan does not exhibit any partial agonist activity at the AT
1
receptor and has much
(about 20,000-fold) greater affinity for the AT
1
receptor than for the AT
2
receptor.
Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin
II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or
substance P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials
where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (p
35
<0.05) lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6%
versus 7.9%, respectively). In a clinical trial of patients with a history of dry cough during ACE
inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide
diuretic experienced coughing, compared to 68.5% of those treated with an ACE inhibitor (p <0.05).
Valsartan does not bind to or block other hormone receptors or ion channels known to be important in
cardiovascular regulation.
Administration of valsartan to patients with hypertension results in a drop in blood pressure without
affecting pulse rate.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs
within 2 hours, and the peak drop in blood pressure is achieved within 4–6 hours. The
antihypertensive effect persists over 24 hours after administration. During repeated administration, the
maximum reduction in blood pressure with any dose is generally attained within 2–4 weeks and is
sustained during long-term therapy. Abrupt withdrawal of valsartan has not been associated with
rebound hypertension or other adverse clinical events.
Amlodipine/Valsartan
Over 1,400 hypertensive patients received Copalia once daily in two placebo-controlled trials. Adults
with mild to moderate uncomplicated essential hypertension (mean sitting diastolic blood pressure
≥95 and <110 mmHg) were enrolled. Patients with high cardiovascular risks – heart failure, type I and
poorly controlled type II diabetes and history of myocardial infarction or stroke within one year –
were excluded.
The combination of amlodipine and valsartan produces dose-related additive reduction in blood
pressure across its therapeutic dose range. The antihypertensive effect of a single dose of the
combination persisted for 24 hours.
A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation
of blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients
not adequately controlled on valsartan 160 mg in 75% of patients treated with amlodipine/valsartan
10 mg/160 mg and 62% of patients treated with amlodipine/valsartan 5 mg/160 mg, compared to 53%
of patients remaining on valsartan 160 mg. The addition of amlodipine 10 mg and 5 mg produced an
additional reduction in systolic/diastolic blood pressure of 6.0/4.8 mmHg and 3.9/2.9 mmHg,
respectively, compared to patients who remained on valsartan 160 mg only.
A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation
of blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients
not adequately controlled on amlodipine 10 mg in 78% of patients treated with amlodipine/valsartan
10 mg/160 mg, compared to 67% of patients remaining on amlodipine 10 mg. The addition of
valsartan 160 mg produced an additional reduction in systolic/diastolic blood pressure of
2.9/2.1 mmHg compared to patients who remained on amlodipine 10 mg only.
Copalia was also studied in an active-controlled study of 130 hypertensive patients with diastolic
blood pressure ≥110 mmHg and <120 mmHg. In this study (baseline blood pressure 171/113 mmHg),
an Copalia regimen of 5 mg/160 mg titrated to 10 mg/160 mg reduced sitting blood pressure by
36/29 mmHg as compared to 32/28 mmHg with a regimen of lisinopril/hydrochlorothiazide
10 mg/12.5 mg titrated to 20 mg/12.5 mg.
In two long-term follow-up studies the effect of Copalia was maintained for over one year. Abrupt
withdrawal of Copalia has not been associated with a rapid increase in blood pressure.
In patients not adequately controlled on amlodipine 5 mg, amlodipine/valsartan 5 mg/80 mg may
achieve blood pressure control similar to amlodipine 10 mg with less oedema. In patients adequately
controlled on amlodipine 10 mg but who experience unacceptable oedema, amlodipine/valsartan
5 mg/80 mg may achieve similar blood pressure control with less oedema. Age, gender and race did
not influence the response to Copalia.
36
Copalia has not been studied in any patient population other than hypertension. Valsartan has been
studied in patients with post myocardial infarction and heart failure. Amlodipine has been studied in
patients with chronic stable angina, vasospastic angina and angiographically documented coronary
artery disease.
5.2 Pharmacokinetic properties
Linearity
Amlodipine and valsartan exhibit linear pharmacokinetics.
Amlodipine
Absorption:
After oral administration of therapeutic doses of amlodipine alone, peak plasma
concentrations of amlodipine are reached in 6–12 hours. Absolute bioavailability has been calculated as
between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.
Distribution:
Volume of distribution is approximately 21 l/kg.
In vitro
studies with amlodipine have
shown that approximately 97.5% of circulating drug is bound to plasma proteins in hypertensive
patients.
Biotransformation:
Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive
metabolites.
Excretion:
Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of
approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for
7–8 days. Ten per cent of original amlodipine and 60% of amlodipine metabolites are excreted in urine.
Valsartan
Absorption:
Following oral administration of valsartan alone, peak plasma concentrations of valsartan
are reached in 2–4 hours. Mean absolute bioavailability is 23%. Valsartan shows multiexponential
decay kinetics (t
½α
<1 h and t
½ß
about 9 h). Food decreases exposure (as measured by AUC) to
valsartan by about 40% and peak plasma concentration (C
max
) by about 50%, although from about 8 h
post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in
AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and
valsartan can therefore be given either with or without food.
Distribution:
The steady-state volume of distribution of valsartan after intravenous administration is
about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly
bound to serum proteins (94–97%), mainly serum albumin.
Biotransformation:
Valsartan is not transformed 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.
Excretion:
Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of
dose), mainly as unchanged drug. 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.
Amlodipine/Valsartan
Following oral administration of Copalia, peak plasma concentrations of valsartan and amlodipine are
reached in 3 and 6–8 hours, respectively. The rate and extent of absorption of Copalia are equivalent
to the bioavailability of valsartan and amlodipine when administered as individual tablets.
Special populations
Paediatric patients (age below 18 years)
No pharmacokinetic data are available in the paediatric population.
37
Elderly (age 65 years or over)
Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly
patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC)
and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in the
young therefore caution is required when increasing the dosage.
Renal impairment
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expected
for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation
was seen between renal function and systemic exposure to valsartan.
Hepatic impairment
Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase of
approximately 40–60% in AUC. On average, in patients with mild to moderate chronic liver disease
exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers (matched by
age, sex and weight). Caution should be exercised in patients with liver disease (see section 4.2).
5.3 Preclinical safety data
Adverse reactions observed in animal studies with possible clinical relevance were as follows:
Histopathological signs of inflammation of the glandular stomach was seen in male rats at an exposure
of about 1.9 (valsartan) and 2.6 (amlodipine) times the clinical doses of 160 mg valsartan and 10 mg
amlodipine. At higher exposures, there were ulceration and erosion of the stomach mucosa in both
females and males. Similar changes were also seen in the valsartan alone group (exposure 8.5–
11.0 times the clinical dose of 160 mg valsartan).
An increased incidence and severity of renal tubular basophilia/hyalinisation, dilation and casts, as
well as interstitial lymphocyte inflammation and arteriolar medial hypertrophy were found at an
exposure of 8–13 (valsartan) and 7–8 (amlodipine) times the clinical doses of 160 mg valsartan and
10 mg amlodipine. Similar changes were found in the valsartan alone group (exposure 8.5–11.0 times
the clinical dose of 160 mg valsartan).
In an embryo-foetal development study in the rat, increased incidences of dilated ureters, malformed
sternebrae, and unossified forepaw phalanges were noticed at exposures of about 12 (valsartan) and 10
(amlodipine) times the clinical doses of 160 mg valsartan and 10 mg amlodipine. Dilated ureters were
also found in the valsartan alone group (exposure 12 times the clinical dose of 160 mg valsartan).
There were only modest signs of maternal toxicity (moderate reduction of body weight) in this study.
The no-observed-effect-level for developmental effects was observed at 3- (valsartan) and 4-
(amlodipine) fold the clinical exposure (based on AUC).
For the single compounds there was no evidence of mutagenicity, clastogenicity or carcinogenicity.
38
6.
6.1 List of excipients
Tablet core:
Cellulose microcrystalline
Crospovidone Type A
Silica, colloidal anhydrous
Magnesium stearate
Coating:
Hypromellose
Titanium dioxide (E171)
Iron oxide, yellow (E172)
Iron oxide, red (E172)
Macrogol 4000
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PVC/PVDC blisters. One blister contains 7, 10 or 14 film-coated tablets.
Pack sizes: 7, 14, 28, 30, 56, 90, 98 or 280 film-coated tablets.
PVC/PVDC perforated unit dose blisters. One blister contains 7, 10 or 14 film-coated tablets.
Pack sizes: 56, 98 or 280 film-coated tablets and multipacks containing 280 (4x70 or 20x14) film-
coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
39
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/06/372/017
EU/1/06/372/018
EU/1/06/372/019
EU/1/06/372/020
EU/1/06/372/021
EU/1/06/372/022
EU/1/06/372/023
EU/1/06/372/024
EU/1/06/372/031
EU/1/06/372/032
EU/1/06/372/033
EU/1/06/372/036
EU/1/06/372/039
9.
16.01.2007
40
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
41
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Novartis Pharma GmbH
Roonstraße 25
D-90429 Nuremberg
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 8.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
42
ANNEX III
LABELLING AND PACKAGE LEAFLET
43
A. LABELLING
44
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON OF UNIT PACK
1.
Copalia 5 mg/80 mg film-coated tablets
amlodipine/valsartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 5 mg amlodipine (as amlodipine besylate) and 80 mg valsartan.
3.
LIST OF EXCIPIENTS
4.
7 film-coated tablets
14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
90 film-coated tablets
98 film-coated tablets
280 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
45
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/372/001
7 film-coated tablets
EU/1/06/372/002
14 film-coated tablets
EU/1/06/372/003
28 film-coated tablets
EU/1/06/372/005
56 film-coated tablets
EU/1/06/372/006
90 film-coated tablets
EU/1/06/372/007
98 film-coated tablets
EU/1/06/372/008
280 film-coated tablets
EU/1/06/372/025
56 x 1 film-coated tablet (unit dose)
EU/1/06/372/026
98 x 1 film-coated tablet (unit dose)
EU/1/06/372/027
280 x 1 film-coated tablet (unit dose)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Copalia 5 mg/80 mg
46
EU/1/06/372/004
30 film-coated tablets
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX)
1.
Copalia 5 mg/80 mg film-coated tablets
amlodipine/valsartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 5 mg amlodipine (as amlodipine besylate) and 80 mg valsartan.
3.
LIST OF EXCIPIENTS
4.
70 film-coated tablets
Component of a multipack comprising 4 cartons, each containing 70 tablets.
14 film-coated tablets
Component of a multipack comprising 20 cartons, each containing 14 tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
Store in the original package in order to protect from moisture.
47
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/372/034
280 film-coated tablets (20x14)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Copalia 5 mg/80 mg
48
EU/1/06/372/037
280 film-coated tablets (4x70)
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON OF MULTIPACK (WITH BLUE BOX)
1.
Copalia 5 mg/80 mg film-coated tablets
amlodipine/valsartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 5 mg amlodipine (as amlodipine besylate) and 80 mg valsartan.
3.
LIST OF EXCIPIENTS
4.
280 film-coated tablets
Multipack comprising 4 cartons, each containing 70 tablets.
280 film-coated tablets
Multipack comprising 20 cartons, each containing 14 tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
Store in the original package in order to protect from moisture.
49
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/372/034
280 film-coated tablets (20x14)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Copalia 5 mg/80 mg
50
EU/1/06/372/037
280 film-coated tablets (4x70)
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Copalia 5 mg/80 mg film-coated tablets
amlodipine/valsartan
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
51
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON OF UNIT PACK
1.
Copalia 5 mg/160 mg film-coated tablets
amlodipine/valsartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 5 mg amlodipine (as amlodipine besylate) and 160 mg valsartan.
3.
LIST OF EXCIPIENTS
4.
7 film-coated tablets
14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
90 film-coated tablets
98 film-coated tablets
280 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
52
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/372/009
7 film-coated tablets
EU/1/06/372/010
14 film-coated tablets
EU/1/06/372/011
28 film-coated tablets
EU/1/06/372/013
56 film-coated tablets
EU/1/06/372/014
90 film-coated tablets
EU/1/06/372/015
98 film-coated tablets
EU/1/06/372/016
280 film-coated tablets
EU/1/06/372/028
56 x 1 film-coated tablet (unit dose)
EU/1/06/372/029
98 x 1 film-coated tablet (unit dose)
EU/1/06/372/030
280 x 1 film-coated tablet (unit dose)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Copalia 5 mg/160 mg
53
EU/1/06/372/012
30 film-coated tablets
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX)
1.
Copalia 5 mg/160 mg film-coated tablets
amlodipine/valsartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 5 mg amlodipine (as amlodipine besylate) and 160 mg valsartan.
3.
LIST OF EXCIPIENTS
4.
70 film-coated tablets
Component of a multipack comprising 4 cartons, each containing 70 tablets.
14 film-coated tablets
Component of a multipack comprising 20 cartons, each containing 14 tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
Store in the original package in order to protect from moisture.
54
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/372/035
280 film-coated tablets (20x14)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Copalia 5 mg/160 mg
55
EU/1/06/372/038
280 film-coated tablets (4x70)
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON OF MULTIPACK (WITH BLUE BOX)
1.
Copalia 5 mg/160 mg film-coated tablets
amlodipine/valsartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 5 mg amlodipine (as amlodipine besylate) and 160 mg valsartan.
3.
LIST OF EXCIPIENTS
4.
280 film-coated tablets
Multipack comprising 4 cartons, each containing 70 tablets.
280 film-coated tablets
Multipack comprising 20 cartons, each containing 14 tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
Store in the original package in order to protect from moisture.
56
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/372/035
280 film-coated tablets (20x14)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Copalia 5 mg/160 mg
57
EU/1/06/372/038
280 film-coated tablets (4x70)
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Copalia 5 mg/160 mg film-coated tablets
amlodipine/valsartan
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
58
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON OF UNIT PACK
1.
Copalia 10 mg/160 mg film-coated tablets
amlodipine/valsartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 10 mg amlodipine (as amlodipine besylate) and 160 mg valsartan.
3.
LIST OF EXCIPIENTS
4.
7 film-coated tablets
14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
90 film-coated tablets
98 film-coated tablets
280 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
59
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/372/017
7 film-coated tablets
EU/1/06/372/018
14 film-coated tablets
EU/1/06/372/019
28 film-coated tablets
EU/1/06/372/021
56 film-coated tablets
EU/1/06/372/022
90 film-coated tablets
EU/1/06/372/023
98 film-coated tablets
EU/1/06/372/024
280 film-coated tablets
EU/1/06/372/031
56 x 1 film-coated tablet (unit dose)
EU/1/06/372/032
98 x 1 film-coated tablet (unit dose)
EU/1/06/372/033
280 x 1 film-coated tablet (unit dose)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Copalia 10 mg/160 mg
60
EU/1/06/372/020
30 film-coated tablets
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX)
1.
Copalia 10 mg/160 mg film-coated tablets
amlodipine/valsartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 10 mg amlodipine (as amlodipine besylate) and 160 mg valsartan.
3.
LIST OF EXCIPIENTS
4.
70 film-coated tablets
Component of a multipack comprising 4 cartons, each containing 70 tablets.
14 film-coated tablets
Component of a multipack comprising 20 cartons, each containing 14 tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
Store in the original package in order to protect from moisture.
61
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/372/036
280 film-coated tablets (20x14)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Copalia 10 mg/160 mg
62
EU/1/06/372/039
280 film-coated tablets (4x70)
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON OF MULTIPACK (WITH BLUE BOX)
1.
Copalia 10 mg/160 mg film-coated tablets
amlodipine/valsartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 10 mg amlodipine (as amlodipine besylate) and 160 mg valsartan.
3.
LIST OF EXCIPIENTS
4.
280 film-coated tablets
Multipack comprising 4 cartons, each containing 70 tablets.
280 film-coated tablets
Multipack comprising 20 cartons, each containing 14 tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
Store in the original package in order to protect from moisture.
63
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/372/036
280 film-coated tablets (20x14)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Copalia 10 mg/160 mg
64
EU/1/06/372/039
280 film-coated tablets (4x70)
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Copalia 10 mg/160 mg film-coated tablets
amlodipine/valsartan
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
65
B. PACKAGE LEAFLET
66
PACKAGE LEAFLET: INFORMATION FOR THE USER
Copalia 5 mg/80 mg film-coated tablets
amlodipine/valsartan
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Copalia is and what it is used for
3.
How to take Copalia
4.
Possible side effects
5.
How to store Copalia
6.
Further information
1.
WHAT COPALIA IS AND WHAT IT IS USED FOR
Copalia tablets contain two substances called amlodipine and valsartan. Both of these substances help
to control high blood pressure.
−
Amlodipine belongs to a group of substances called “calcium channel blockers”. Amlodipine
stops calcium from moving into the blood vessel wall which stops the blood vessels from
tightening.
−
Valsartan belongs to a group of substances called “angiotensin-II receptor antagonists”.
Angiotensin II is produced by the body and makes the blood vessels tighten, thus increasing the
blood pressure. Valsartan works by blocking the effect of angiotensin II.
This means that both of these substances help to stop the blood vessels tightening. As a result, the
blood vessels relax and blood pressure is lowered.
Copalia is used to treat high blood pressure in patients whose blood pressure is not controlled enough
with either amlodipine or valsartan on its own.
2.
BEFORE YOU TAKE COPALIA
Do not take Copalia
−
if you are allergic (hypersensitive) to amlodipine or other medicines of the dihydropyridine
type,
−
if you are allergic (hypersensitive) to valsartan or any of the other ingredients of Copalia. If you
think you may be allergic, talk to your doctor before taking Copalia.
−
if you have severe liver problems, such as biliary cirrhosis or cholestasis.
−
if you have severe kidney problems or if you are having dialysis.
−
if you are more than 3 months pregnant. (It is also better to avoid Copalia in early pregnancy -
see Pregnancy section).
If any of the above applies to you, do not take Copalia and talk to your doctor
.
67
2.
Before you take Copalia
Take special care with Copalia
−
if you have been sick (vomiting or diarrhoea).
−
if you are taking diuretics (a type of medicine also called “water tablets” which increases the
amount of urine you produce).
−
if you are taking other medicines or substances that increase the level of potassium in your
blood (e.g. some types of diuretics, potassium supplements or salt substitutes containing
potassium).
−
if you have liver or kidney problems.
−
if you have a condition affecting the renal glands called “primary hyperaldosteronism”.
−
if you have had heart failure.
−
if your doctor has told you that you have a narrowing of the valves in your heart (called “aortic
or mitral stenosis”) or that the thickness of your heart muscle is abnormally increased (called
“obstructive hypertrophic cardiomyopathy”).
If any of these apply to you, tell your doctor before taking Copalia.
You must tell your doctor if you think that you are (
or might become
) pregnant. Copalia is not
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it
may cause serious harm to your baby if used at that stage (see section Pregnancy).
The use of Copalia in children and adolescents is not recommended.
Also tell your doctor if you have had a kidney transplant or if you had been told that you have a
narrowing of your kidney arteries.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. Your doctor may need to change the dose or take
other precautions. In some cases you may have to stop taking one of the medicines. This applies
especially to the medicines listed below:
−
lithium (a medicine used to treat some types of depression);
−
potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and
other substances that may increase potassium levels;
−
anticonvulsant agents (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone),
rifampicin, St. John’s wort;
−
nitroglycerin and other nitrates, or other substances called “vasodilators”;
−
medicines used for HIV/AIDS (e.g. ritonavir) or for treatment of fungal infections (e.g.
ketoconazole).
Taking Copalia with food and drink
You can take Copalia with or without food.
Copalia and older people
Caution is required when increasing the dosage.
Pregnancy and breast-feeding
Pregnancy
You must tell your doctor if you think you are (
or might become
) pregnant. Your doctor will normally
advise you to stop taking Copalia before you become pregnant or as soon as you know you are
pregnant and will advise you to take another medicine instead of Copalia. Copalia is not recommended
in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious
harm to your baby if used after the third month of pregnancy.
68
Breast-feeding
Tell your doctor if you are breast-feeding
or about to start breast-feeding
. Copalia is not recommended
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish
to breast-feed, especially if your baby is newborn, or was born prematurely.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
This medicine may make you feel dizzy. This can affect how well you can concentrate. So, if you are
not sure how this medicine will affect you, do not drive, use machinery, or do other activities that you
need to concentrate on.
3.
HOW TO TAKE
COPALIA
Always take this medicine exactly as your doctor has told you. You should check with your doctor if
you are not sure. This will help you get the best results and lower the risk of side effects.
The usual dose of Copalia is one tablet per day.
−
It is advisable to take your medicine at the same time each day, preferably in the morning.
−
Swallow the tablets with a glass of water.
−
You can take Copalia with or without food.
Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose.
Do not exceed the prescribed dose.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
If you take more Copalia than you should
If you have taken too many tablets of Copalia, or if someone else has taken your tablets, consult a
doctor immediately.
If you forget to take Copalia
If you forget to take this medicine, take it as soon as you remember. Then take your next dose at its
usual time. However, if it is almost time for your next dose, skip the dose you missed. Do not take a
double dose to make up for a forgotten tablet.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Copalia can cause side effects, although not everybody gets them.
Some side effects can be serious:
A few patients have experienced these serious side effects
(affecting less than 1 in 1,000 patients)
.
If
any of the following happen,
tell your doctor straight away:
Allergic reaction with symptoms such as rash, itching, swelling of face or lips or tongue, difficulty
breathing, low blood pressure (feeling of faintness, light-headedness).
69
Other possible side effects:
Common (affecting less than 1 in 10 patients)
: Influenza; blocked nose, sore throat and discomfort
when swallowing; headache; swelling of arms, hands, legs, ankles or feet; tiredness; redness and warm
feeling of the face and/or neck.
Uncommon
(affecting less than 1 in 100 patients)
: Dizziness; nausea and abdominal pain; dry mouth;
drowsiness, tingling or numbness of the hands or feet; vertigo; fast heart beat including palpitations;
dizziness on standing up; cough; diarrhoea; constipation; skin rash, redness of the skin; joint swelling,
back pain; pain in joints.
Rare
(affecting less than 1 in 1,000 patients)
: Feeling anxious; ringing in the ears (tinnitus); fainting;
passing more urine than normal or feeling more of an urge to pass urine; inability to get or maintain an
erection; sensation of heaviness; low blood pressure with symptoms such as dizziness, light-
headedness; excessive sweating; skin rash all over your body; itching; muscle spasm.
If any of these affect you severely, tell your doctor.
Side effects with amlodipine or valsartan alone which can be serious:
These side effects may occur with certain frequencies, which are defined as follows:
very common:
affects more than 1 user in 10
common:
affects 1 to 10 users in 100
uncommon:
affects 1 to 10 users in 1,000
rare:
affects 1 to 10 users in 10,000
very rare:
affects less than 1 user in 10,000
not known:
frequency cannot be estimated from the available data
Amlodipine
Common:
Vomiting.
Uncommon:
Hair loss; change in bowel habits, feeling bloated, indigestion, stomach discomfort after
meal; stomach pain, nausea; bleeding, tender or enlarged gums; breathlessness; breast enlargement in
men; runny or stuffy nose, sneezing; yellow skin and eyes, nausea, loss of appetite, light-coloured
urine; high level of sugar in the blood; inability to achieve or maintain an erection; increased need to
pass urine; fever, sore throat or mouth ulcers due to infections; mood swings; muscle pain; sensation
of numbness or tingling in fingers and toes; severe upper stomach pain; spontaneous bleeding or
bruising; rash, purplish-red spots, fever, itching; swelling mainly of the face and throat; skin
reddening, blistering of lips, eyes or mouth, skin peeling.
Rare:
Crushing chest pain, irregular heart beat, angina pain.
Very rare:
Yellowing of the skin and eyes, changes in the results of some liver function tests; purple
skin patches, rash and itching, stiff limbs, trembling hands.
Valsartan
Not known:
Decrease in red blood cells, fever, sore throat or mouth sores due to infections,
spontaneous bleeding or bruising, high level of potassium in the blood, abnormal liver test results,
decreased renal functions and severely decreased renal functions, swelling mainly of the face and the
throat, muscle pain, rash, purplish-red spots, fever, itching, allergic reaction.
If you experience any of these, tell your doctor straight away.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE COPALIA
Keep out of the reach and sight of children.
Do not use Copalia after the expiry date stated on the carton and blister.
Do not store above 30°C.
Store in the original package in order to protect from moisture.
Do not use any Copalia pack that is damaged or shows signs of tampering.
70
6.
FURTHER INFORMATION
What Copalia contains
−
The active substances of Copalia are amlodipine (as amlodipine besylate) and valsartan. Each
tablet contains 5 mg amlodipine and 80 mg valsartan.
−
The other ingredients are cellulose microcrystalline; crospovidone type A; silica, colloidal
anhydrous; magnesium stearate; hypromellose; macrogol 4000; talc, titanium dioxide (E171);
iron oxide, yellow (E172).
What Copalia looks like and contents of the pack
Copalia 5 mg/80 mg tablets are round and dark yellow with “NVR” on one side and “NV” on the other
side.
Copalia is available in packs containing 7, 14, 28, 30, 56, 90, 98 or 280 tablets and in multipacks
comprising 4 cartons, each containing 70 tablets, or 20 cartons, each containing 14 tablets. Not all
pack sizes may be available in your country.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
Manufacturer
Novartis Pharma GmbH
Roonstraße 25
D-90429 Nuremberg
Germany
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma GmbH
Tél/Tel: +49 911 273 0
България
Novartis Pharma Services Inc.
Тел.: +359 2 976 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
71
Eesti
Novartis Pharma Services Inc.
Tel: +372 60 62 400
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
Ελλάδα
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
J. Uriach y Cia., S.A.
Tel: +34 93 864 96 92
Portugal
Bialport-Produtos Farmacêuticos, S.A.
Tel: +351 22 986 61 00
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 77
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis s.Slovakia r.o.
Tel: +421 2 5542 5439
Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 9 61 33 22 11
Κύπρος
Δημητριάδης και Παπαέλληνας Λτδ
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
Latvija
Novartis Pharma Services Inc.
Tel: +371 7 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
{MM/YYYY}.
72
PACKAGE LEAFLET: INFORMATION FOR THE USER
Copalia 5 mg/160 mg film-coated tablets
amlodipine/valsartan
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Copalia is and what it is used for
2.
Before you take Copalia
3.
How to take Copalia
4.
How to store Copalia
6.
Further information
1.
WHAT COPALIA IS AND WHAT IT IS USED FOR
Copalia tablets contain two substances called amlodipine and valsartan. Both of these substances help
to control high blood pressure.
−
Amlodipine belongs to a group of substances called “calcium channel blockers”. Amlodipine
stops calcium from moving into the blood vessel wall which stops the blood vessels from
tightening.
−
Valsartan belongs to a group of substances called “angiotensin-II receptor antagonists”.
Angiotensin II is produced by the body and makes the blood vessels tighten, thus increasing the
blood pressure. Valsartan works by blocking the effect of angiotensin II.
This means that both of these substances help to stop the blood vessels tightening. As a result, the
blood vessels relax and blood pressure is lowered.
Copalia is used to treat high blood pressure in patients whose blood pressure is not controlled enough
with either amlodipine or valsartan on its own.
2.
BEFORE YOU TAKE COPALIA
Do not take Copalia
−
if you are allergic (hypersensitive) to amlodipine or other medicines of the dihydropyridine
type,
−
if you are allergic (hypersensitive) to valsartan or any of the other ingredients of Copalia. If you
think you may be allergic, talk to your doctor before taking Copalia.
−
if you have severe liver problems, such as biliary cirrhosis or cholestasis.
−
if you have severe kidney problems or if you are having dialysis.
−
if you are more than 3 months pregnant. (It is also better to avoid Copalia in early pregnancy -
see Pregnancy section).
If any of the above applies to you, do not take Copalia and talk to your doctor
.
73
-
Keep this leaflet. You may need to read it again.
5.
Possible side effects
Take special care with Copalia
−
if you have been sick (vomiting or diarrhoea).
−
if you are taking diuretics (a type of medicine also called “water tablets” which increases the
amount of urine you produce).
−
if you are taking other medicines or substances that increase the level of potassium in your
blood (e.g. some types of diuretics, potassium supplements or salt substitutes containing
potassium).
−
if you have liver or kidney problems.
−
if you have a condition affecting the renal glands called “primary hyperaldosteronism”.
−
if you have had heart failure.
−
if your doctor has told you that you have a narrowing of the valves in your heart (called “aortic
or mitral stenosis”) or that the thickness of your heart muscle is abnormally increased (called
“obstructive hypertrophic cardiomyopathy”).
If any of these apply to you, tell your doctor before taking Copalia.
You must tell your doctor if you think that you are (
or might become
) pregnant. Copalia is not
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it
may cause serious harm to your baby if used at that stage (see section Pregnancy).
The use of Copalia in children and adolescents is not recommended.
Also tell your doctor if you have had a kidney transplant or if you had been told that you have a
narrowing of your kidney arteries.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. Your doctor may need to change the dose or take
other precautions. In some cases you may have to stop taking one of the medicines. This applies
especially to the medicines listed below:
−
lithium (a medicine used to treat some types of depression);
−
potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and
other substances that may increase potassium levels;
−
anticonvulsant agents (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone),
rifampicin, St. John’s wort;
−
nitroglycerin and other nitrates, or other substances called “vasodilators”;
−
medicines used for HIV/AIDS (e.g. ritonavir) or for treatment of fungal infections (e.g.
ketoconazole).
Taking Copalia with food and drink
You can take Copalia with or without food.
Copalia and older people
Caution is required when increasing the dosage.
Pregnancy and breast-feeding
Pregnancy
You must tell your doctor if you think you are (
or might become
) pregnant. Your doctor will normally
advise you to stop taking Copalia before you become pregnant or as soon as you know you are
pregnant and will advise you to take another medicine instead of Copalia. Copalia is not recommended
in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious
harm to your baby if used after the third month of pregnancy.
74
Breast-feeding
Tell your doctor if you are breast-feeding
or about to start breast-feeding
. Copalia is not recommended
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish
to breast-feed, especially if your baby is newborn, or was born prematurely.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
This medicine may make you feel dizzy. This can affect how well you can concentrate. So, if you are
not sure how this medicine will affect you, do not drive, use machinery, or do other activities that you
need to concentrate on.
3.
HOW TO TAKE
COPALIA
Always take this medicine exactly as your doctor has told you. You should check with your doctor if
you are not sure. This will help you get the best results and lower the risk of side effects.
The usual dose of Copalia is one tablet per day.
−
It is advisable to take your medicine at the same time each day, preferably in the morning.
−
Swallow the tablets with a glass of water.
−
You can take Copalia with or without food.
Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose.
Do not exceed the prescribed dose.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
If you take more Copalia than you should
If you have taken too many tablets of Copalia, or if someone else has taken your tablets, consult a
doctor immediately.
If you forget to take Copalia
If you forget to take this medicine, take it as soon as you remember. Then take your next dose at its
usual time. However, if it is almost time for your next dose, skip the dose you missed. Do not take a
double dose to make up for a forgotten tablet.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Copalia can cause side effects, although not everybody gets them.
Some side effects can be serious:
A few patients have experienced these serious side effects
(affecting less than 1 in 1,000 patients)
.
If
any of the following happen,
tell your doctor straight away:
Allergic reaction with symptoms such as rash, itching, swelling of face or lips or tongue, difficulty
breathing, low blood pressure (feeling of faintness, light-headedness).
75
Other possible side effects:
Common (affecting less than 1 in 10 patients)
: Influenza; blocked nose, sore throat and discomfort
when swallowing; headache; swelling of arms, hands, legs, ankles or feet; tiredness; redness and warm
feeling of the face and/or neck.
Uncommon (affecting less than 1 in 100 patients)
: Dizziness; nausea and abdominal pain; dry mouth;
drowsiness, tingling or numbness of the hands or feet; vertigo; fast heart beat including palpitations;
dizziness on standing up; cough; diarrhoea; constipation; skin rash, redness of the skin; joint swelling,
back pain; pain in joints.
Rare (affecting less than 1 in 1,000 patients)
: Feeling anxious; ringing in the ears (tinnitus); fainting;
passing more urine than normal or feeling more of an urge to pass urine; inability to get or maintain an
erection; sensation of heaviness; low blood pressure with symptoms such as dizziness, light-
headedness; excessive sweating; skin rash all over your body; itching; muscle spasm.
If any of these affect you severely, tell your doctor.
Side effects with amlodipine or valsartan alone which can be serious:
These side effects may occur with certain frequencies, which are defined as follows:
very common:
affects more than 1 user in 10
common:
affects 1 to 10 users in 100
uncommon:
affects 1 to 10 users in 1,000
rare:
affects 1 to 10 users in 10,000
very rare:
affects less than 1 user in 10,000
not known:
frequency cannot be estimated from the available data
Amlodipine
Common:
Vomiting.
Uncommon:
Hair loss; change in bowel habits, feeling bloated, indigestion, stomach discomfort after
meal; stomach pain, nausea; bleeding, tender or enlarged gums; breathlessness; breast enlargement in
men; runny or stuffy nose, sneezing; yellow skin and eyes, nausea, loss of appetite, light-coloured
urine; high level of sugar in the blood; inability to achieve or maintain an erection; increased need to
pass urine; fever, sore throat or mouth ulcers due to infections; mood swings; muscle pain; sensation
of numbness or tingling in fingers and toes; severe upper stomach pain; spontaneous bleeding or
bruising; rash, purplish-red spots, fever, itching; swelling mainly of the face and throat; skin
reddening, blistering of lips, eyes or mouth, skin peeling.
Rare:
Crushing chest pain, irregular heart beat, angina pain.
Very rare:
Yellowing of the skin and eyes, changes in the results of some liver function tests; purple
skin patches, rash and itching, stiff limbs, trembling hands.
Valsartan
Not known:
Decrease in red blood cells, fever, sore throat or mouth sores due to infections,
spontaneous bleeding or bruising, high level of potassium in the blood, abnormal liver test results,
decreased renal functions and severely decreased renal functions, swelling mainly of the face and the
throat, muscle pain, rash, purplish-red spots, fever, itching, allergic reaction.
If you experience any of these, tell your doctor straight away.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE COPALIA
Keep out of the reach and sight of children.
Do not use Copalia after the expiry date stated on the carton and blister.
Do not store above 30°C.
Store in the original package in order to protect from moisture.
Do not use any Copalia pack that is damaged or shows signs of tampering.
76
6.
FURTHER INFORMATION
What Copalia contains
-
The active substances of Copalia are amlodipine (as amlodipine besylate) and valsartan. Each
tablet contains 5 mg amlodipine and 160 mg valsartan.
-
The other ingredients are cellulose microcrystalline; crospovidone type A; silica, colloidal
anhydrous; magnesium stearate; hypromellose; macrogol 4000; talc, titanium dioxide (E171);
iron oxide, yellow (E172).
What Copalia looks like and contents of the pack
Copalia 5 mg/160 mg tablets are oval and dark yellow “NVR” on one side and “ECE” on the other
side.
Copalia is available in packs containing 7, 14, 28, 30, 56, 90, 98 or 280 tablets and in multipacks
comprising 4 cartons, each containing 70 tablets, or 20 cartons, each containing 14 tablets. Not all
pack sizes may be available in your country.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
Manufacturer
Novartis Pharma GmbH
Roonstraße 25
D-90429 Nuremberg
Germany
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma GmbH
Tél/Tel: +49 911 273 0
България
Novartis Pharma Services Inc.
Тел.: +359 2 976 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
77
Eesti
Novartis Pharma Services Inc.
Tel: +372 60 62 400
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
Ελλάδα
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
J. Uriach y Cia., S.A.
Tel: +34 93 864 96 92
Portugal
Bialport-Produtos Farmacêuticos, S.A.
Tel: +351 22 986 61 00
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 77
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439
Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 9 61 33 22 11
Κύπρος
Δημητριάδης και Παπαέλληνας Λτδ
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
Latvija
Novartis Pharma Services Inc.
Tel: +371 7 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
{MM/YYYY}.
78
PACKAGE LEAFLET: INFORMATION FOR THE USER
Copalia 10 mg/160 mg film-coated tablets
amlodipine/valsartan
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Copalia is and what it is used for
3.
How to take Copalia
4.
Possible side effects
5.
How to store Copalia
6.
Further information
1.
WHAT COPALIA IS AND WHAT IT IS USED FOR
Copalia tablets contain two substances called amlodipine and valsartan. Both of these substances help
to control high blood pressure.
−
Amlodipine belongs to a group of substances called “calcium channel blockers”. Amlodipine
stops calcium from moving into the blood vessel wall which stops the blood vessels from
tightening.
−
Valsartan belongs to a group of substances called “angiotensin-II receptor antagonists”.
Angiotensin II is produced by the body and makes the blood vessels tighten, thus increasing the
blood pressure. Valsartan works by blocking the effect of angiotensin II.
This means that both of these substances help to stop the blood vessels tightening. As a result, the
blood vessels relax and blood pressure is lowered.
Copalia is used to treat high blood pressure in patients whose blood pressure is not controlled enough
with either amlodipine or valsartan on its own.
2.
BEFORE YOU TAKE COPALIA
Do not take Copalia
−
if you are allergic (hypersensitive) to amlodipine or other medicines of the dihydropyridine
type,
−
if you are allergic (hypersensitive) to valsartan or any of the other ingredients of Copalia. If you
think you may be allergic, talk to your doctor before taking Copalia.
−
if you have severe liver problems, such as biliary cirrhosis or cholestasis.
−
if you have severe kidney problems or if you are having dialysis.
−
if you are more than 3 months pregnant. (It is also better to avoid Copalia in early pregnancy -
see Pregnancy section).
If any of the above applies to you, do not take Copalia and talk to your doctor
.
79
2.
Before you take Copalia
Take special care with Copalia
−
if you have been sick (vomiting or diarrhoea).
−
if you are taking diuretics (a type of medicine also called “water tablets” which increases the
amount of urine you produce).
−
if you are taking other medicines or substances that increase the level of potassium in your
blood (e.g. some types of diuretics, potassium supplements or salt substitutes containing
potassium).
−
if you have liver or kidney problems.
−
if you have a condition affecting the renal glands called “primary hyperaldosteronism”.
−
if you have had heart failure.
−
if your doctor has told you that you have a narrowing of the valves in your heart (called “aortic
or mitral stenosis”) or that the thickness of your heart muscle is abnormally increased (called
“obstructive hypertrophic cardiomyopathy”).
If any of these apply to you, tell your doctor before taking Copalia.
You must tell your doctor if you think that you are (
or might become
) pregnant. Copalia is not
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it
may cause serious harm to your baby if used at that stage (see section Pregnancy).
The use of Copalia in children and adolescents is not recommended.
Also tell your doctor if you have had a kidney transplant or if you had been told that you have a
narrowing of your kidney arteries.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. Your doctor may need to change the dose or take
other precautions. In some cases you may have to stop taking one of the medicines. This applies
especially to the medicines listed below:
−
lithium (a medicine used to treat some types of depression);
−
potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and
other substances that may increase potassium levels;
−
anticonvulsant agents (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone),
rifampicin, St. John’s wort;
−
nitroglycerin and other nitrates, or other substances called “vasodilators”;
−
medicines used for HIV/AIDS (e.g. ritonavir) or for treatment of fungal infections (e.g.
ketoconazole).
Taking Copalia with food and drink
You can take Copalia with or without food.
Copalia and older people
Caution is required when increasing the dosage.
Pregnancy and breast-feeding
Pregnancy
You must tell your doctor if you think you are (
or might become
) pregnant. Your doctor will normally
advise you to stop taking Copalia before you become pregnant or as soon as you know you are
pregnant and will advise you to take another medicine instead of Copalia. Copalia is not recommended
in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious
harm to your baby if used after the third month of pregnancy.
80
Breast-feeding
Tell your doctor if you are breast-feeding
or about to start breast-feeding
. Copalia is not recommended
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish
to breast-feed, especially if your baby is newborn, or was born prematurely.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
This medicine may make you feel dizzy. This can affect how well you can concentrate. So, if you are
not sure how this medicine will affect you, do not drive, use machinery, or do other activities that you
need to concentrate on.
3.
HOW TO TAKE
COPALIA
Always take this medicine exactly as your doctor has told you. You should check with your doctor if
you are not sure. This will help you get the best results and lower the risk of side effects.
The usual dose of Copalia is one tablet per day.
−
It is advisable to take your medicine at the same time each day, preferably in the morning.
−
Swallow the tablets with a glass of water.
−
You can take Copalia with or without food.
Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose.
Do not exceed the prescribed dose.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
If you take more Copalia than you should
If you have taken too many tablets of Copalia, or if someone else has taken your tablets, consult a
doctor immediately.
If you forget to take Copalia
If you forget to take this medicine, take it as soon as you remember. Then take your next dose at its
usual time. However, if it is almost time for your next dose, skip the dose you missed. Do not take a
double dose to make up for a forgotten tablet.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Copalia can cause side effects, although not everybody gets them.
Some side effects can be serious:
A few patients have experienced these serious side effects
(affecting less than 1 in 1,000 patients)
.
If
any of the following happen,
tell your doctor straight away:
Allergic reaction with symptoms such as rash, itching, swelling of face or lips or tongue, difficulty
breathing, low blood pressure (feeling of faintness, light-headedness).
81
Other possible side effects:
Common (affecting less than 1 in 10 patients)
: Influenza; blocked nose, sore throat and discomfort
when swallowing; headache; swelling of arms, hands, legs, ankles or feet; tiredness; redness and warm
feeling of the face and/or neck.
Uncommon (affecting less than 1 in 100 patients)
: Dizziness; nausea and abdominal pain; dry mouth;
drowsiness, tingling or numbness of the hands or feet; vertigo; fast heart beat including palpitations;
dizziness on standing up; cough; diarrhoea; constipation; skin rash, redness of the skin; joint swelling,
back pain; pain in joints.
Rare (affecting less than 1 in 1,000 patients)
: Feeling anxious; ringing in the ears (tinnitus); fainting;
passing more urine than normal or feeling more of an urge to pass urine; inability to get or maintain an
erection; sensation of heaviness; low blood pressure with symptoms such as dizziness, light-
headedness; excessive sweating; skin rash all over your body; itching; muscle spasm.
If any of these affect you severely, tell your doctor.
Side effects with amlodipine or valsartan alone which can be serious:
These side effects may occur with certain frequencies, which are defined as follows:
very common:
affects more than 1 user in 10
common:
affects 1 to 10 users in 100
uncommon:
affects 1 to 10 users in 1,000
rare:
affects 1 to 10 users in 10,000
very rare:
affects less than 1 user in 10,000
not known:
frequency cannot be estimated from the available data
Amlodipine
Common:
Vomiting.
Uncommon:
Hair loss; change in bowel habits, feeling bloated, indigestion, stomach discomfort after
meal; stomach pain, nausea; bleeding, tender or enlarged gums; breathlessness; breast enlargement in
men; runny or stuffy nose, sneezing; yellow skin and eyes, nausea, loss of appetite, light-coloured
urine; high level of sugar in the blood; inability to achieve or maintain an erection; increased need to
pass urine; fever, sore throat or mouth ulcers due to infections; mood swings; muscle pain; sensation
of numbness or tingling in fingers and toes; severe upper stomach pain; spontaneous bleeding or
bruising; rash, purplish-red spots, fever, itching; swelling mainly of the face and throat; skin
reddening, blistering of lips, eyes or mouth, skin peeling.
Rare:
Crushing chest pain, irregular heart beat, angina pain.
Very rare:
Yellowing of the skin and eyes, changes in the results of some liver function tests; purple
skin patches, rash and itching, stiff limbs, trembling hands.
Valsartan
Not known:
Decrease in red blood cells, fever, sore throat or mouth sores due to infections,
spontaneous bleeding or bruising, high level of potassium in the blood, abnormal liver test results,
decreased renal functions and severely decreased renal functions, swelling mainly of the face and the
throat, muscle pain, rash, purplish-red spots, fever, itching, allergic reaction.
If you experience any of these, tell your doctor straight away.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE COPALIA
Keep out of the reach and sight of children.
Do not use Copalia after the expiry date stated on the carton and blister.
Do not store above 30°C.
Store in the original package in order to protect from moisture.
Do not use any Copalia pack that is damaged or shows signs of tampering.
82
6.
FURTHER INFORMATION
What Copalia contains
−
The active substances of Copalia are amlodipine (as amlodipine besylate) and valsartan. Each
tablet contains 10 mg amlodipine and 160 mg valsartan.
−
The other ingredients are cellulose microcrystalline; crospovidone type A; silica, colloidal
anhydrous; magnesium stearate; hypromellose; macrogol 4000; talc, titanium dioxide (E171);
iron oxide, yellow (E172), iron oxide, red (E172).
What Copalia looks like and contents of the pack
Copalia 10 mg/160 mg tablets are oval and light yellow with “NVR” on one side and “UIC” on the
other side.
Copalia is available in packs containing 7, 14, 28, 30, 56, 90, 98 or 280 tablets and in multipacks
comprising 4 cartons, each containing 70 tablets, or 20 cartons, each containing 14 tablets. Not all
pack sizes may be available in your country.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
Manufacturer
Novartis Pharma GmbH
Roonstraße 25
D-90429 Nuremberg
Germany
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma GmbH
Tél/Tel: +49 911 273 0
България
Novartis Pharma Services Inc.
Тел.: +359 2 976 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
83
Eesti
Novartis Pharma Services Inc.
Tel: +372 60 62 400
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
Ελλάδα
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
J. Uriach y Cia., S.A.
Tel: +34 93 864 96 92
Portugal
Bialport-Produtos Farmacêuticos, S.A.
Tel: +351 22 986 61 00
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 77
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439
Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 9 61 33 22 11
Κύπρος
Δημητριάδης και Παπαέλληνας Λτδ
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
Latvija
Novartis Pharma Services Inc.
Tel: +371 7 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
{MM/YYYY}.
84
Source: European Medicines Agency
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