Amlohope is indicated as substitution therapy for the treatment of hypertension in patients who are sufficiently adjusted when both active substances are administered as single tablets at the same strength as in the combination preparation.

1.1  Posology

Amlohope is indicated as substitution therapy for the treatment of hypertension in patients whose blood pressure is sufficiently managed by concomitant administration of the single products at the same strength as in the combination preparation.

 

The recommended daily dose is 1 hard capsule of the prescribed strength. Taking the combination product is not suitable for initial therapy.

If dose adjustment is necessary, this should only be done via the single agents. After dose adjustment, the change to the appropriate combination preparation of Amlohope is possible.

 

 

Special populations

Diuretic treated patients

Caution should be exercised in patients treated with diuretics, since fluid and/or salt deficiency can occur in these patients. Renal function and serum potassium should be monitored regularly.

 

Impaired hepatic function

Treatment with ramipril should only be initiated under strict medical supervision in patients with impaired hepatic function. The maximum daily dose is 2.5 mg ramipril.

 

 

In patients with impaired hepatic function, the half-life of amlodipine may be prolonged. To date, there are no specific dose recommendations for amlodipine for this patient group, therefore particular caution is required when taking the medicinal product (see section 4.4).

 

In general, treatment with Amlohope in the case of impaired hepatic function is not recommended, as the maximum daily dose for this patient group is exceeded with this drug.

 

Impaired renal function

In order to determine the optimal initial and maintenance dose in patients with impaired renal function, an individual dose adjustment should be done by separate adjustment of the ramipril and amlodipine components (details can be found in the Summary of Product Characteristics for the respective individual components).

 

The daily dose of ramipril in patients with renal impairment should be determined based on creatinine clearance.

·     If creatinine clearance is ≥ 60 ml/min, no adjustment of the initial dose is necessary; the maximal daily

dose is 10 mg.

 

·     With a creatinine clearance of < 60 ml/min and in hypertensive patients on hemodialysis, Amlohopeis recommended only in patients who were adjusted to 2.5 mg or 5 mg ramipril as the optimal maintenance dose. For hemodialysis patients, the medicinal product should be administered a few hours after completing  hemodialysis.

 

No dose adjustment of amlodipine is necessary in the case of patients with impaired renal function.

 

Amlodipine is not dialyzable. In patients requiring dialysis, amlodipine should be used with caution (see section 4.4).

 

Regular monitoring of renal function and serum potassium is necessary during treatment with Amlohope. If renal function deteriorates, it is recommended to discontinue treatment with Amlohope and instead to administer the individual components at appropriately adjusted dosages.

 

Elderly patients

The initial dose of ramipril should be lower and subsequent dose adjustment should be more gradual, as the chance of side effects is higher.

 

Administration of Amlohopeis not recommended in very old and frail patients.

 

The usual dosages of amlodipine may be administered to elderly patients. However, caution is advised when increasing the dose (see section 5.2).

 

Pediatric population

The use of Amlohopein children and adolescents under 18 years of age is not recommended, as there is insufficient data on safety and efficacy. The data currently available for ramipril are described in sections 4.8, 5.1 and 5.2. However, no specific dosage recommendations can be given.

 

Method of administration

Amlohope should be taken once daily at the same time of day or independently of meals. The hard capsule must not be chewed or crushed. The hard capsules should be taken with sufficient fluids (e.g. water). The hard capsules should not be taken with grapefruit juice.

For ramipril • History of angioedema (hereditary, idiopathic, or due to previous angioedema with ACE inhibitors or angiotensin II receptor antagonists [AIIRAs]). • Concomitant use of sacubitril/valsartan therapy. Treatment with Amlohope may be started 36 hours after the last dose of sacubitril/valsartan (see also sections 4.4 and 4.5) • Extracorporeal treatments leading to blood coming into contact with negatively charged surfaces (see section 4.5) • Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney • 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6) • In hypotensive or hemodynamically unstable patients. The concomitant use of Amlohope with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1). For amlodipine • Severe hypotension • Shock (including cardiogenic shock) • Obstruction of the left ventricular discharge tract (e.g. higher grade aortic stenosis) • Hemodynamically unstable heart failure after acute myocardial infarction For Amlohope • Hypersensitivity to the amlodipine, dihydropyridine derivatives, ramipril or other ACE inhibitors (ACE = angiotensin-converting enzyme) or to any of the excipients listed in section 6.1. Additionally for Amlohope5 mg/10 mg/- 10 mg/10 mg • Hypersensitivity to azorubine Additionally for Amlohope5 mg/5 mg/- 10 mg/5 mg • Hypersensitivity to Allura Red

1.1  For ramipril

Special populations Pregnancy

Treatment with ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti- hypertensive treatments which have an established safety profile for use in pregnancy. If pregnancy is confirmed, treatment with ACE inhibitors should be discontinued immediately and, where required, alternative treatment should be initiated (see sections 4.3 and 4.6).

 

Patients at high risk of hypotension

·     Patients with strongly activated renin-angiotensin-aldosterone system

There is a risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition. This applies in particular if an ACE inhibitor is administered for the first time or initially with a diuretic or at the first dose increase.

Significant activation of the renin-angiotensin-aldosterone system is to be expected and medical supervision including blood pressure monitoring is necessary in the following patients for example:

-     Patients with severe hypertension

-     Patients with decompensated heart failure

-     Patients with hemodynamically relevant left ventricular inflow or outflow impediment (e.g. aortic or mitral valve stenosis)

-     Patients with unilateral renal artery stenosis with a second functional kidney

-     Patients with manifest or latent fluid or salt depletion (including patients on diuretics)

-     Patients with liver cirrhosis and/or ascites

-     Patients undergoing major surgery or during anesthesia with agents that can cause hypotension Generally, it is recommended to correct dehydration, hypovolemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed up against the risk of volume overload).

 

·     Transient or persistent heart failure post myocardial infarction

 

·     Patients at risk of cardiac or cerebral ischemia in the case of acute hypotension

The patient must be monitored carefully during the initial phase of treatment.

 

Elderly patients See section 4.2

 

Surgery

It is recommended that treatment with ACE inhibitors such as ramipril should be discontinued where possible one day before surgery.

 

Monitoring of renal function

Renal function should be monitored before and during treatment and any corresponding dose adjustment should be performed during the initial weeks of treatment in particular. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a kidney transplant.

 

Hypersensitivity/angioedema

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8).

 

Concomitant use of ACE inhibitors and sacubitril/valsartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/valsartan may be started 36 hours after the last dose of Ramipril HEXAL plus Amlodipine. Treatment with Amlohopemay be started 36 hours after the last dose of sacubitril/valsartan (see also sections 4.3 and 4.5).

 

 

Concomitant administration of ACE inhibitors and racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin can lead to an increased risk of angioedema (e.g. swelling of the respiratory tract or tongue with or without difficulty breathing) (see section 4.5). Caution is advised when treatment with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin is started in patients who already take ACE inhibitors.

 

 

In the case of angioedema, treatment must be discontinued.

Emergency therapy should be initiated immediately. The patient should be kept under observation for at least 12-24 hours and only discharged after complete resolution of the symptoms.

 

Intestinal angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

 

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. Temporary discontinuation of ramipril should be considered prior to desensitization.

 

Monitoring of electrolytes: Hyperkalemia

Hyperkalemia has been observed in some patients treated with ACE inhibitors including ramipril. ACE inhibitors can trigger hyperkalemia because they inhibit the release of aldosterone. The effect is generally not significant in patients with normal renal function. However, hyperkalemia can occur in patients with renal impairment, aged over 70 years, with uncontrolled diabetes mellitus, states such as dehydration, acute cardiac decompensation, metabolic acidosis, or in patients taking potassium substitutes (including salt substitutes), potassium-sparing diuretics or other active substances that increase plasma potassium levels (e.g. heparin, trimethoprim, co-trimoxazole, also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin receptor inhibitors). If concomitant use of the above-mentioned substances is deemed appropriate, regular monitoring of serum potassium is recommended. Potassium- sparing diuretics and angiotensin receptor inhibitors should be used with caution in patients receiving ACE inhibitors and potassium level and renal function should be monitored (see section 4.5).

 

Monitoring of electrolytes: Hyponatremia

Syndrome of Inappropriate Anti-diuretic Hormone Secretion (SIADH) and subsequent hyponatremia has been observed in some patients treated with ramipril. It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatremia.

 

Neutropenia/agranulocytosis

In rare cases, neutropenia/agranulocytosis, as well as thrombocytopenia and anemia, have been observed and bone marrow depression has also been reported. Monitoring of leukocyte counts is recommended to recognize potential leukopenia. More frequent monitoring is advisable in the initial phase of treatment and in patients with impaired renal function, in patients with concomitant collagenosis (e.g. lupus erythematosus or scleroderma) and all patients who are treated concomitantly with other drugs that can cause blood count changes (see sections 4.5 and 4.8).

 

Ethnic differences

ACE inhibitors cause angioedema more frequently in black patients than in non-black patients.

 

As with other ACE inhibitors, ramipril may be less effective at lowering blood pressure in black patients than in non-black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

 

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

 

Patients undergoing diuretic therapy See section 4.2

 

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

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

 

For amlodipine

The safety and efficacy of amlodipine in a hypertensive crisis has not yet been confirmed. Special populations

Patients with heart failure

Caution is advised when treating patients with heart failure. In a placebo-controlled long-term study in patients with severe heart failure (NYHA classes III and IV), pulmonary edema was reported more frequently on amlodipine than on placebo (see section 5.1).

Calcium channel blockers, including amlodipine, should be used with caution in patients with decompensated heart failure, as they can increase the risk of future cardiovascular events and the risk of mortality.

 

Patients with hepatic impairment

The half-life of amlodipine is prolonged in patients with impaired hepatic function and AUC values are higher; so far there are no dosage recommendations. Amlodipine should therefore be started within the lower dosage range and should be administered with caution both at the start of treatment and with a dose increase. In patients with severely impaired liver function, slow dose titration and close monitoring may be necessary.

 

Elderly patients

In elderly patients, the dosage should only be increased with caution (see sections 4.2 and 5.2).

 

Patients with renal impairment

Amlodipine can be used in this patient group at the usual dose. There is no correlation between the degree of renal impairment and changes in amlodipine plasma levels. Amlodipine is not dialyzable.

 

 

Special warnings relating to the other components

Amlohope5 mg/5 mg and 10 mg/5 mg hard capsules contain the colorant Allura Red (E129) which can cause allergic reactions.

Amlohope5 mg/10 mg and 10 mg/10 mg hard capsules contain the colorant Azorubine (E122) which can cause allergic reactions.

1.1  For ramipril

Contraindicated  combinations

Extracorporeal treatments in which blood comes into contact with negatively charged surfaces, such as dialysis or hemofiltration with certain high-flux membranes (e.g. polyacrylic nitrile membranes) and low- density lipoprotein apheresis with dextran sulfate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of anti-hypertensive agent.

 

Medicines that increase the risk of angioedema: Concomitant use of ACE inhibitors and sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see sections 4.3 and 4.5).

 

Precautionary measures for use

Potassium-sparing diuretics, potassium substitutes or potassium-containing salt substitutes and other active substances that increase serum potassium (including angiotensin II antagonists, tacrolimus, cyclosporine, heparin): Hyperkalemia may occur, therefore serum potassium must be closely monitored.

 

Although serum potassium levels usually remain within the normal range, hyperkalemia may occur in some patients treated with ramipril. Potassium-sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements or potassium-containing salt supplements may cause a significant increase in serum potassium. Caution is also advised if ramipril is administered together with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole), because trimethoprim is known to act like a potassium-sparing diuretic such as amiloride. An increased incidence of hyperkalemia in patients who took ACE inhibitors and trimethoprim or trimethoprim in a fixed-dose combination with sulfamethoxazole (co-trimoxazole) was observed, therefore the combination of ramipril with the aforementioned drugs is not recommended. If concomitant use is indicated, it must be carried out with caution and with regular monitoring of the serum potassium (see section 4.4).

Cyclosporine

Hyperkalemia can occur with concomitant use of ACE inhibitors and cyclosporine. Monitoring of serum potassium is recommended.

 

Heparin

Hyperkalemia can occur with concomitant use of ACE inhibitors and heparin. Monitoring of serum potassium is recommended.

Antihypertensives (e.g. diuretics) and other active substances that lower the blood pressure (e.g. nitrates, tricyclic antidepressants, anesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): An increase in the risk of a drop in blood pressure is to be expected (see section 4.2 on diuretics).

 

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ACE inhibitors, angiotensin II receptor antagonists, or aliskiren:

Clinical trial data has shown that the dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared to the use of a single agent that acts on the RAAS (see sections 4.3, 4.4 and 5.1).

 

Vasopressor sympathomimetics and other active substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine), which may weaken the antihypertensive effect of ramipril: Regular blood pressure monitoring is recommended.

 

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other active substances that can alter blood counts: Increased probability of hematological reactions (see section 4.4).

 

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Regular monitoring of lithium levels is necessary.

 

Anti-diabetic agents including insulin: Hypoglycemia may occur. Regular monitoring of blood glucose levels is recommended.

 

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the anti-hypertensive effect of ramipril is to be expected. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of deterioration of renal function and to an increase in serum potassium levels.

 

Medicines that increase the risk of angioedema

Concomitant use of ACE inhibitors with NEP inhibitors (such as racecadotril), mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and DPP-IV inhibitors (vildagliptin) can lead to an increased risk of angioedema Caution is advisable at the start of treatment (see section 4.4).

 

For amlodipine

 

Influence of other medicines on amlodipine

CYP3A4 inhibitors:

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antimycotics, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in amlodipine exposure. The clinical consequences of the altered pharmacokinetics can be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment can be necessary.

Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin together with amlodipine. Close monitoring of patients is recommended with concomitant administration of clarithromycin and amlodipine.

 

 

CYP3A4 inducers:

Concomitant use of known CYP3A4 inducers may lead to different plasma levels of amlodipine. Thus, blood pressure should be monitored and dose regulation should be considered, both during as well as after concomitant administration of strong CYP3A4 inducers in particular (e.g. rifampicin, St. John’s wort [Hypericum  perforatum]).

 

Grapefruit and grapefruit juice:

Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended because the bioavailability of amlodipine can be increased in some patients as a result. This would lead to increased blood pressure reduction.

 

Dantrolene (infusion):

In animals, lethal ventricular fibrillation and circulatory collapse in connection with hyperkalemia were observed after administration of verapamil and intravenous dantrolene. Due to the risk of hyperkalemia, it is recommended to avoid concomitant administration of calcium blockers such as amlodipine in patients susceptible to hyperthermia or being treated due to malignant hyperthermia.

Influence of amlodipine on other medicines

Medicines with antihypertensive effect: The blood pressure lowering effect of amlodipine can intensify the blood pressure lowering effect of other antihypertensives.

 

Tacrolimus:

With concomitant administration of amlodipine, there is a risk of increased tacrolimus levels in the blood. In order to avoid toxicity from tacrolimus, patients treated with the drug must monitor tacrolimus levels in the blood and adjust the dose if necessary.

 

Cyclosporine:

No studies were conducted to record drug interactions with cyclosporine and amlodipine in healthy subjects or other patient groups. One exception is patients who have undergone kidney transplantation, where variable increases in trough level concentrations (average 0% to 40%) of cyclosporine were observed. In patients who have undergone kidney transplantation, monitoring of cyclosporine levels should be considered and, if necessary, the cyclosporine dose reduced.

 

Simvastatin:

Simultaneous multiple administration of 10 mg amlodipine with 80 mg simvastatin led to a 77% increase in simvastatin exposure compared to administration of simvastatin alone. In patients receiving amlodipine, the dose of simvastatin should be limited to 20 mg daily.

 

Atorvastatin, digoxin, or warfarin:

In clinical interaction studies, amlodipine showed no effect on the pharmacokinetics of atorvastatin, digoxin or warfarin.

 

Mammalian target of rapamycin (mTOR) inhibitors

mTOR inhibitors such as sirolimus, temsirolimus and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use with mTOR inhibitors, amlodipine can increase the effect of the mTOR inhibitor.

For ramipril

 

 

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy is inconclusive; however, a small increase in risk cannot be excluded. Unless continuing ACE inhibitor therapy is considered essential, patients planning pregnancy should be switched to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. If pregnancy is confirmed, treatment with ACE inhibitors should be discontinued immediately and, where required, alternative treatment should be initiated.

 

ACE inhibitor therapy exposure during the second and third trimesters is known to have fetotoxic effects (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxic effects (renal failure, hypotension, hyperkalemia) (see also section 5.3). In the event of exposure to ACE inhibitors from the second trimester of the pregnancy onwards, ultrasound examinations of renal function and the skull are recommended.

 

Infants whose mothers have taken ACE inhibitors should be checked frequently for hypotension (see sections 4.3 and 4.4).

 

 

For amlodipine

The safety of amlodipine in pregnant women has not yet been confirmed.

 

In animal experimental studies, reproductive toxicity was observed at high doses (see section 5.3).

 

Use during pregnancy is only recommended if no safer treatment alternatives are available and the disease represents a higher risk for mother and fetus.

 

Breastfeeding For ramipril

Because insufficient information is available regarding the use of ramipril during breastfeeding, ramipril is not recommended. An alternative treatment with a more suitable safety profile is preferable during breastfeeding, especially while nursing a newborn or preterm infant.

 

For amlodipine

Amlodipine is excreted in human breast milk. The proportion of the maternal dose transferred to the infant is estimated at an interquartile range of 3 to 7%, with a maximum of 15%. It is not known whether amlodipine has effects on infants.

 

In the decision to either continue/discontinue treatment with amlodipine, the benefit of breastfeeding for the child and the benefits of treatment with amlodipine for the mother must be taken into consideration.

 

Fertility

 

For amlodipine

 

Reversible biochemical changes were observed in the heads of spermatozoa in some patients treated with calcium blockers. The clinical data regarding a possible influence of amlodipine on fertility is still insufficient. In a study in rats, there were negative effects on the fertility of male animals (see section 5.3).

Some adverse effects (e.g. dizziness, headache, fatigue or nausea) may impair the ability to concentrate and react in the patient and thus represent a risk in situations where these skills are of particular importance (e.g. driving or operating machines). This is particularly the case at the start of treatment or when changing over from other preparations. Driving a vehicle or operating machines is inadvisable for several hours after the first dose or subsequent dose increases.

Summary of the safety profile

 

Ramipril

 

The most frequently reported adverse effects in treatment with ramipril are hyperkalemia, headache, dizziness, hypotension, orthostatic hypotension, syncope, dry cough, bronchitis, sinusitis, dyspnea, gastrointestinal inflammation, digestive disorders, digestive complaints, dyspepsia, diarrhea, nausea, vomiting, skin rash especially maculopapular, muscle cramps, myalgia, pain in the chest, fatigue.

Serious side effects include agranulocytosis, pancytopenia, hemolytic anemia, myocardial infarction, angioedema, vasculitis, bronchospasm, acute pancreatitis, liver failure, acute renal failure, hepatitis, exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Amlodipine

 

The most frequently reported side effects during treatment with amlodipine are somnolence, dizziness, headache, palpitations, skin redness with warmth, abdominal pain, nausea, ankle swelling, edema, and fatigue.

 

Serious adverse effects are leukopenia, thrombocytopenia, myocardial infarction, atrial fibrillation, ventricular tachycardia, vasculitis, acute pancreatitis, hepatitis, angioedema, erythema multiforme, exfoliative dermatitis, toxic epidermal necrolysis and Steven-Johnson syndrome.

 

The following frequency categories are used for side effects occurring during treatment with the individual active substances:

 

Very common (³ 1/10) Common (³ 1/100 to < 1/10)

Uncommon (³ 1/1,000 to < 1/100) Rare (³ 1/10,000 to < 1/1,000) Very rare (< 1/10,000)

Not known (cannot be estimated from the available data)

 

MedDRA system organ class	Frequency	Ramipril	Amlodipine
Blood and lymphatic system disorders	Uncommon	Eosinophilia
	Rare	Decrease in leukocyte count (including neutropenia/agranulocytosis), Decrease in erythrocyte count, decreased hemoglobin values, decrease in platelet count
	Very rare		Leucopenia, thrombocytopenia
	Not known	Bone marrow failure, pancytopenia, Hemolytic anemia
Immune system disorders	Very rare		Allergic reactions
	Not known	Anaphylactic or anaphylactoid reactions, Increase in antinuclear antibodies
Endocrine disorders	Not known	Syndrome of inadequate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders	Common	Increase in serum potassium concentration
	Uncommon	Anorexia, reduced appetite
	Very rare		Hyperglycemia
	Not known	Decrease in serum sodium concentration
Psychiatric disorders	Uncommon	Depressive mood, anxiety, Nervousness, restlessness, sleep disorders including somnolence	Mood changes (including anxiety), insomnia, depression
	Rare	Confusional states	Confusion
	Not known	Attention disorders
Nervous system disorders	Common	Headache, dizziness	Headache, dizziness, somnolence (especially at the start of treatment)
	Uncommon	Vertigo, paresthesia,	Tremor, dysgeusia, syncope,

 

MedDRA system organ class	Frequency	Ramipril	Amlodipine
		ageusia,dysgeusia	hypesthesia, Paresthesia
	Rare	Tremor, balance disorder
	Very rare		Increased muscle tone (hypertension), Peripheral neuropathy
	Not known	Cerebral ischemia including ischemic stroke and transient ischemic attacks, impairment of psychomotor skills, feeling of burning, parosmia	Extrapyramidal  disease
Eye disorders	Common		Vision disorders (including diplopia)
	Uncommon	Vision disorders, including blurred vision
	Rare	Conjunctivitis
Ear and labyrinth disorders	Uncommon		Tinnitus
	Rare	Hearing impaired, tinnitus
Cardiac disorders	Common		Palpitations
	Uncommon	Myocardial ischemia, including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema	arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)
	Very rare		Myocardial  infarction
Vascular disorders	Common	Hypotension, orthostatic hypotension, Syncope	Skin redness with feeling of warmth
	Uncommon	Flushing	Hypotension
	Rare	Vascular stenosis, hypoperfusion,  vasculitis
	Very rare		Vasculitis
	Not known	Raynaud’s  phenomenon
Respiratory, thoracic and mediastinal disorders	Common	Dry cough, bronchitis, Sinusitis, dyspnea	Dyspnea
	Uncommon	Bronchospasm, including deterioration of bronchial asthma, blocked nose	Cough, rhinitis
Gastrointestinal disorders	Common	Inflammation of the gastrointestinal tract, digestive disorders, digestive complaints, dyspepsia, diarrhea, nausea, vomiting	Nausea, abdominal pain, dyspepsia, altered bowel movements (including diarrhea and constipation)
	Uncommon	Pancreatitis (deaths were reported in rare exceptions in connection with ACE inhibitors), increase in	vomiting, dry mouth

 

MedDRA system organ class	Frequency	Ramipril	Amlodipine
		pancreatic enzymes, angioedema of the small intestine, Upper abdominal pain incl. Gastritis, constipation, dry mouth
	Rare	Glossitis
	Very rare		Pancreatitis, gastritis, gingival hyperplasia
	Not known	Aphthous stomatitis
Hepatobiliary  disorders	Uncommon	Increase in liver enzymes and/or conjugated bilirubin
	Rare	Cholestatic jaundice, hepatocellular  damage
	Very rare		Jaundice*, hepatitis*, increased liver enzyme values*
	Not known	Acute liver failure, cholestatic or cytolytic hepatitis (in rare exceptional cases with fatal outcome)
Skin and subcutaneous tissue disorders	Common	Rash in particular maculopapular
	Uncommon	Angioedema; in rare exceptional cases the airway obstruction due to angioedema can be fatal, pruritus, Hyperhidrosis	alopecia, purpura, skin discoloration, Hyperhidrosis, pruritus, rash, exanthema, urticaria
	Rare	Exfoliative dermatitis, urticaria, onycholysis
	Very rare	Photosensitivity	Angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke’s edema, photosensitivity
	Not known	Toxic epidermal necrolysis, Stevens- Johnson syndrome, erythema multiforme, pemphigoid, deterioration of psoriasis, psoriasiform dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia	Toxic epidermal necrolysis
Skeletal and connective tissue disorders	Common	Muscle spasms, myalgia	Ankle swelling, muscle cramps
	Uncommon	Arthralgia	arthralgia, myalgia, back pain

 

MedDRA system organ class	Frequency	Ramipril	Amlodipine
Renal and urinary disorders	Uncommon	Renal impairment including acute renal failure, increased urine excretion, Deterioration of pre-existing proteinuria, increase in serum urea, Increase in serum creatinine	micturition disorders, nocturia, increased urination
Reproductive system and breast disorders	Uncommon	Transient erectile impotence, decreased libido	Impotence,  gynecomastia
	Not known	Gynecomastia
General disorders and administration site conditions	Very common		Edema
	Common	Chest pain, fatigue	Fatigue, asthenia
	Uncommon	Pyrexia	Chest pain, pain, Malaise
	Rare	Asthenia
Investigations	Uncommon		Weight gain, Weight loss

 

* usually associated with cholestasis For ramipril

Pediatric population

The safety of ramipril was investigated in 325 children and adolescents aged 2 to 16 years in two clinical trials. While the nature and severity of the side effects are similar to those in adults, the frequency of the following side effects is higher in children:

Tachycardia, blocked nose and rhinitis, “common” (i.e. ≥ 1/100 to < 1/10) in the pediatric population, and “uncommon” (i.e. ≥ 1/1,000 to < 1/100) in adults.

Conjunctivitis “common” (i.e. ≥ 1/100 to < 1/10) in the pediatric population and “rare” (i.e. ≥ 1/10,000 to

< 1/1,000) in adults.

Tremor and urticaria “uncommon” (i.e. ≥ 1/1,000 to < 1/100) in the pediatric population and “rare” (i.e.

≥ 1/10,000 to < 1/1,000) in adults.

 

The overall safety profile for ramipril in the pediatric population does not differ significantly from the safety profile in adults.

 

Additionally for Amlohope5 mg/5 mg/- 10 mg/5 mg

Allura Red can cause allergic reactions.

 

 

Additionally for Amlohope5 mg/10 mg/- 10 mg/10 mg

Azorubine can cause allergic reactions.

1.1  For ramipril Symptoms

Symptoms associated with overdose of ACE inhibitors may include excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

 

Treatment

The patient should be monitored closely and receive symptomatic and supportive therapy. Potential measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore hemodynamic stability, such as administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by dialysis.

 

For amlodipine

There is limited experience with intended overdose in humans.

 

Symptoms

The available data suggest that a prominent overdose can lead to pronounced peripheral vasodilation and possibly to reflex tachycardia. Cases of pronounced and probable persistent systemic hypotension culminating in shock, including shock with fatal outcome, were reported.

 

Treatment

Clinically relevant hypotension due to an overdose of amlodipine requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the extremities and monitoring of fluid balance and urine excretion. A vasoconstrictor can be administered to restore the vascular tone and blood pressure if this is not contraindicated. Intravenously administered calcium gluconate can be beneficial once the effects of calcium channel blockade are reversed.

 

Gastric lavage can be helpful in certain cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine.

 

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Pharmacotherapeutic group: ACE inhibitors and calcium channel blockers ATC code C09BB07

 

Mechanism of action of ramipril

Ramiprilat, the active metabolite of the prodrug Ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyzes the

 

conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.

 

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

 

Pharmacodynamic  effects

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

 

In most patients, the onset of the antihypertensive effect of a single dose becomes apparent 1-2 hours after oral administration. The peak effect of a single dose is generally achieved 3-6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

 

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3- 4 weeks. It has been shown that the antihypertensive effect is sustained under long-term therapy lasting 2 years.

 

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

 

Two large randomized, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies showed no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE inhibitors and angiotensin II receptor blockers.

ACE inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse events. CV death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

 

Pediatric population

In a randomized, double-blind clinical study involving 244 pediatric patients with hypertension (73% primary hypertension), aged 6-16 years, patients received either low dose, medium dose or high dose of ramipril to achieve plasma concentrations of Ramiprilat corresponding to the adult dose range of 1.25 mg,

5 mg and 20 mg on the basis of body weight. At the end of 4 weeks, ramipril was ineffective in the endpoint of lowering systolic blood pressure but lowered diastolic blood pressure at the highest dose. Both medium and high doses of ramipril showed significant reduction of both systolic and diastolic BP in children with confirmed  hypertension.

 

This effect was not seen in a 4-week, randomized, double-blind dose-escalation study with withdrawal attempt in 218 pediatric patients aged 6-16 years (75% primary hypertension), where both diastolic and systolic blood pressures demonstrated a modest rebound effect but not a statistically significant return to the baseline, This applied for all three dose levels tested (low dose [0.625 mg-2.5 mg], medium dose [2.5 mg- 10 mg] or high dose [5 mg-20 mg] ramipril based on body weight). Ramipril did not have a linear dose/response relation in the pediatric population studied.

 

Mechanism of action of amlodipine

Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle cells.

 

The antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle.

 

In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24-hour interval. Due to the slow onset of action, no acute drop in blood pressure is expected.

 

 

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids. Amlodipine is also suitable for use in patients with asthma, diabetes or gout.

 

Use in patients with heart failure

 

In patients with NYHA class II to IV heart failure, hemodynamic studies and controlled clinical studies showed no clinical deterioration due to amlodipine in the measured parameters, resilience, left ventricular ejection fraction and clinical symptoms. A placebo-controlled study (PRAISE) investigating patients with NYHA grade III and IV heart failure who were treated with digoxin, diuretics and ACE inhibitors showed that amlodipine did not increase the mortality risk or the combined mortality and morbidity in patients with heart failure. In a follow-up, long term, placebo-controlled study (PRAISE-2) of amlodipine tablets in patients with NYHA Grade III and IV heart failure without clinical symptoms or objective findings suggestive of underlying ischemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, Amlodipine tablets had no effect on total cardiovascular mortality. In this same population amlodipine tablets were associated with increased reports of pulmonary edema.

 

 

Treatment to prevent heart attack (ALLHAT) trial

 

A randomized double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare newer drug therapies: amlodipine 2.5-10 mg/d (calcium channel blocker) or lisinopril 10-40 mg/d (ACE-inhibitor) as first-line therapies to that of the thiazide diuretic chlorthalidone 12.5-25 mg/d in mild to moderate hypertension. A total of 33,357 hypertensive patients aged 55 or older were randomized and observed for a mean of

4.9 years. The patients had at least one additional CHD risk factor, including: previous myocardial infarction or stroke (> 6 months prior to enrollment) or documentation of other atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), HDL-C < 35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).

The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.98 95% CI 0.90-1.07 p=0.65. Among secondary endpoints, the incidence of heart failure (component of a composite combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone group (10.2% vs 7.7%, RR 1.38, 95% CI 1.25-1.52 p<0.001).

However, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy (RR 0.96; 95% CI 0.89-1.02 p=0.20).

 

Pediatric population (aged 6 years and over)

In a study involving 268 children aged 6-17 years with predominantly secondary hypertension, comparison of a 2.5 mg dose, and 5 mg dose of amlodipine with placebo, showed that both doses reduced systolic blood pressure significantly more than placebo. The difference between the two doses was not statistically significant.

The long-term effects of amlodipine on growth, puberty and general development were not investigated. The long-term efficacy of amlodipine in the case of therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood has also not been established.

 

The European Medicines Agency has waived the obligation to submit study results for Amlohopefor all approved indications in all subgroups of the pediatric population (see information on the pediatric population in section 4.2).

Ramipril

Absorption

Following oral administration ramipril is rapidly resorbed from the gastrointestinal tract: Peak plasma concentrations of ramipril are reached within 1 hour. Based on urinary recovery, the extent of resorption is at least 56% and is not significantly influenced by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of 2.5 mg and 5 mg ramipril is 45%.

 

Peak plasma concentrations of ramiprilat, the sole active metabolite of ramipril, are reached 2 to 4 hours after ramipril intake. Steady state plasma concentrations of ramiprilat after once daily dosing with the usual doses of ramipril are reached by about the fourth day of treatment.

 

Distribution

The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%.

 

Biotransformation

Ramipril is almost completely metabolized to ramiprilat, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat.

 

Elimination

Excretion of the metabolites is primarily a renal function.

 

Plasma concentrations of ramiprilat decline in a polyphasic manner. Because of its potent, saturable binding to ACE and slow dissociation from the enzyme, ramiprilat shows a prolonged terminal elimination phase at very low plasma concentrations.

 

After multiple once-daily doses of ramipril, the effective half-life of ramiprilat concentrations was 13 to

17 hours for the 5 to 10 mg doses and longer for the lower 1.25 to 2.5 mg doses. This difference is related to the saturable capacity of the enzyme to bind ramiprilat.

 

Breastfeeding

A single oral 10 mg dose of ramipril produced an undetectable level of ramipril and its metabolite in breast milk. However, the effect of multiple doses is not known.

 

Other special populations

Patients with renal impairment (see section 4.2)

Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal ramiprilat clearance is proportionally related to creatinine clearance. This results in elevated plasma concentrations of ramiprilat, which decrease more slowly than in subjects with normal renal function.

 

Patients with hepatic impairment (see section 4.2)

In patients with impaired liver function, the metabolism of ramipril to ramiprilat was delayed, due to diminished activity of hepatic esterases. The plasma ramipril levels in these patients were increased. Peak plasma concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function.

 

Pediatric population

The pharmacokinetic profile of ramipril was studied in 30 pediatric hypertensive patients, aged 2-16 years, weighing ≥10 kg. After doses of 0.05 to 0.2 mg/kg, ramipril was rapidly and extensively metabolized to ramiprilat. Peak plasma concentrations of ramiprilat occurred within 2 to 3 hours. Ramiprilat clearance correlated highly with the logarithm of body weight (p < 0.01) as well as dose (p < 0.001). Clearance and volume of distribution increased with the increasing age of the children for each dose group. The dose of

0.05 mg/kg in children achieved exposure levels comparable to those in adults treated with ramipril 5 mg. The dose of 0.2 mg/kg in children resulted in exposure levels higher than the maximum recommended dose of 10 mg per day in adults.

 

Amlodipine

Resorption, distribution and plasma protein binding

Amlodipine is absorbed well after oral administration of therapeutic doses. Peak plasma concentration is achieved 6-12 hours after administration. The absolute bioavailability is approximately 64-80%.

 

The volume of distribution is 21 l/kg body weight. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Bioavailability is not influenced by food intake. Biotransformation/elimination

The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing.

Amlodipine is extensively metabolized by the liver to inactive metabolites. 10% of the parent compound and 60% of the metabolites are excreted in the urine.

 

Use in the case of hepatic impairment

Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic impairment have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.

 

Use in elderly patients

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger patients. Amlodipine clearance tends to be decreased in elderly patients, with resulting increases in AUC and elimination half-life. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.

 

Use in the pediatric population

A study on population kinetics was conducted in 74 hypertensive children aged from 12 months to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving between 1.25 and 20 mg amlodipine given either once or twice daily. In children 6 to 12 years and in adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 L/hr respectively in males and 16.4 and 21.3 L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.

For ramipril

Oral administration of ramipril has been found to be devoid of acute toxicity in rodents and dogs.

 

Studies involving chronic oral administration have been conducted in rats, dogs and monkeys. Indications of plasma electrolyte shifts and changes in the compositions of the blood were found in all 3 species.

 

As an expression of the pharmacodynamic activity of ramipril, pronounced enlargement of the juxtaglomerular apparatus was noted in the dog and monkey from daily doses of 250 mg/kg/d. Rats, dogs and monkeys tolerated daily doses of 2, 2.5 and 8 mg/kg/d respectively without side effects. Irreversible kidney damage has been observed in very young rats given a single dose of ramipril.

 

Reproduction toxicology studies in the rat, rabbit and monkey did not disclose any teratogenic properties. Fertility was not impaired either in male or in female rats.

The administration of ramipril to female rats during the fetal period and lactation produced irreversible renal damage (dilatation of the renal pelvis) in the offspring at daily doses of 50 mg/kg body weight or higher.

 

Extensive mutagenicity testing using several test systems has yielded no indication that ramipril possesses mutagenic or genotoxic properties.

 

For amlodipine

Reproductive toxicity

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labor and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans (based on mg/kg).

 

Impairment of fertility

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day This corresponds to 8 times the maximum recommended human dose of 10 mg on a mg/m2 basis. In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle- stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.

 

Carcinogenic/mutagenic  potential

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice the maximum recommended clinical dose* of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.

 

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

 

* based on a patient weight of 50 kg

Capsule filling

·     Crospovidone (type B) (Ph.Eur.)

·     Hypromellose

·     Microcrystalline  cellulose

·     Glycerol dibehenate (Ph.Eur.)

 

Amlohope5 mg/5 mg

Capsule bottom and capsule cap

·     Brilliant blue FCF (E133)

·     Allura red (E129)

 

·     Titanium dioxide (E171)

·     Gelatin

 

Amlohope10 mg/5 mg

Capsule bottom

·     Iron(III) oxide (E172)

·     Titanium dioxide (E171)

·     Gelatin

 

Capsule cap

·     Brilliant blue FCF (E133)

·     Allura red (E129)

·     Titanium dioxide (E171)

·     Gelatin

 

Amlohope5 mg/10 mg

Capsule bottom

·     Iron(III) oxide (E172)

·     Titanium dioxide (E171)

·     Gelatin

 

Capsule cap

·     Indigo carmine (E132)

·     Azorubine (E122)

·     Titanium dioxide (E171)

·     Gelatin

 

Amlohope10 mg/10 mg

Capsule bottom and capsule cap

·     Indigo carmine (E132)

·     Azorubine (E122)

·     Titanium dioxide (E171)

·     Gelatin

 

Not applicable

2 years

Keep this medicine out of the sight and reach of children.

 

Do not use Amlohope after the expiry date which is stated on the carton {year/month) date refers to the last day of that month.

 

Do not store above 30°C.

 

Do not use Amlohope if you notice the visible signs (e.g. discoloration) of deterioration.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

unmarked self-closing Coni Snap type, size 3, hard gelatin capsules with opaque, amethyst coloured body and opaque amethyst coloured cap. filled with white or almost white, odourless or almost odourless granular powder, free of mechanical impurities.

 

Amlohope, 10 mg/5 mg, hard capsules:

unmarked self-closing Coni Snap type, size 0, hard gelatin capsules with opaque, flesh coloured body and opaque, amethyst coloured cap filled with white or almost white, odourless or almost odourless granular powder, free of mechanical impurities.

Amlohope, 5 mg/10 mg, hard capsules:

unmarked self-closing Coni Snap type, size 0, hard gelatin capsules with opaque, flesh coloured body and opaque maroon coloured cap filled with white or almost white, odourless or almost odourless granular powder, free of mechanical impurities.

Amlohope, 10 mg/10 mg, hard capsules:

unmarked self-closing Coni Snap type, size 0, hard gelatin capsules with opaque, maroon coloured body and opaque maroon coloured cap filled with white or almost white, odourless or almost odourless granular powder, free of mechanical impurities.

 

Package:

10, 20, 30, 50 or 100 hard capsules in blister packs, in carton box.

Not all pack sizes may be marketed

Unused medicinal product or waste material should be disposed of in accordance with national regulations