Hypertension

Since this drug may cause excessively decreased blood pressure, this drug should not be used as an initial therapy for hypertension.

One tablet (8 mg/2.5 mg or 8 mg/5 mg as candesartan cilexetil/ amlodipine) is Orally administered once daily. This drug should not be used as an initial therapy for hypertension.

Dosage should be determined for each patient based on the following dosage and administration of candesartan cilexetil and amlodipine besilate.

Candesarta cilexetil

Hypertension

The recommended initial dose and usual maintenance dose of Candesartan is ۸ mg once daily. In some patients whose blood pressure is not adequately controlled, the dose can be increased to 16 mg once daily and to a maximum of 32 mg once daily. Therapy should be adjusted according to blood pressure response

Amlodipin besilate

Hypertension

Usually the adults’ dose is 5mg of amlodipine is orally administered once a day. The dosage may be appropriately adjusted according to the patient’s symptom, and dose can be increased up to 10 mg once a day when the effect is insufficient.

In principle, switching to UNISIA® Tablets should be considered when candesartan cilexetil 8mg and amlodipine 2.5 ‐ 5mg are coadministrated, or when the blood pressure is not controlled sufficiently by administration of one of them.

Use in special populations

• Elderly patients

Unisia tablets should be administered carefully while closely observing the patients' condition with attention to following points.

It is generally acknowledged that an excessive fall of blood pressure should be avoided in the elderly (cerebral infarction, etc., may occur).

In the pharmacokinetics study of amlodipine besilate in the elderly, tendency of higher blood concentration and longer half- life were observed. Therefore, Unisia tablets should be administered carefully, taking such measures as starting with a lower dose.

In small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily

• Pediatric patients

The safety of Unisia tablets in low birth weight infants, neonates, nursing infants, infants and children has not been established (no clinical experience).

• Patients with renal impairment

The starting dose is 4 mg in patients with renal impairment, including patients on hemodialysis. The dose should be titrated according to response. There is limited experience in patients with very severe or end‐stage renal impairment (Clareatinine <15 ml/min) (see section 4.4).

• Patients with hepatic impairment

An initial dose of 4 mg once daily is recommended in patients with mild to moderate hepatic impairment. The dose may be adjusted according to response. Candesartan Cilexetil is contraindicated in patients with severe hepatic impairment and/or cholestasis (see sections 4.3 and 5.2).

• Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautious and should start at the lower end of the dosing range. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment

 

‐ Patients with hypersensitivity to any component of candesartan cilexetil/amlodipine besilate tablet or dihydropyridines. ‐ Pregnant women or women having possibilities of being pregnant. ‐ Patients with diabetes on aliskiren fumarate (excluding patients with significantly uncontrolled blood pressure despite treatment with other antihypertensive therapy). ‐ Severe hepatic impairment, biliary cirrhosis or cholestasis. ‐ Concomitant use of Unisia with aliskiren‐containing products in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) ‐ Second and third trimesters of pregnancy (see sections 4.4 and 4.6). ‐ Severe hypotension. ‐ Shock (including cardiogenic shock). ‐ Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy and high‐grade aortic stenosis). ‐ Haemodynamically unstable heart failure after acute myocardial infarction.

Renal artery stenosis

Other drugs that affect the renin‐angiotensin‐aldosterone system, i.e. angiotensin converting enzyme (ACE) inhibitors, may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. A similar effect may be anticipated with angiotensin II receptor antagonists.

Since candesartan cilexetil may rapidly deteriorate renal function in patients with bilateral or unilateral artery stenosis due to a decrease in renal blood flow and/or glomerular filtration pressure, administration of this drug should be avoided unless it is considered therapeutically essential.

Hyperkalemia

Since candesartan cilexetil may aggravate hyperkalemia in patients with hyperkalemia, administration of this drug should be avoided unless it is considered therapeutically essential.

Additionally, since hyperkalemia may occur in patients whose serum potassium level is liable to increase due to renal dysfunction or uncontrolled diabetes mellitus, etc., caution should be paid to serum potassium levels.

Renal dysfunction

Candesartan cilexetil may rarely cause a sudden fall in blood pressure, resulting in shock, syncope, transient unconsciousness, or renal hypofunction. Therefore, blood Pressure, renal function and the patient's condition should be closely observed while administration of this drug especially to the following patients:

• Patients on hemodialysis
• Patients on strict dietary salt restriction
• Patients under diuretic therapy (especially patients who have recently started diuretic therapy)
• Patients with hyponatremia
• Patients with renal dysfunction
• Patients with heart failure

Coadministration with aliskiren fumarate

In patients receiving concomitant administration of aliskiren fumarate, since renal dysfunction, hyperkalemia or hypotension may occur, UNISIA® Tablets should be administered carefully while closely observing the patients' condition. In patients with renal dysfunction (eGFR < 60mL/min/1.73m2), concomitant administration of aliskiren fumarate should be avoided unless it is considered therapeutically essential.

Intravascular volume depletion

In patients with intravascular volume and/or sodium depletion symptomatic hypotension may occur, as described for other agents acting on the renin‐angiotensin‐ aldosterone system. Therefore, the use of candesartan cilexetil/amlodipine besilate is not recommended until this condition has been corrected.

Anaesthesia and surgery

Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to blockade of the renin‐angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.

It is recommended not to administer this drug within 24 hours before surgery. (Patients on angiotensin II receptor antagonists may develop a severe fall in blood pressure during anesthesia and surgery due to inhibitory action on renin‐angiotensin system).

Hypotension

Mild hypotensive effect remains after the termination of the administration of amlodipine besilate due to its long blood concentration half-life. Therefore, when using other antihypertensive after the termination of the administration of this drug, patient's condition should be closely observed, such as paying attention to dosage and intervals of administration etc.

Impaired hepatic function

Amlodipine besilate is extensively metabolized by the liver. The t_1/2 and area under the curve (blood concentration‐time) of amlodipine besilate are prolonged in patients with Impaired liver function. The drug should therefore be administered with caution in these patients.

Candesartan cilexetil may aggravate hepatic function, and decrease in clearance of candesartan active metabolite is anticipated.

Other precautions

The patient must be instructed to remove the tablets from the press‐through package (PTP) before they are ingested. [It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, and this could result in serious complications such as mediastinitis.]

Although the causal relationship has not been established, myocardial infarction and arrhythmia (including ventricular tachycardia) were reported during the administration of amlodipine besilate.

“The safety and efficacy of amlodipine in hypertensive crisis have not been established.

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.”

Kidney transplantation:

To date there is no experience of the safe use of Unisia in patients who have had recent kidney transplantation.

Primary hyperaldosteronism:

Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist candesartan as their renin‐angiotensin system is affected by the primary disease.

Angioedema:

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue, has been reported in patients treated with candesartan. Some of these patients previously experienced angioedema with other medicinal products, including ACE inhibitors. Unisia should be discontinued immediately in patients who develop angioedema and should not be re‐administered.

Heart failure/post‐myocardial infarction:

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 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 candesartan. Evaluation of patients with heart failure or post‐myocardial infarction should always include assessment of renal function.

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 a etiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

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

Aortic and mitral valve stenosis: as with all other vasodilators, special caution is indicated in patients suffering from mitral stenosis or significant aortic stenosis that is not high grade.”

 

Candesartan cilexetil

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. A similar effect may occur with angiotensin II receptor antagonists and careful monitoring of serum lithium levels is recommended during concomitant use.

Attenuation of the antihypertensive effect may occur when simultaneously administering angiotensin II receptor antagonists and non‐steroidal anti‐inflammatory drugs (NSAIDs; i.e. selective COX‐2 inhibitors, acetylsalicylic acid (> 3 g/day) and non‐ selective NSAIDs).

As with ACE inhibitors, concomitant use of angiotensin II receptor antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre‐existing renal function. The combination should be administered with caution, especially in older and volume‐depleted patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.

The antihypertensive effect of candesartan cilexetil/amlodipine besilate may be enhanced by other medicinal products with blood pressure lowering properties.

Based on experience with the use of other drugs that affect the renin‐angiotensin‐aldosterone system, concomitant use of potassium‐sparing diuretics, potassium Supplements or salt substitutes or other drugs that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum potassium.

Amlodipine besilate

When used with erythromycin in young patients and diltiazem in elderly patients, the plasma concentration of amlodipine increased by 22% and 50 % respectively. Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors; however, no adverse events attributable to such interaction have been reported.

• There is no data available regarding the effect of CYP3A4 inducers on amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.
• Administration of amlodipine besilate with grapefruit juice is not recommended since bioavailability may be increased in certain patients resulting in increased blood pressure lowering effects.

Unisia Tablets should be administered with care when coadministered with the following drugs:

Drugs	Signs, Symptoms, and Treatment	Mechanisms and Risk Factors
Other drugs with hypotensive effect beta blockers, nitroglycerin, sildenafil, etc.	Hypotensive effect may be intensified. Caution should be made to dose adjustment etc.	Different antihypertensive mechanisms affect each other synergistically.
Potassium-sparing diuretics spironolactone, triamtelene, etc. Eplerenone Potassium supplements	Since an elevation of serum potassium level may occur, caution should be taken.	Potentiation of potassium‐sparing activity due to the inhibitory effect of candesartan cilexetil on aldosterone secretion. Risk factor: patients with renal dysfunction in particular
Diuretics furosemide, trichlormethiazide, etc.	When Unisia® tablets are administered to patients under diuretic therapy for the first time; its antihypertensive effect may be enhanced. Therefore, UNISIA® Tablets should be administered carefully.	Since renin activity is frequently enhanced in patients under diuretic therapy, they are more susceptible to the antihypertensive effect of candesartan cilexetil.

Aliskiren fumarate	Since renal dysfunction, Hyperkalemia or hypotension may occur, renal function, serum  potassium level and blood pressure should be closely monitored. In patients with renal Juice with this drug.	Blockade of the Renin‐Angiotensin System may     be enhanced by coadministration of aliskiren  fumarate. Concentration of amlodipine may be increased.
Simvastatin	It has been reported that the AUC of simvastatin increased by 77% when amlodipine besilate and simvastatin 80mg (non‐ approved high dose in Japan) were coadministered.	The mechanism is unknown.
Tacrolimus	The blood concentration of Tacrolimus may be    increased when amlodipine besilate is coadministered,     and then adverse reactions to Tacrolimus such as renal dysfunction may occur. When amlodipine besilate is coadministered, the blood concentration of      Tacrolimus should be monitored and  the dosage of Tacrolimus should be adjusted if necessary.	Since  Amlodipine besilate  and Tacrolimus are metabolized by mainly  CYP3A4,  Tacrolimus metabolism is considered to be inhibited by coadministarion.

 

Use in pregnancy

Pregnancy Category D

Animal studies with candesartan cilexetil have demonstrated late foetal and neonatal Injury in the kidney. The mechanism is believed to be pharmacologically mediated through effects on the renin‐angiotensin‐aldosterone system.

In humans, foetal renal perfusion, which is dependent upon the development of the renin‐angiotensin‐aldosterone system, begins in the second trimester. Thus risk to the foetus increases if candesartan cilexetil is administered during the second or third trimesters of pregnancy.

Amlodipine: the safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses. Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.

Candesartan: The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy. The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy.

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)

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.”

Amlodipine has been shown to prolong both the gestation period and the duration of Labor in animal studies.

Based on the above information, candesartan cilexetil/amlodipine besilate should not be used in pregnancy. If pregnancy is detected during treatment, candesartan cilexetil/amlodipine besilate should be discontinued.

Use in lactation

• It is not known whether candesartan is excreted in human milk. However, candesartan is excreted in the milk of lactating rats.

It is not known whether amlodipine besilate is excreted in human milk. However, it has been reported that amlodipine besilate transfers to mother's milk in animal studies.

Because of the potential for adverse effects on the nursing infant, breast feeding should be discontinued if the use of amlodipine besilate/candesartan cilexetil is considered essential.

The effect of candesartan cilexetil/amlodipine besilate on the ability to drive and use machines has not been studied, but based on its pharmacodynamic properties candesartan cilexetil/amlodipine besilate is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or weariness may occur during the treatment of hypertension.

Patients should be cautioned against engaging operation of machinery involving risk, such as working at a height, and driving motor vehicles.

Clinical study

In controlled clinical study (Japan) with candesartan cilexetil/amlodipine besilate, adverse reactions, including abnormalities in laboratory data, were observed in 35 (11.6%) of 302 patients.

Following adverse reactions were observed in either in the above study or spontaneous reports of candesartan cilexetil or amlodipine besilate, and so on. If any adverse reaction is observed, appropriate measures should be taken, such as discontinuation of this drug.

Clinically significant adverse reactions (frequency unknown.)

• Angioedema: Since angioedema manifested by facial, labial, glossal and laryngopharyngeal swellings may occur, patients should be closely observed. If any abnormality is observed, UNISIA® Tablets should be discontinued, and appropriate measures should be taken.
•  Shock, syncope or unconsciousness: Since shock, syncope or unconsciousness due to lowering of blood pressure may occur, close observation should be made. If coldness, vomiting, unconsciousness, etc. are observed, appropriate measures should be immediately taken. Condition of the patients should be closely observed while administration of UNISIA® Tablets, especially in patients on hemodialysis, those on strict dietary salt restriction, those under diuretic therapy, and those with heart failure.
• Acute renal failure: Since acute renal failure may occur, patients should be closely observed. If any abnormality is observed, UNISIA® Tablets should be discontinued, and appropriate measures should be taken.
• Hyperkalemia: Since severe hyperkalemia may occur, patients should be closely observed. If any abnormality is observed, appropriate measures should immediately be taken.
• Hepatic dysfunction or jaundice: Since hepatic dysfunction, including increased AST(GOT),  ALT(GPT), GTP etc. or jaundice may occur, patients should be closely observed. If any abnormality is observed, UNISIA® Tablets should be discontinued, and appropriate measures should be taken.
• Agranulocytosis, white blood cell decreased: Since agranulocytosis and white blood cell decreased may occur, patients should be closely observed. If any abnormality is observed, UNISIA® Tablets should be d i s co n t i nu ed , an d a p p r o p r i a t e measures should be taken.
• Rhabdomyolysis: Since rhabdomyolysis, which is characterized by muscle ache, weakness, increased CK (CPK), and increased blood and urinary myoglobin, may occur, patient should be closely observed. In such a case, administration of UNISIA® Tablets should be immediately discontinued, and appropriate measures should be taken.
• Interstitial pneumonia: Interstitial pneumonia with fever, coughing, dyspnea, abnormal chest X‐ray, etc., may occur. In such a case, UNISIA® Tablets should be discontinued and appropriate measures, such as treatment with an adrenocortical hormone, should be taken.
• Hypoglycemia: Since hypoglycemia may occur (liable to occur in patients on diabetic therapy), close observation should be made. If feeling of weakness or hungry, cold sweat, tremor of hands, decreased mental concentration, convulsions, disturbed consciousness, etc. are observed, UNISIA® Tablets should be discontinued, and appropriate measures should be taken.
• Platelet count decreased: Since platelet count decreased may occur, patients should be closely observed. If any abnormality is observed, UNISIA® Tablets should be discontinued, and appropriate measures should be taken.
• Atrioventricular block: Since atrioventricular block (initial symptoms: bradycardia, dizziness etc.) may occur, if any abnormality is observed, UNISIA® Tablets should be discontinued, and appropriate measures should be taken.

Other adverse reactions

	0.1 ‐ <5%	frequency unknown
Hypersensitivity*		Rash, eczema, urticaria, pruritus , photosensitivity, erythema multiforme or vasculitis
Cardiovascular	Dizziness**, hot flushes (feeling hot, flushed face etc.), or blood pressure decreased	Lightheadedness**, dizziness on standing up** , chest pain, palpitations, extrasystole , atrial fibrillation, bradycardia, sinoatrial block ,sinus arrest, or tachycardia

Psychoneurologic		Headache, dull headache, insomnia, sleepiness, numbness of tongue, numbness of limbs, mood swings, peripheral nerve disorders, tremor, or extrapyramidal disorder
Gastrointestinal	Stomach discomfort, abdominal distension, or diarrhoea	Nausea, vomiting, anorexia, epigastric pain, constipation, loose stools, frequent bowel movements, stomatitis, taste abnormality, thirst, dyspepsia, gastroenteritis, or pancreatitis
Hepatic	Increased ALT(GPT) or ɣ‐GTP	Increased AST(GOT), ALP or LDH, or ascites
6) Hematologic	White blood cell increased ,or eosinophil count increased	Anemia, white blood cell decreased, erythrocytes decreased, or purpura
7) Renal	Increased BUN	Increased creatinine, or proteinuria
8) Others	Cough, tinnitus, increased blood CK(CPK), increased blood uric acid, or ureteric calculus	Malaise, weakness, fatigue, epistaxis, pollakiuria, nocturia, urinary occult blood positive, edema, increased blood potassium, decreased blood potassium, increased total cholesterol, increased CRP, decreased serum total protein, hyponatraemia, pain in lumbar region and back, myalgia, arthralgia, muscle spasm, hypertonia, erectile disturbance, urination impaired, gingival hypertrophy (by continuous use), gynaecomastia, alopecias, heavy sweating, rhinitis, weight gain, weight decreased, pain, skin discolouration, pyrexia, abnormal visual acuity, dyspnoea, dysaesthesia, hyperglycaemia, diabetes mellitus, or glucose urine present

*In such a case, Unisia tablets should be discontinued.
**In such a case, appropriate measures, such as reducing the dosage and temporarily discontinuing Unisia tablets, should be taken.

This drug is a combination of candesartan cilexetil 8mg and amlodipine 2.5mg or 5mg. Since adverse reactions by both candesartan cilexetil and amlodipine besilate may occur, the use of this drug should be considered appropriately.

• Candesartan cilexetil

Common adverse reactions:

Infections and infestations:

Respiratory infection:

Nervous system disorders:

Dizziness/vertigo, headache

The following adverse reactions have been reported very rarely (<1/10,000) in post marketing experience:

Respiratory, thoracic and mediastinal disorders:

Cough

Gastrointestinal disorders:

Nausea

Blood and lymphatic system disorders:

Leukopenia, neutropenia and agranulocytosis

Metabolism and nutrition disorders:

Hyperkalaemia, hyponatraemia

Hepato‐biliary disorders:

Increased liver enzymes, abnormal hepatic function or hepatitis

Skin and subcutaneous tissue disorders:

Angioedema, rash, urticaria, pruritus

Musculoskeletal, connective tissue and bone disorders:

Back pain

Renal and urinary disorders:

Renal impairment, including renal failure in susceptible patients

• Amlodipine besilate

Common: Cardiac disorders: Palpitations

Very rare: very rare (≤1/10,000).

•  Blood and lymphatic system disorders: Leukocytopenia, thrombocytopenia
• Immune system disorders: Allergic reactions
• Metabolism and nutrition disorders: Hyperglycaemia
• Nervous system disorders :Hypertonia, peripheral neuropathy
• Cardiac disorders: Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)
• Vascular disorders: Vasculitis
• Respiratory, thoracic and mediastinal disorders: Cough
• Gastrointestinal disorders: Pancreatitis, gastritis, gingival hyperplasia
• Hepato‐biliary disorders: Hepatitis, jaundice, hepatic enzymes increased*
• Skin and subcutaneous tissue disorders :Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens‐Johnson syndrome, Quincke oedema, photosensitivity

Rare (≥1/10,000 to ≤1/1,000)

• Psychiatric disorders: Confusion

Uncommon (≥1/1,000 to ≤1/100)

• Investigations Weight increase, weight decrease
• General disorders and administration site conditions Chest pain, asthenia, pain, malaise
• Eye disorders Visual disturbance (including diplopia)
• Ear and labyrinth disordersTinnitus
• Vascular disorders Hypotension
• Respiratory, thoracic and mediastinal disorders Dyspnoea, rhinitis
• Gastrointestinal disorders Vomiting, dyspepsia, altered bowel habits (including diarrhoea and constipation), dry mouth
• Skin and subcutaneous tissue disorders
• Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema
• Musculoskeletal and connective tissue disorders Arthralgia, myalgia, muscle cramps, back pain
• Renal and urinary disorders Micturition disorder, nocturia, increased urinary frequency
• Reproductive system and breast disorders Impotence, gynecomastia
• Respiratory, thoracic and mediastinal disorders Dyspnoea, rhinitis
• Psychiatric disorders Insomnia, mood changes (including anxiety), depression
• Nervous system disorders: Tremor, dysgeusia, syncope, hypoesthesia, paresthesia

Common (≥1/100 to <1/10)

• Nervous system disorders: Somnolence, dizziness, headache (especially at the beginning of the treatment)
• Vascular disorders: Flushing
• Gastrointestinal disorders: Abdominal pain, nausea
• Musculoskeletal and connective tissue disorders: Ankle swelling
• General disorders and administration site conditions: Oedema, fatigue
• Cardiac disorders: Palpitations

Not known:

• Extrapyramidal disorder

Reporting of suspected adverse reactions

•  Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC)

Call NPC at +966‐11‐2038222, Exts: 2317‐2356‐2353‐2354‐2334‐2340.

Toll free phone: 8002490000

Fax: +966‐11‐205‐7662E

Mail: npc.drug@sfda.gov.sa

Website: www.sfda.gov.sa/npc

• Other GCC States: Please contact the relevant competent authority

Symptoms

Based on pharmacological considerations, the main manifestation of an overdose of candesartan cilexetil is likely to be symptomatic hypotension and dizziness. In single case reports of overdose up to 672 mg candesartan cilexetil, the patient recovery was uneventful.

Also overdosage of amlodipine besilate might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia.

Management

No specific information is available on the treatment of overdosage with candesartan cilexetil/amlodipine besilate. The following measures are, however, suggested in case of overdosage.

Cardiac and respiratory function should be monitored and blood pressure should be measured frequently. If marked decrease in blood pressure occurs, provide cardiovascular support including elevation of the extremities and the administration of fluids. If the symptom does not improve, administration of vasopressors should be considered with careful attention to circulating blood volume and urine output.

Candesartan is not removed by haemodialysis. Also since amlodipine is highly protein bound, hemodialysis is not likely to be of benefit. Charcoal administration is reported to be effective for inhibition of absorption since AUC of amlodipine decreased by 99% and 49% when activated charcoal was administered immediately after the use of amlodipine and 2 hours after the use of amlodipine, respectively.

Mechanism of Action

• Candesartan cilexetil

Angiotensin II is the primary vasoactive hormone of the renin‐angiotensin‐aldosterone system and plays a significant role in the pathophysiology of hypertension and other cardiovascular disorders. It also has a role in the pathogenesis of organ hypertrophy and end organ damage. The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type 1 (AT₁) receptor.

Candesartan cilexetil is a prodrug which is rapidly converted to the active drug, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist, selective for AT₁ receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.

Candesartan does not influence ACE or other enzyme systems usually associated with the use of ACE inhibitors. Since there is no effect on the degradation of kinins, or on the metabolism of other substances, such as substance P, angiotensin II receptor antagonists are unlikely to be associated with cough. In controlled clinical trials comparing candesartan cilexetil with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. The antagonism of the AT₁ receptors results in dose related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.

•  Amlodipine

Amlodipine besilate acts as a dihydropyridine calcium channel antagonist, and is characterized by gradual onset of action and continuous effect. Dihydropyridine calcium channel antagonist selectively binds to L‐type voltage‐gated calcium channels and reduces calcium influx into cells, causing relaxation of coronary or peripheral vascular smooth muscle.

Clinical studies

Combination Double blind comparative study (Japan) (CCT-001)

The result of double blind comparative study in patients with mild to moderate essential hypertension where a once daily dose of 8 mg/5 mg, 8 mg/2.5 mg, 8 mg/0 mg, 0 mg/5 mg, 4 mg/5 mg, or 4 mg/2.5 mg of candesartan cilexetil/amlodipine was administered, before or after meals, for 12 weeks is as follows. Significant differences in sitting diastolic blood pressure (DBP) at trough and sitting systolic blood pressure (SBP) at trough were observed in 8mg/5mg group compared to both 8 mg/0 mg and 0 mg/5 mg groups and in 8 mg/2.5 mg group compared to 8 mg/0 mg group. The results of this study are shown in the table 1 below

Table 1: Blood pressure changes of the double blind comparative study

Administration group (amlodipine besilate/candesartan cilexetil)	Changes in sitting SBP at trough (mmHg)	Changes in sitting DBP at trough (mmHg)
8 mg/5 mg (n=101)	‐26.77 ± 10.52	‐16.18 ± 8.48
8 mg/2.5 mg (n=36)	‐20.15 ± 9.56	‐11.88 ± 5.55
8 mg/0 mg (n=100)	‐13.91 ± 11.17	‐7.79 ± 8.19
0 mg/5 mg (n=99)	‐19.91 ± 10.71	‐11.23 ± 7.06
0 mg/0 mg (n=36)	‐6.22 ± 12.00	‐3.00 ± 8.35
4 mg/5 mg (n=36)	‐27.08 ± 11.63	‐17.14± 6.91
4 mg/2.5 mg (n=35)	‐16.31 ± 12.35	‐10.20 ± 8.45

Long-term study (Japan) (OCT-001)

The multicenter, open‐label, long‐term study (52 weeks) was conducted in patients with essential hypertension (n=165). The initial dose of candesartan cilexetil and amlodipine besilate was decided after observation period (‐2 weeks). The dosage was gradually increased until the target blood pressure is obtained during the first treatment period (0‐12 weeks), and was appropriately adjusted according to the control of blood pressure or tolerability during the second treatment period (12‐52 weeks). The dosage of candesartan cilexetil/ amlodipine was selected from 8 mg/5 mg, 8 mg/2.5 mg, 4 mg/5 mg or 4 mg/2.5 mg.

Changes in sitting SBP and DBP at trough were ‐22.30 ± 13.05 mmHg and ‐14.02 ± 8.93 mmHg, respectively. Hypotensive effect persisted and stable blood pressure control was obtained for 52 weeks, and decrease of the efficacy due to long‐term administration was not observed.

 

Absorption and distribution

• Candesartan cilexetil

Following oral administration, candesartan cilexetil is converted to the active drug candesartan. The absolute bioavailability of candesartan was approximately 40% after an oral solution of candesartan cilexetil. The relative bioavailability of a tablet formulation of candesartan cilexetil compared with the same oral solution was approximately 34% with very little variability. The mean peak serum concentration (C_max) was reached 3‐4 hours following tablet intake. The candesartan serum concentrations increased linearly with increasing doses in the therapeutic dose range. No gender related differences in the pharmacokinetics of candesartan have been observed. The area under the serum concentration versus time curve (AUC) of candesartan was not significantly affected by food. Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution of candesartan is

0.1 l/kg

•    Amlodipine

The peak serum concentration of unchanged amlodipine was obtained 7‐8 hours following a single administration of amlodipine 1.25‐5 mg to healthy Japanese adults. The concentration of amlodipine in the serum eliminated biphasically. The half- life of elimination phase was about 40 hours. The pharmacokinetics of amlodipine was linear in the dose of 1.25‐5 mg and was not affected by food. In a European study, the bioavailability in healthy subjects after oral administration of amlodipine 10 mg was 64%. Plasma protein binding ratio of amlodipine is calculated as 97.1% (in vitro).

• Combination

Single dose (CPH-007, Japan)

After a single oral administration of a 5 mg/8 mg of amlodipine /candesartan cilexetil combination tablet to healthy adults under fasting, active metabolite candesartan and inactive metabolite M‐II and unchanged amlodipine were detected in the blood, but the unchanged candesartan cilexetil was undetected. Changes of blood concentrations of active metabolite candesartan and amlodipine are as indicated below.

Figure 1: Blood concentrations of active metabolite candesartan and amlodipine after a single oral Administration

 

Table 2: Pharmacokinetic parameters after a single oral administration

Measured compound	Cmax (ng/mL)	Tmax (h)	AUC0‐∞ (ng·h/mL)	T1/2 (h)
Candesartan	78.9±29.6	4.8±0.8	1,117.1±205.7	16.3±9.2
M‐II	10.3±3.3	8.3±3.1	346.3±103.1	19.2±7.5
Amlodipine	3.5±0.7	4.9±0.3	120.3±28.5	37.3±6.3

(Mean ± S.D., n=12)                                                                                       

Effect of meals (CPH-007, Japan)

When a 8 mg/5 mg of candesartan cilexetil/amlodipine combination tablet was administered to 12 healthy adults after meal, the C_max of active metabolite candesartan

Were about 2.1 times higher (under fasting: 78.9 ng/mL, after meal: 160.0 ng/mL) and the Cmax of active metabolite candesartan were about 1.2 times higher (under fasting: 1,171.1 ng•h/mL, after meal: 1,286.7 ng•h/mL) than those under fasting conditions. No changes were observed in the C_max and AUC of amlodipine.

Metabolism and elimination

• Candesartan cilexetil

Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4, but the effect on other cytochrome P450 isoenzymes is presently unknown. Based on in vitro data, no interaction would be expected to occur in vivo with drug whose metabolism is dependent upon cytochrome P450 isozymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The Terminal half‐life (t_1/2) of candesartan is approximately 9 hours. There is no accumulation following multiple doses. Total plasma clearance of candesartan is about 0.37 ml/min/kg, with a renal clearance of about 0.19 ml/min/kg. The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of 14C‐labelled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite while approximately 56% of the dose is recovered in the faeces as candesartan and 10% as the inactive metabolite.

• Amlodipine

Amlodipine is mainly metabolized by CYP3A4. In urine, amlodipine and nine metabolites are detected.

• Combination

After a single oral administration of a 8 mg/5 mg of candesartan cilexetil/amlodipine besilate combination tablet to 12 healthy Japanese adults, unchanged candesartan cilexetil was not detected in the urine, but the active metabolite candesartan, inactive metabolite M‐II and unchanged amlodipine were excreted in the urine. The 48‐hour cumulative urinary excretion rates were 11.9% for candesartan and M‐II combined, and 4.8% for unchanged amlodipine. (CPH‐007)

Pharmacokinetics in special populations

• Elderly

Candesartan cilexetil

In elderly subjects (over 65 years), C_max and AUC of candesartan were increased by approximately 50% and 80%, respectively in comparison to young subjects. However, the blood pressure response and the incidence of adverse events were similar after a given dose of candesartan cilexetil in young and elderly patients.

Amlodipine

When amlodipine was administered in a single dose, C_max and AUC in elderly hypertensive patients and young healthy subjects were 4.24 ng/mL and 2.63 ng/mL, and 116.9 h･ng/mL and 63.2 h･ng/mL respectively. They were significantly higher in elderly Patients, however, Tmax and T_1/2 were not significantly affected.

• Impaired renal function

Candesartan cilexetil

In patients with mild to moderate renal impairment, Cmax and AUC of candesartan increased during repeated dosing by approximately 50% and 70%, respectively, but the terminal t1/2 was not altered, compared to patients with normal renal function. The corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively. The terminal t_1/2 of candesartan was approximately doubled in patients with severe renal impairment. The pharmacokinetics in patients undergoing haemodialysis was similar to those in patients with severe renal impairment.

Amlodipine

In patients with renal impairment, C_max and AUC of amlodipine at single dose increased approximately 1.7 times compared to healthy subjects. T_1/2 was slightly longer without significant difference, but T_max was not altered in patients with renal impairment. During repeated dosing in patients with renal impairment, C_max and AUC increased approximately 3 and 4 times, respectively, compared with those at single dose, however, T_1/2 and Tmax were not altered. It was suggested that these are age‐related changes.

• Impaired hepatic function

Candesartan cilexetil

In patients with mild to moderate hepatic impairment, there was a 23% increase in the AUC of candesartan.

Amlodipine

After administration of amlodipine 2.5 mg in a single dose to 5 Japanese patients with hepatic cirrhosis (Child‐Pugh score A (mild) and B (moderate)), blood concentration increased significantly, T_1/2 slightly prolonged, and AUC was slightly higher than healthy adults, however, no significant differences were observed.

• Drug Interactions

Candesartan cilexetil

No drug interactions of clinical significance have been identified for candesartan cilexetil. Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril.

Amlodipine Reproductive toxicology

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour 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 (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.

Carcinogenesis, mutagenesis

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 patient weight of 50 kg

Candesartan

There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In preclinical safety studies candesartan had effects on the kidneys and on red cell parameters at high doses in mice, rats, dogs and monkeys. Candesartan caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). Effects on the kidneys (such as interstitial nephritis, tubular distension, basophilic tubules; increased plasma concentrations of urea and creatinine) were induced by candesartan which could be secondary to the hypotensive effect leading to alterations of renal perfusion. Furthermore, candesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells. These changes were considered to be caused by the pharmacological action of candesartan. For therapeutic doses of candesartan in humans, the hyperplasia/hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.

Foetotoxicity has been observed in late pregnancy (see section 4.6).

In preclinical studies in normotensive neonatal and juvenile rats, candesartan caused a reduction in body weight and heart weight. As in adult animals, these effects are considered to result from the pharmacological action of candesartan. At the lowest dose of 10 mg/kg exposure to candesartan was between 12 and 78 times the levels found in children aged 1 to <6 who received candesartan cilexetil at a dose of 0.2 mg/kg and 7 to 54 times those found in children aged 6 to <17 who received candesartan cilexetil at a dose of 16 mg. As a no observed effect level was not identified in these studies, the safety margin for the effects on heart weight and the clinical relevance of the finding is unknown.

The renin‐angiotensin‐aldosterone system plays a critical role in kidney development in utero. Renin‐angiotensin‐aldosterone system blockade has been shown to lead to abnormal kidney development in very young mice. Administering drugs that act directly on the renin‐ angiotensin‐aldosterone system can alter normal renal development. Therefore, children aged less than 1 year should not receive Candesartan Cilexetil (see section 4.3). Data from in vitro and in vivo mutagenicity testing indicate that candesartan will not exert mutagenic or clastogenic activities under conditions of clinical use.

There was no evidence of carcinogenicity.

 

 

• D‐Mannitol
• Hydroxypropyl Cellulose LF
• Microcrystalline Celluslose
• Polyethylene Glycol 6000
• Yellow Iron Oxide
• Croscarmellose Sodium
• Magnesium Stearate Vegetable Origin

Not applicable.

24 months

Store below 30°C

Aluminum/PVC‐Aclar blisters

Pack size: 30 Tablets

 

The patient must be instructed to remove the tablets from the press‐through package (PTP) before they are ingested. [It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, and this could result in serious complications such as mediastinitis.]