Exforge 5/80 Uses, Dosage, Side Effects, Precautions & Warnings

Generic  drug of the Therapeutic class: Cardiology and angiology
Active ingredients: Valsartan , Amlodipine

what is Exforge ?

The combination of valsartan with amlodipine is used for high blood pressure, when an angiotensin II blocker or a diuretic alone does not lower blood pressure sufficiently.

PRESENTATION (S) AVAILABLE FOR EXFORGE 5 MG / 80 MG

4 presentations are available for this drug:

• 56 PVC PVDC blister (s) of 1 tablet (s)
• PVC PVDC blister pack (s) of 30 tablet (s)
• PVC PVDC blister (s) of 56 tablet (s)
• PVC PVDC blister (s) of 90 tablet (s)

FEATURE	DESCRIPTION
Pharmaceutical class	substances that affect the renin-angiotensin system
Active substance (s)	for one tablet: valsartan (80 mg), amlodipine besilate
General medicine	no
Pharmaceutical form	coated tablet
Route (s) of administration	oral
Social security reimbursement rate	65%
Laboratory	NOVARTIS PHARMA SAS
Conditions of issue	available by simple prescription

what is Exforge medication used for and indication?

Treatment of essential hypertension.

Exforge is indicated in adult patients whose blood pressure is not adequately controlled while taking amlodipine or valsartan as monotherapy.

Exforge  Dosage

Dosage

• The recommended dose of Exforge is one tablet per day.
• Exforge 5 mg / 80 mg can be administered in patients whose blood pressure is not sufficiently controlled with amlodipine 5 mg or valsartan 80 mg alone.
• Exforge 5 mg / 160 mg can be administered in patients whose blood pressure is not sufficiently controlled with amlodipine 5 mg or valsartan 160 mg alone.
• Exforge 10 mg / 160 mg can be administered in patients whose blood pressure is not adequately controlled with amlodipine 10 mg or valsartan 160 mg alone or with Exforge 5 mg / 160 mg.
• Exforge can be taken with or without food.
• Individual dose adjustment of each component (amlodipine and valsartan) is recommended before switching to the fixed dose combination. A direct switch from monotherapy to a fixed-dose combination may be considered if it is clinically justified.
• For convenience, patients taking valsartan and amlodipine separately as tablets or capsules, may instead take the dosage of Exforge corresponding to the same doses of both components.

Impaired kidney function

• There are no clinical data in patients with severely impaired renal function. No dosage adjustment is necessary in patients with mild to moderate renal impairment. In case of moderate deterioration of renal function, it is advisable to monitor potassium and creatinine levels.

Impaired liver function

• Exforge is contraindicated in patients with severely impaired hepatic function.
• Patients with impaired hepatic function or disorders due to obstruction of the bile ducts should be given special attention when using Exforge. .
• In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg. Amlodipine dosage recommendations have not been established in patients with mild to moderate hepatic impairment. When switching to amlodipine or Exforge in eligible hypertensive patients (see section Therapeutic indications) with impaired hepatic function, the lowest dose of amlodipine available as monotherapy or

Elderly subjects (65 years and over)

• Care is required when increasing doses in the elderly. When switching to amlodipine or Exforge in eligible elderly hypertensive subjects (see section Therapeutic indications), the lowest dose of amlodipine available as monotherapy or amlodipine in combination, respectively, should be used.

Pediatric population

• The safety and efficacy of Exforge in children below 18 years of age have not been established. No data is available.

Administration mode

• Oral route.
• It is recommended that Exforge be taken with water.

Exforge Contraindications

• Hypersensitivity to the active substances, to dihydropyridines or to any of the excipients listed in the Composition section.
• Severe deterioration of liver function, biliary cirrhosis or cholestasis.
• The combination of Exforge with medicinal products containing aliskiren in patients with diabetes or renal impairment (GFR <60 ml / min / 1.73 m2) (see sections Interactions with other medicinal products and other forms of ‘interactions and Pharmacodynamic properties).
• 2nd and 3rd trimesters of pregnancy (see Warnings and precautions for use and Pregnancy and breast-feeding sections).
• Severe hypotension.
• Shock (including cardiogenic shock).
• Obstruction of the left ventricular outflow tract (for example, obstructive hypertrophic cardiomyopathy and high degree aortic stenosis).
• Hemodynamically unstable heart failure after acute myocardial infarction.

how does Exforge work?

Linearity

• The pharmacokinetics of amlodipine and valsartan are linear.

Amlodipine

• Absorption: Following oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached within 6 to 12 hours. The absolute bioavailability ranges from 64 to 80%. The bioavailability of amlodipine is not affected by food.
• Distribution: the volume of distribution is approximately 21 l / kg. In vitro studies have shown that circulating amlodipine is approximately 97.5% bound to plasma proteins in hypertensive patients.
• Biotransformation: Amlodipine is almost completely (approximately 90%) metabolized in the liver to inactive metabolites.
• Elimination: The plasma elimination of amlodipine is biphasic, with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma concentrations are reached after 7-8 days of continuous administration. Ten percent of the parent drug and 60% of the metabolites are excreted in the urine.

Valsartan

• Absorption: Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached within 2 to 4 hours. The mean absolute bioavailability is 23%. Valsartan is characterized by multiexponential kinetic decay (t _½α <1 h and t _½ß approximately 9 h). Food decreases exposure (as measured by AUC) to valsartan by approximately 40% and maximum plasma concentration (C _max) by approximately 50%, although approximately 8 hours after administration, plasma levels of valsartan are similar whether the patient has been fasting or not. However, this reduction in AUC is not accompanied by a clinically significant reduction in the therapeutic effect and therefore valsartan can be administered with or without food.
• Distribution: The volume of distribution at steady state of valsartan following intravenous administration is approximately 17 liters, indicating that valsartan does not diffuse extensively into the tissues. Serum protein binding of valsartan is strong (94-97%); it mainly binds to albumin.
• Biotransformation: Valsartan does not undergo significant transformation since only about 20% of the dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.
• Elimination: Valsartan is eliminated primarily in the faeces (approximately 83% of the dose) and urine (approximately 13% of the dose), mainly as unchanged drug. After intravenous administration, the plasma clearance of valsartan is approximately 2 l / h and its renal clearance is 0.62 l / h (approximately 30% of the total clearance). The half-life of valsartan is 6 hours.

Amlodipine / valsartan

• After oral administration of Exforge, peak plasma concentrations of valsartan and amlodipine are reached within 3 and 6 to 8 hours, respectively. The rate and rate of absorption of Exforge is equivalent to the bioavailability of valsartan and amlodipine when administered as separate tablets.

Specific population groups

Children (under 18)

• No pharmacokinetic data are available in children.

Elderly subjects (65 years and over)

• The time to peak plasma concentration of amlodipine is similar in young patients and in elderly patients. In elderly patients, the clearance of amlodipine tends to decrease, resulting in increases in the area under the curve (AUC) and elimination half-life. The mean systemic exposure (AUC) of valsartan is 70% higher in the elderly compared to the young subject; therefore, caution is required when increasing the dosage.

Impaired kidney function

• The pharmacokinetics of amlodipine are not significantly influenced by impaired renal function. No correlation was found between renal function and systemic exposure to valsartan, which was expected with a substance whose renal clearance represents only 30% of the total plasma clearance.

Impaired liver function

• Patients with hepatic impairment experience decreased clearance of amlodipine resulting in an approximately 40-60% increase in AUC. In patients with mild to moderate chronic liver disease, exposure (measured by AUC values) to valsartan is on average twice as high as that found in healthy volunteers (matched for age, sex and the weight). The product should be administered with caution to patients with hepatic disease .

How To Store Exforge?

• Cip: 34009 3781759 2
• Storage conditions: Unopened: t <30 ° for 36 months (Store away from humidity, Store in its packaging).
• List 1
• Approved by Local
  Authorities Reimbursement: 65%

What are side effects of Exforge?

Summary of the safety profile

• The safety of Exforge has been evaluated in five controlled clinical studies in 5,175 patients, of which 2,613 received valsartan in combination with amlodipine. The following side effects occurred most frequently or are the most important or the most severe: nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, edema, edema with positive sign of the scoop, facial edema, peripheral edema, fatigue, flushing vasomotor, asthenia and hot flashes.

Tabulated list of adverse reactions

• Adverse reactions are classified by frequency as follows: very common (≥ 1/10); common (≥ 1/100, <1/10); uncommon (≥ 1 / 1,000, <1/100); rare (≥ 1 / 10,000, <1 / 1,000); very rare
• (<1 / 10,000); not known (frequency cannot be estimated from the available data).

System classes MedDRA organs	Side effects	Frequency
		Exforge	Amlodipine	Valsartan
Infections and infestations	Nasopharyngitis	Frequent	–	–
	Influenza	Frequent	–	–
Blood and lymphatic system disorders	Decreased hemoglobin and hematocrit	–	–	Frequency not known
	Leukopenia	–	Very rare	–
	Neutropenia	–	–	Frequency not known
	Thrombocytopenia, sometimes with purpura	–	Very rare	Frequency indeterminate
Immune system disorders	Hypersensitivity	Rare	Very rare	Frequency not known
Metabolism and nutrition disorders	Anorexia	Rare	–	–
	Hypercalcemia	Rare	–	–
	Hyperglycemia	–	Very rare	–
	Hyperlipidemia	Rare	–	–
	Hyperuricemia	Rare	–	–
	Hypokalaemia	Frequent	–	–
	Hyponatremia	Rare	–	–
Psychiatric disorders	Depression	–	Rare	–
	Anxiety	Rare	–	–
	Insomnia / sleep disturbances	–	Rare	–
	Mood disorders	–	Rare	–
	Confusion	–	Rare	–
Nervous system disorders	Coordination disorders	Rare	–	–
	Vertiginous sensations	Rare	Frequent	–
	Dizzying orthostatic sensations	Rare	–	–
	Dysgeusia	–	Rare	–
	Extra-pyramidal syndrome	–	Frequency not known	–
	Headache	Frequent	Frequent	–
	Hypertonia	–	Very rare	–
	Paresthesias	Rare	Rare	–
	Peripheral neuropathy, neuropathy	–	Very rare	–
	Drowsiness	Rare	Frequent	–
	Syncope	–	Rare	–
	Tremors	–	Rare	–
	Hypoaesthesia	–	Rare	–
Eye disorders	Visual disturbances	Rare	Rare	–
	Reduced vision	Rare	Rare	–
Ear and labyrinth disorders	Tinnitus	Rare	Rare	–
	Dizziness	Rare	–	Rare

Cardiac disorders	Palpitations	Rare	Frequent	–
	Syncope	Rare	–	–
	Tachycardia	Rare	–	–
	Arrhythmias (including bradycardia, ventricular tachycardia, and fibrillation little finger)	–	Very rare	–
	Myocardial infarction	–	Very rare	–
Vascular disorders	Flushing	–	Frequent	–
	Hypotension	Rare	Rare	–
	Orthostatic hypotension	Rare	–	–
	Vasculitis	–	Very rare	Frequency indeterminate
Respiratory, thoracic and mediastinal disorders	Cough	Rare	Very rare	Rare
	Dyspnea	–	Rare	–
	Pharyngolaryngeal pain	Rare	–	–
	Rhinitis	–	Rare	–
Gastrointestinal disorders	Abdominal discomfort, pain upper abdominal	Rare	Frequent	Rare
	Transit changes intestinal	–	Rare	–
	Constipation	Rare	–	–
	Diarrhea	Rare	Rare	–
	Dry mouth	Rare	Rare	–
	Dyspepsia	–	Rare	–
	Gastritis	–	Very rare	–
	Gingival hyperplasia	–	Very rare	–
	Nausea	Rare	Frequent	–
	Pancreatitis	–	Very rare	–
	Vomiting	–	Rare	–
Hepatobiliary disorders	Abnormal liver function test, including increased level bilirubin blood	–	Very rare*	Frequency not known
	Hepatitis	–	Very rare	–
	Intrahepatic cholestasis, jaundice	–	Very rare	–

Skin and subcutaneous tissue disorders	Alopecia	–	Rare	–
	Angioedema	–	Very rare	Frequency indeterminate
	Bullous dermatosis	–	–	Frequency indeterminate
	Erythema	Rare	–	–
	Erythema multiforme	–	Very rare	–
	Exanthema	Rare	Rare	–
	Hyperhidrosis	Rare	Rare	–
	Reactions photosensitivity	–	Rare	–
	Pruritus	Rare	Rare	Frequency indeterminate
	Purpura	–	Rare	–
	Skin rash	Rare	Rare	Frequency indeterminate
	Skin discoloration	–	Rare	–
	Urticaria and other forms rash	–	Very rare	–
	Exfoliative dermatitis	–	Very rare	–
	Stevens Syndrome Johnson	–	Very rare	–
	Angioedema	–	Very rare	–
	Epidermal necrolysis toxic	–	Frequency indeterminate	–
Musculoskeletal and connective tissue disorders	Arthralgia	Rare	Rare	–
	Back pain	Rare	Rare	–
	Joint swelling	Rare	–	–
	Muscle spasms	Rare	Rare	–
	Myalgia	–	Rare	Frequency indeterminate
	Ankle swelling	–	Frequent	–
	Feeling of heaviness	Rare	–	–
Kidney and urinary tract disorders	Rate increase blood creatinine	–	–	Frequency indeterminate
	Urination disorders	–	Rare	–
	Nocturia	–	Rare	–
	Pollakiuria	Rare	Rare	–
	Polyuria	Rare	–	–
	Kidney failure and impaired function renal	–	–	Frequency not known
Reproductive system and breast	Incapacity	–	Rare	–
	Erectile dysfunction	Rare	–	–
	Gynecomastia	–	Rare	–

General disorders and administration site conditions	Asthenia	Frequent	Rare	–
	Embarrassment, discomfort	–	Rare	–
	Tired	Frequent	Frequent	Rare
	Facial edema	Frequent	–	–
	Flushing, hot flashes	Frequent	–	–
	Chest pain no cardiac	–	Rare	–
	Edema	Frequent	Frequent	–
	Peripheral edema	Frequent	–	–
	Pain	–	Rare	–
	Edema with positive sign of bucket	Frequent	–	–
Investigations	Rate increase blood potassium	–	–	Frequency indeterminate
	Weight gain	–	Rare	–
	Weightloss	–	Rare	–

* Usually suggesting cholestasis Additional information on the combination

Peripheral edema, a known side effect of amlodipine, was generally seen at a lower incidence in patients who received amlodipine / valsartan than those who received amlodipine alone. In double-blind, controlled clinical trials, the dose-dependent incidence of peripheral edema was as follows:

% of patients who presented with peripheral edema		Valsartan (mg)
		0	40	80	160	320
Amlodipine (mg)	0	3.0	5.5	2.4	1.6	0.9
	2.5	8.0	2.3	5.4	2.4	3.9
	5	3.1	4.8	2.3	2.1	2.4
	10	10.3	N / A	N / A	9.0	9.5

• The mean incidence of peripheral edema, calculated from data obtained with each dose, was 5.1% with the amlodipine / valsartan combination.

Additional information on individual components

• Side effects previously reported with one of the individual ingredients (amlodipine or valsartan) may also be potential side effects with Exforge, even if they have not been seen in clinical trials or during the marketing.

Amlodipine

Frequent	Drowsiness, dizziness, palpitations, abdominal pain, nausea, ankle edema.
Rare	Insomnia, mood swings (including anxiety), depression, tremor, dysgeusia, syncope, hypoaesthesia, visual disturbance (including diplopia), tinnitus, hypotension, dyspnea, rhinitis, vomiting, dyspepsia, alopecia, purpura, discoloration skin, hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain, urination disorder, increased urinary frequency, impotence, gynecomastia, chest pain, malaise, increased urination weight, weight reduction.
Rare	Confusion.
Very rare	Leukocytopenia, thrombocytopenia, allergic reactions, hyperglycemia, hypertonia, peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, hepatic enzymes, elevation angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, angioedema, photosensitivity.
Undetermined	Toxic epidermal necrolysis

* usually suggesting cholestasis

• Exceptional cases of extrapyramidal syndrome have been reported.

Valsartan

Undetermined

Decreased hemoglobin, decreased hematocrit, neutropenia, thrombocytopenia, increased serum potassium, increased hepatic function values ​​including increased bilirubinemia, renal failure and renal function impairment, increased serum creatinine, angioedemas, myalgia, vasculitis, hypersensitivity including serum sickness.

Exforge Interactions

Amlodipine Interactions

Combinations requiring precautions for use

CYP3A4 inhibitors

• A study in elderly patients has shown that diltiazem inhibits the metabolism of amlodipine, possibly via CYP3A4 (the plasma concentration increases by approximately 50% and the effect of amlodipine is increased). The possibility that more potent CYP3A4 inhibitors (i.e., ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem is not excluded.
• CYP3A4 inducers (anticonvulsants [e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidon], rifampicin, St. John’s wort extract)
• Co-administration may result in decreased plasma concentrations of amlodipine. Clinical monitoring and possible dosage adjustment of amlodipine during treatment with the inducer and after its discontinuation is indicated.

Associations to take into account

Other

• As monotherapy, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual trinitrin / nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, antacids (aluminum hydroxide gel, magnesium hydroxide, simethicone), cimetidine, nonsteroidal anti-inflammatory drugs, antibiotics and oral hypoglycemic agents.

Interactions related to valsartan

Not recommended associations

Lithium

• Reversible increases in serum lithium up to toxic values ​​have been reported with concomitant administration of ACE inhibitors. Despite the lack of data on the concomitant use of valsartan and lithium, this combination is not recommended. If the use of such a combination proves necessary, strict monitoring of lithemia is recommended (see section Special warnings and precautions for use ).
• Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances likely to increase potassium levels Monitoring of serum potassium is recommended in the event of concomitant combination of a drug modifying potassium levels with valsartan .

Combinations requiring precautions for use

• Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g / day) and non-selective NSAIDs
• A decrease in the antihypertensive effect is possible with concomitant administration of angiotensin II antagonists and NSAIDs. Therefore, the concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening renal function and increased serum potassium. Therefore, monitoring of renal function at the start of treatment and hydration of the patient is recommended.

Other

• No clinically significant interaction has been demonstrated between valsartan administered as monotherapy and the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

Interactions common to the association

• No interaction studies have been performed with Exforge and other drugs.

Associations to take into account

Other antihypertensives

• Commonly used antihypertensive drugs (eg alpha blockers, diuretics) and other drugs that may cause hypotension as a side effect (eg tricyclic antidepressants, alpha blockers for the treatment of benign prostatic hyperplasia) may increase blood pressure. antihypertensive effect of the association.

Drive and use machines

• Patients receiving Exforge who drive motor vehicles or use machines should be informed that they may occasionally experience dizziness or fatigue.
• Amlodipine may have minor or moderate influence on the ability to drive and use machines. If patients treated with amlodipine experience dizziness, headache, fatigue or nausea, their ability to respond may be impaired.

Warnings and Precautions

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

Pregnancy

• Angiotensin II Receptor Antagonists (ARB II) should not be started during pregnancy. Patients planning to become pregnant should switch to alternative antihypertensive drugs with an established safety profile for use during pregnancy, unless continued ARB II therapy is considered essential. If pregnancy is diagnosed, treatment with an ARB II should be stopped immediately, and if necessary, alternative treatment should be started (see sections 4.3 and Pregnancy and breast-feeding).

Sodium and / or volume depletion

• Excessive hypotension was observed in 0.4% of patients treated with Exforge for uncomplicated hypertension in placebo-controlled studies. Symptomatic hypotension may occur in patients with an activated renin-angiotensin system (such as patients with volume and / or sodium depletion receiving high doses of diuretics) who receive treatment with angiotensin receptor antagonists. It is recommended to correct this hypotension before administration of Exforge or to institute close medical supervision at the start of treatment.
• If hypotension occurs with Exforge, place the patient in a supine position and infuse saline intravenously as needed. The treatment can be resumed once the blood pressure has stabilized.

Hyperkalaemia

• The concomitant intake of potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium or other drugs which may increase serum potassium levels (heparin, etc.) should be done with caution and be accompanied by ‘frequent monitoring of serum potassium.

Renal artery stenosis

• Exforge should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or single kidney arterial stenosis, since the possible increase in blood urea and serum creatinine in patients. such patients.

Kidney transplant

• To date, there is no experience of the safe use of Exforge in patients who have recently undergone kidney transplantation.

Impaired liver function

• Valsartan is eliminated primarily unchanged in the bile. The half-life of amlodipine is increased and its AUC (Area Under the Curve) is greater in patients with hepatic impairment; dosage recommendations have not been established. In case of administration of Exforge, special monitoring should be initiated in patients with mild to moderate impaired hepatic function or disorders due to obstruction of the bile ducts.
• In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg.

Impaired kidney function

• No dose adjustment of Exforge is necessary for mild to moderate renal impairment (GFR> 30 ml / min / 1.73 m²). In case of moderate deterioration of renal function, it is advisable to monitor potassium and creatinine levels.

Primary hyperaldosteronism

• Patients with primary hyperaldosteronism should not be treated with valsartan (angiotensin II antagonist); their renin-angiotensin system is altered by this disease.

Angioedemas

• Angioedema, including swelling of the larynx and glottis, leading to airway obstruction and / or swelling of the face, lips, pharynx and / or tongue has been reported in patients treated with valsartan. Some of these patients have had a history of angioedema with other drugs, including ACE inhibitors. Exforge should be discontinued immediately in patients who develop angioedema and should not be re-administered.

Heart failure / post myocardial infarction

• Due to the inhibition of the renin-angiotensin-aldosterone system, changes in renal function are to be expected in individuals at risk. In patients with severe heart failure whose renal function may be dependent on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors or angiotensin receptor antagonists has been associated with oliguria and / or a gradual increase in blood urea and (in rare cases) acute renal failure and / or death. Similar results have been reported with valsartan. Assessment of patients with heart failure or post myocardial infarction should always include an assessment of renal function.
• In a long-term, placebo-controlled study of amlodipine (PRAISE-2) in patients with New York Heart Association Classification (NYHA) grade III or IV non-ischemic heart failure, amlodipine has been associated with an increase in reported cases of pulmonary edema; however, the incidence of worsening heart failure versus placebo was not significant.
• Calcium channel blockers including amlodipine should be used with caution in patients with congestive heart failure because they may increase the risk of cardiovascular events and mortality.

Aortic and mitral stenosis

• As with all other vasodilators, patients with mitral stenosis or severe aortic stenosis that is not very tight should be given special attention.

Double blockage of the renin-angiotensin-aldosterone system (RAAS)

• The combination of ACEI, ARIII or aliskiren has been shown to increase the risk of hypotension, hyperkalaemia, and impaired renal function (including the risk of acute renal failure). Therefore, the double blockade of RAAS by the combination of ACE inhibitors, ARA II or aliskiren is not recommended (see sections 4.4 and Pharmacodynamic properties).
• However, if such a combination is considered absolutely necessary, it can only be done under the supervision of a specialist and with close and frequent monitoring of renal function, blood ionogram and blood pressure. ACE inhibitors and ARBs II should not be combined in patients with diabetic nephropathy.
• Exforge has only been studied in the hypertensive patient population.

PREGNANCY & BREAST-FEEDING & FERTILITY

Pregnancy

Amlodipine:

• In women, the safety of amlodipine during pregnancy has not been established. In animal studies, reprotoxicity has been observed at high doses ( see Preclinical Safety ). Use during pregnancy is only recommended if a safer alternative is not available and when the disease itself poses greater risks to the mother and the fetus.

Valsartan:

• The use of receptor antagonists of angiotensin II (ARA II) is not recommended during the 1 ^st  trimester of pregnancy ( see Warnings and Precautions ). The use of ARBs is against-indicated during the 2 ^e and 3 ^e  trimesters of pregnancy ( see Contraindications , Warnings and Precautions ).
• The available epidemiological data concerning the risk of teratogenicity after exposure to ACE inhibitors in the ^1st trimester of pregnancy do not allow to conclude; however, a small increase in risk cannot be excluded. Although there are no controlled epidemiologic data on the risk with angiotensin II receptor blockers (ARBs II), similar risks may exist for this class of drugs. Patients planning to become pregnant should switch to alternative antihypertensive drugs with an established safety profile for use during pregnancy, unless continued ARB II therapy is considered essential. If pregnancy is diagnosed, treatment with an ARB II should be stopped immediately, and, if necessary, alternative treatment should be started.
• In humans, exposure to treatment with ARB in the 2 ^e and 3 ^e  trimesters of pregnancy is known to induce fetal toxicity (decreased renal function, oligohydramnios, delay of ossification of cranial bones) and toxicity in newborns (renal failure, hypotension, hyperkalaemia): see Preclinical safety .
• If exposed to ARBs from 2 ^th  trimester of pregnancy, it is recommended to make an ultrasound check of renal function and the bones of the skull.
• Newborns born to mothers treated with ARA II should be closely monitored for blood pressure (hypotension): see Contraindications , Warnings and Precautions for use .

Feeding with milk

• Amlodipine is excreted in breast milk. The proportion of maternal dose received by the infant has been estimated at an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. No information is available regarding the use of Exforge during breastfeeding, therefore Exforge is not recommended and alternative treatments with more established breastfeeding safety profiles are preferable, particularly during breastfeeding. breastfeeding a newborn or premature baby.

Fertility

There are no clinical fertility studies with Exforge.

Valsartan:

• Valsartan has no effect on the reproductive capacity of male or female rats at oral doses up to 200 mg / kg / day. This dose corresponds to 6 times the recommended human dose expressed in mg / m ² (the calculations assume an oral dose of 320 mg / day and a patient’s weight of 60 kg).

Amlodipine:

• Reversible biochemical changes in the sperm head have been reported in some patients treated with calcium channel blockers. There is insufficient clinical data regarding the potential effect of amlodipine on fertility. In a study carried out in rats, adverse effects were detected on male fertility ( see Preclinical safety ).

What happens if I overdose from Exforge?

Symptoms

• There are no data regarding overdose with Exforge. The clinical picture of overdose with valsartan would likely be dominated by pronounced hypotension with dizziness. Overdosage with amlodipine could cause extensive peripheral vasodilation and possibly reflex tachycardia. Pronounced and possibly prolonged systemic hypotension up to fatal shock has been reported.

Treatment

• In case of recent ingestion, the possibility of inducing vomiting and performing gastric lavage should be considered. Administration of activated charcoal to healthy volunteers immediately after ingestion of amlodipine or within two hours afterwards significantly decreased the absorption of amlodipine. In the event of clinically significant hypotension due to overdose with Exforge, active cardiovascular supportive therapy, with frequent monitoring of cardiac and respiratory function, elevation of extremities, and control of blood volume and urine output should be initiated. A vasoconstrictor can be used to restore vascular tone and blood pressure, provided there are no contraindications to its use.
• It is unlikely that valsartan and amlodipine can be removed by hemodialysis.

What is  Forms and Composition ?

SHAPES and PRESENTATIONS

5 mg / 80 mg film-coated tablet (round, bevelled edge, debossed with “NVR” on one side and “NV” on the other side; dark yellow; approximate size: 8.20 mm in diameter), 5 mg / 160 mg (oval, imprinted “NVR” on one side and “ECE” on the other side; dark yellow; approximate size: 14.2 mm [length] x 5.7 mm [width]) and 10 mg / 160 mg (oval, debossed with “NVR” on one side and “UIC” on the other side; light yellow; approximate size: 14.2 mm [length] x 5.7 mm [width ]):   Boxes of 30 and 90, in blister packs of 10.

COMPOSITION

	p tablet
Amlodipine besilate expressed as amlodipine	5 mg	5 mg	10 mg
Valsartan	80 mg	160 mg	160 mg

Excipients (common): Tablet core: microcrystalline cellulose, crospovidone (type A), colloidal anhydrous silica, magnesium stearate. Coating: hypromellose, substitution type 2910 (3 mPa.s), titanium dioxide E 171, iron oxide yellow E 172, iron oxide red E 172 (10 mg / 160 mg tab), macrogol 4000, talc.

NOT’s

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Additional information:

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Special warnings:

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