Duoforce Film coated tablets.

Treatment of mild to moderate essential hypertension in patients whose blood pressure is normalized with the individual components in the same doses as the proposed fixed dose combination of DUOFORCE.

Patients receiving valsartan and amlodipine from separate tablets may be switched to DUOFORCE containing the same component doses.

Posology

The recommended dose is one tablet per day (the 2 strengths are listed under section 2).

Special Population

In Elderly: Normal dosage regimens are recommended.

Children and adolescents: DUOFORCE is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy (see section 4.4).

Renal impairment: No dosage adjustment is required for patients with mild to moderate renal impairment. Patients with severe renal impairment dosages may need to be reduced (see section 4.4).

Hepatic impairment: Caution should be exercised when administering DUOFORCE to patients with hepatic impairment or biliary obstructive disorders (see section 4.4 and see section 4.8).

Method of administration

For Oral use. It is recommended to take DUOFORCE with some water.

DUOFORCE is contraindicated in:

• Hypersensitivity to any of the components of DUOFORCE listed in section 6.1.
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Aortic stenosis
• Severe renal function impairment (creatinine clearance less than 30 mL/min)
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.5).
• Concomitant use of fluoroquinolones with ACE inhibitors/Angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (Creatinine Clearance u2264 30mL/min) and in elderly patients.
• Porphyria.
• Lithium therapy: Concomitant administration with DUOFORCE may lead to toxic blood concentrations of lithium (see section 4.5).
• The concomitant use of DUOFORCE with aliskiren-containing products is contraindicated. (see sections 4.4 and 4.5)
• Severe hepatic impairment, biliary cirrhosis or cholestasis
• Severe hypotension
• Shock (including cardiogenic shock)
• Haemodynamically unstable heart failure or after an acute myocardial infarction
• Pregnancy and lactation (see Section 4.6).

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. When pregnancy is diagnosed, treatment with DUOFORCE should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Sodium- and/or volume-depleted patients

Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with amlodipine/valsartan in placebo-controlled studies. In patients with an activated renin-angiotensin system (such as volume- and/or salt-depleted patients receiving high doses of diuretics) who are receiving angiotensin receptor blockers, symptomatic hypotension may occur. Correction of this condition prior to administration of amlodipine/valsartan or close medical supervision at the start of treatment is recommended. If hypotension occurs with amlodipine/valsartan, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood pressure has been stabilized.

Hyperkalaemia

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels (see Section 4.3 and 4.5).

Renal artery stenosis

DUOFORCE should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine may increase in such patients.

Kidney transplantation

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

Hepatic impairment

Valsartan is mostly eliminated unchanged via the bile. The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Particular caution should be exercised when administering amlodipine/valsartan to patients with mild to moderate hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan.

Renal impairment

No dosage adjustment of amlodipine/valsartan is required for patients with mild to moderate renal impairment (GFR >30 mL/min/1.73 m2). Monitoring of potassium levels and creatinine is advised in moderate renal impairment.

Primary hyperaldosteronism

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

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 valsartan. Some of these patients previously experienced angioedema with other medicinal products, including angiotensin converting enzyme (ACE) inhibitors. Amlodipine/valsartan 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 valsartan. 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 aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

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.

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

There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of DUOFORCE, and aliskiren is therefore contraindicated (see section 4.3).

Interactions common to the combination

No drug and drug interaction studies have been performed with DUOFORCE and other medicinal products.

To be taken into account with concomitant use

Other antihypertensive medicines commonly used antihypertensive medicines (e.g. alpha blockers, diuretics) and other medicinal products which may cause hypotensive adverse effects (e.g. tricyclic antidepressants, alpha blockers for treatment of benign prostate hyperplasia) may increase the antihypertensive effect of the combination.

Interactions linked to amlodipine.

Concomitant use not recommended

Grapefruit or grapefruit juice: Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients, resulting in increased blood pressure lowering effects.

Caution required with concomitant use

CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required. Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co administered with clarithromycin.

CYP3A4 inducers (anticonvulsant medicines [e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, and primidone], rifampicin, Hypericum perforatum): Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).

Simvastatin: Co-administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose of simvastatin to 20 mg daily in patients on amlodipine.

Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Tacrolimus

There is a risk of increased tacrolimus blood levels when co administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

To be taken into account with concomitant use

Others: In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or ciclosporin.

Interactions linked to valsartan

Concomitant use not recommended

Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists, including valsartan. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use. If a diuretic is also used, the risk of lithium toxicity may presumably be increased further with amlodipine/valsartan.

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels: If a medicine that affects potassium levels is to be prescribed in combination with valsartan, monitoring of potassium plasma levels is advised.

Caution required with concomitant use

Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs: When angiotensin II antagonists are administered simultaneously with NSAIDs attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.

Inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir): The results of an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and of the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.

Dual blockade of the RAAS with ARBs, ACE inhibitors or aliskiren: Clinical trial data have shown that dual blockade of the RAAS through the combined use of ACE inhibitors, ARBs or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting medicine (see Sections 4.3, 4.4).

Others: In monotherapy with valsartan, no interactions of clinical significance have been found with the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

Concomitant use of fluoroquinolones and ACE inhibitors/Angiotensin receptor blockers: Concomitant use of fluoroquinolones and ACE inhibitors/Angiotensin receptor blockers may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).

Safety in pregnancy and lactation has not been established (see section 4.3). When pregnancy is planned or confirmed DUOFORCE should be discontinued. Women of childbearing potential / Contraception in males and females: Women of childbearing age should ensure effective contraception.

Pregnancy

DUOFORCE is contraindicated during pregnancy (see section 4.3) Medicines affecting the renin-angiotensin system, such as DUOFORCE, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women.

Breastfeeding

DUOFORCE is contraindicated during lactation. Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 u2013 7 %, with a maximum of 15 %. The effect of amlodipine on infants is unknown.

Fertility

There are no clinical studies on fertility with amlodipine/valsartan e.g. DUOFORCE.

Patients taking DUOFORCE and driving vehicles or using machines should take into account that dizziness or weariness may occasionally occur.

a. Tabulated list of adverse reactions

System Organ Class Description Frequency Amlodipine/valsartan Amlodipine Valsartan

Infections and infestations

• Nasopharyngitis
• Influenza

Blood and lymphatic system disorders

• Decrease in haemoglobin and in haematocrit
• Leukopenia
• Neutropenia
• Thrombocytopenia, sometimes with purpura

Immune system disorders

• Hypersensitivity

Metabolism and nutrition disorders

• Anorexia
• Hypercalcaemia
• Hyperglycaemia
• Hyperlipidaemia
• Hyperuricaemia
• Hypokalaemia
• Hyponatraemia

Psychiatric disorders

• Depression
• Anxiety
• Insomnia/sleep disturbances
• Mood swings
• Confusion

Nervous system disorders

• Coordination abnormal
• Dizziness
• Dizziness postural
• Dysgeusia
• Extrapyramidal syndrome
• Headache
• Hypertonia
• Paraesthesia
• Peripheral neuropathy, neuropathy
• Somnolence
• Syncope
• Tremor
• Hypoesthesia

Eye disorders

• Visual disturbance

Ear and labyrinth disorders

• Tinnitus
• Vertigo

Cardiac disorders

• Palpitations
• Syncope
• Tachycardia
• Dysrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation)
• Myocardial infarction

Vascular disorders

• Flushing
• Hypotension
• Orthostatic hypotension
• Vasculitis

Respiratory, thoracic and mediastinal disorders

• Cough
• Dyspnoea
• Pharyngolaryngeal pain
• Rhinitis

Gastro-intestinal disorders

• Change of bowel habit
• Constipation
• Diarrhoea
• Dry mouth
• Dyspepsia
• Gastritis
• Gingival hyperplasia
• Nausea
• Pancreatitis
• Vomiting
• Liver function test abnormal, including blood bilirubin increase
• Hepatitis

Skin and Subcutaneous tissue disorders

• Angioedema
• Alopecia
• Dermatitis bullous
• Erythema
• Erythema multiforme
• Exanthema
• Hyperhidrosis
• Photosensitivity reaction
• Pruritus
• Purpura
• Rash
• Skin discolouration
• Urticaria and other forms of rash
• Exfoliative dermatitis
• Stevens-Johnson syndrome
• Quincke oedema
• Toxic Epidermal Necrolysis

Musculo-skeletal and connective tissue disorders

• Back pain
• Joint swelling
• Muscle spasm
• Myalgia
• Ankle swelling
• Sensation of heaviness
• Increased blood creatinine

Renal and urinary disorders

• Micturition disorder
• Nocturia
• Pollakiuria
• Polyuria
• Renal failure and impairment

Reproductive system and breast disorders

• Erectile dysfunction

General disorders and Administration site conditions

• Discomfort, malaise
• Asthenia
• Fatigue
• Facial oedema
• Flushing, hot flush
• Non cardiac chest pain
• Oedema
• Pitting oedema
• Increased serum potassium

f. Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via The u20186.04 Adverse Drug Reactions Reporting Formu2019. Found under SAHPRAu2019s publications: https://www/sahpra.org.za/Publications/Index/8.

Symptoms

There is no experience of overdose with amlodipine/valsartan. The major symptom of overdose with valsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine may result in excessive peripheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported. Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support.

Treatment

If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption. Clinically significant hypotension due to amlodipine/valsartan overdose calls for active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Both valsartan and amlodipine are unlikely to be removed by haemodialysis.