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CSP Fosinopril + HCTZ 24 November 2010 4.2 Posology and method of administration Renal impairment The usual dose of fosinopril sodium / HCTZ is recommended for patients with mild-to-moderate renal impairment (creatinine clearance >30 mL/min, serum creatinine roughly 3 mg/dL or 265 mol/L). However, fosinopril sodium / HCTZ is not recommended for patients with severe renal dysfunction (creatinine clearance <30 mL/min) since loop diuretics are preferred to thiazides. 4.3 Contraindications Fosinopril sodium / HCTZ is contraindicated in patients who are hypersensitive to this product, other angiotencin-converting enzyme (ACE) inhibitors, other sulfonamide-derived drugs (eg, thiazides), or any of the inactive components. Hypersensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma. Fosinopril sodium/HCTZ is also contraindicated in patients who are anuric. The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy. 4.4 Special warnings and precautions for use Head and Neck Angioedema: Angioedema has been seen in patients treated with ACE inhibitors, including fosinopril sodium. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and can be fatal. Emergency therapy, should be promptly instituted. Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of fosinopril; some cases required medical therapy. Intestinal Angioedema: Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C -1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving another ACE inhibitor, enalapril, sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore, caution should be used in patients treated with ACE inhibitors undergoing such desensitizations procedures. Anaphylactoid reactions during high-flux dialysis/lipoprotein apheresis membrane exposure: Anaphylactoid reactions have been reported in patients hemodialyzed with high-flux dialysis membranes while on therapy with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication. Fosinopril sodium ES/PSUR/ 0014/001 1/7 CSP November 2010 Neutropenia/Agranulocytosis: ACE inhibitors have been reported rarely to cause agranulocytosis and bone marrow depression; these occur more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Monitoring of white blood cell counts should be considered in such patients. Thiazide diuretics have been also reported rarely to cause agranulocytosis and bone marrow depression. Hypotension: Fosinopril can cause symptomatic hypotension; this occurs rarely, and is most likely to occur in patients who are volume- and/or salt-depleted as a result of prolonged diuretic therapy, salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with fosinopril sodium/HCTZ. In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria, azotemia, and rarely with acute renal failure and death. In such patients, fosinopril sodium/HCTZ therapy should be initiated under close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dose is increased. Thiazides may potentiate the action of other hypertensive drugs. In addition, the antihypertensive effects of thiazide diuretics may be increased in the postsympathectomy patient. Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor 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 ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. Fetal/Neonatal Morbidity and Mortality: When used in pregnancy, ACE inhibitors can cause injury and even death to the developing fetus. Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Impaired Renal Function: Fosinopril sodium / HCTZ should be used with caution in patients with severe renal disease (creatinine clearance <30 mL/min/1.73m2). Cumulative effects of HCTZ and HCTZ-associated precipitation of azotemia may occur in patients with impaired renal function. Also, as a consequence of fosinopril’s inhibiting the renin-angiotensin-aldosterone system, changes in renal function can occur in susceptible individuals. In hypertensive patients with renal artery stenosis in one or both kidneys, increases in blood urea nitrogen and serum creatinine may occur during treatment with an ACE inhibitor. These increases are usually reversible upon discontinuation of therapy. In such patients, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease develop increases in blood urea nitrogen and serum creatinine, usually minor or transient, when fosinopril was given concomitantly with a diuretic. This effect is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of fosinopril sodium / HCTZ may be required. Impaired Hepatic Function: Fosinopril sodium/HCTZ should be used with caution in patients with impaired hepatic function or progressive liver disease since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Patients with impaired liver function could develop elevated plasma levels of Fosinopril sodium ES/PSUR/ 0014/001 2/7 CSP November 2010 fosinopril. In a study in patients with alcoholic or biliary cirrhosis, the apparent total body clearance of fosinoprilat was decreased and the plasma AUC approximately doubled. Electrolyte Imbalance: Determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. Thiazides, including HCTZ, can cause fluid or electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Patients should be periodically observed for clinical signs or symptoms of fluid and electrolyte imbalance, such as dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea or vomiting. Although hypokalemia may develop when thiazide diuretics are used, especially with brisk diuresis or in the presence of severe cirrhosis, concurrent therapy with fosinopril reduces diuretic-induced hypokalemia. The net effect of fosinopril sodium/HCTZ may be to elevate, reduce or leave serum potassium unchanged. Chloride deficit is generally mild and usually does not require treatment. Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulceration, have not been seen. Thiazides should be discontinued before carrying out tests for parathyroid function. Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesemia. Metabolic Disorders: Hyperuricemia may occur, and an acute attack of gout may be precipitated in certain patients receiving thiazide therapy. Insulin requirements in diabetic patients may be altered and latent diabetes mellitus may become manifested during thiazide administration. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. Cough: Cough has been reported with the use of ACE inhibitors, including fosinopril. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough. Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, fosinopril may augment the hypotensive response. Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation ot activation of systemic lupus erythematosus. Paediatric use: Safety and effectiveness in children have not been established. Geriatric use: Among patients who received fosinopril/HCTZ in clinical studies, 20% were 65 to 75 years old. Overall differences in effectiveness or safety were not observed between these patients and younger patients; however, greater sensitivity of some older individuals cannot be ruled out. Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take fosinopril/HCTZ. 4.5 Interaction with other medicinal products and other forms of interaction Alcohol, barbiturates, or narcotics: Potentiation of thiazide diuretic-induced orthostatic hypotension may occur. Antacids: Antacids (aluminum hydroxide, magnesium hydroxide, and simethicone) may impair absorption of fosinopril sodium/HCTZ. Therefore, concomitant administration of these agents should be separated by 2 hours. Fosinopril sodium ES/PSUR/ 0014/001 3/7 CSP November 2010 Antidiabetic drugs (oral agents and insulin): Thiazides may elevate blood glucose levels; thus, dosage adjustments of antidiabetic agents may be necessary. Antigout medications: Dosage adjustments of antigout medication may be necessary, since HCTZ may raise the level of blood uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Calcium salts: Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly. Cholestyramine resin and colestipol HCl: May delay or decrease absorption of HCTZ. Thiazide diuretics should be taken at least one hour before or four to six hours after these medications. Lithium: Increased serum lithium levels and risk of lithium toxicity have been reported in patients receiving ACE inhibitors and/or diuretic agents concomitantly with lithium. Fosinopril sodium/HCTZ and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. Inhibitors of Endogenous Prostaglandin Synthesis: In some patients, these agents can reduce the effects of diuretics. Also, indomethacin has been reported to reduce the antihypertensive effect of other ACE inhibitors, especially in cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents (eg, aspirin) may have a similar effect. Other diuretics and antihypertensive medications: The thiazide component of fosinopril sodium/HCTZ may potentiate the actions of other antihypertensive drugs, especially ganglionic or peripheral adrenergicblocking drugs. HCTZ may interact with diazoxide; blood glucose, serum uric acid levels, and blood pressure should be monitored. Potassium supplements and potassium-sparing diuretics: Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of fosinopril sodium/HCTZ and such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently. Drugs used during surgery: The effects of nondepolarizing muscle relaxants, preanesthetics and anesthetics used in surgery (eg, tubocurarine chloride and gallamine triethiodide) may be potentiated by HCTZ; dosage adjustments may be required. Fluid and electrolyte imbalances should be monitored and corrected prior to surgery if feasible. Caution should be used in patients taking fosinopril sodium/HCTZ and pressor agents (eg, norepinephrine) who undergo surgery. Preanesthetic and anesthetic agents should be given in reduced dosage, and if possible, HCTZ therapy discontinued one week prior to surgery. Interference with serological testing: Fosinopril sodium/HCTZ may cause a false low measurement of serum digoxin levels with assays utilizing the charcoal absorption method. Other kits, which utilizes the antibody coated-tube method, may be used instead. Therapy with fosinopril sodium/HCTZ should be interrupted for a few days before carrying out tests for parathyroid function. 4.6 Pregnancy and lactation The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the second and third trimester 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. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be discontinued immediately, and, if appropriate, alternative therapy should be started. Fosinopril sodium 4/7 CSP November 2010 ES/PSUR/ 0014/001 Exposure to ACE inhibitor 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 ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 qnd 4.4). There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used. Lactation: Both fosinopril and HCTZ are detectable in breast milk. Because no information is available regarding the use of Fosinopril sodium / HCTZ during breastfeeding, Fosinopril sodium / HCTZ is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. 4.8 Undesirable effects The list of undesirable effects shown below is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories: very common (≥1/10), common (≥1/100, < 1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), and not known (cannot be estimated from the available data). System Organ Class Frequency MedDRA Terms Infections and infestations Common Upper respiratory tract infection Not known Pharyngitis, rhinitis Blood and lymphatic system disorders Not known Lymphadenopathy, leukopenia, neutropenia, , agranulocytosis, thrombocytopenia, anaemia (including aplastic anaemia and haemolytic anaemia) Metabolism and nutrition disorders Not known Gout, hypokalemia, hyponatremia, and hypochloremic alkalosis Psychiatric disorders Not known Depression, libido disorder Nervous system disorders Common Headache, dizziness Fosinopril sodium ES/PSUR/ 0014/001 5/7 CSP November 2010 System Organ Class Frequency MedDRA Terms Not known Somnolence, paraesthesia, hypoaesthesia, syncope, cerebrovascular accident Eye disorders Not known Visual disturbance Ear and labyrinth disorders Not known Tinnitus, vertigo Cardiac disorders Not known Arrhythmia, angina pectoris, myocardial infarction Vascular disorders Not known Hypotension, orthostatic hypotension, intermittent claudication, vasculitis necrotising, flushing Respiratory, thoracic and mediastinal disorders Common Cough, Not known Sinus congestion, respiratory distress, pneumonitis, pulmonary oedema, bronchospasm Gastrointestinal disorders Not known Nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, gastritis, oesophagitis, pancreatitis, dysgeusia Hepato-biliary disorders Not known Hepatitis, jaundice cholestatic Skin and subcutaneous tissue disorders Not known Angioedema, rash, StevensJohnson syndrome, purpura, pruritus, urticaria, photosensitivity reaction Musculoskeletal, connective tissue and bone disorders Common Musculoskeletal pain Not known Myalgia, muscle spasms, arthralgia Renal and urinary disorders Not known Pollakiuria, dysuria, renal failure Reproductive system and breast disorders Not known Sexual dysfunction General disorders and administration site conditions Common Fatigue Not known Oedema, chest pain, asthenia, pyrexia Fosinopril sodium ES/PSUR/ 0014/001 6/7 CSP November 2010 System Organ Class Frequency MedDRA Terms Investigations Not known Liver function test abnormal (transaminases increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased and blood bilirubin increased), blood electrolytes abnormal, blood uric acid abnormal, blood glucose abnormal, blood magnesium abnormal, blood cholesterol abnormal, blood triglycerides abnormal, blood calcium abnormal During clinical trials with fosinopril sodium/HCTZ, the incidence of adverse events in the elderly (65 years old) was similar to that seen in younger patients. 4.9 Overdose No specific information is available on the treatment of overdosage with fosinopril sodium/HCTZ; treatment should be symptomatic and supportive. Therapy with fosinopril sodium/HCTZ should be discontinued and the patient closely monitored. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures. Fosinopril is poorly removed from the body by hemodialysis or peritoneal dialysis. Fosinopril sodium ES/PSUR/ 0014/001 7/7 CSP November 2010