Inhibace Plus - Product Information
|Condition:||Hypertension (High Blood Pressure)|
|Class:||Angiotensin converting enzyme inhibitors|
|Ingredients:||Cilazapril, Hydrochlorothiazide, Cornstarch, Hydroxypropyl methycellulose, Lactose, Red iron oxide, Sodium stearyl fumarate, Talc, Titanium dioxide|
Summary Product Information
|Route of Administration||Dosage Form / Strength||Non-medicinal Ingredients|
|Oral||Film-coated tablet (cilazapril/hydrochlorothiazide) 5 mg /12.5 mg||Cornstarch, hydroxypropyl methylcellulose, lactose, red iron oxide, sodium stearyl fumarate, talc, and titanium dioxide.|
Indications and Clinical Use
INHIBACE PLUS (cilazapril and hydrochlorothiazide) is indicated for treatment of mild to moderate essential hypertension in patients for whom combination therapy is appropriate.
In using INHIBACE PLUS consideration should be given to the risk of angioedema (see Warnings and Precautions).
Cilazapril should normally be used in those patients in whom treatment with diuretic or beta-blocker was found ineffective or has been associated with unacceptable adverse effects.
INHIBACE PLUS is not indicated for initial therapy. Patients in whom cilazapril and diuretic are initiated simultaneously can develop symptomatic hypotension (see Warnings and Precautions; Drug Interactions).
Patients should be titrated on the individual drugs. If the fixed combination represents the dosage determined by this titration, the use of INHIBACE PLUS may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary, it is advisable to use individual drugs.
The safety and efficacy of INHIBACE PLUS in congestive heart failure and renovascular hypertension have not been established and therefore, its use in these conditions is not recommended.
The safety and efficacy of concomitant use of INHIBACE with antihypertensive agents other than thiazide diuretics have not been established.
Although clinical experience has not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out (see Warnings and Precautions, ACTIONS AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
The safety and effectiveness of the use of INHIBACE PLUS in children have not been established. Therefore, use in this age group is not recommended.
INHIBACE PLUS (cilazapril and hydrochlorothiazide) is contraindicated in:
- Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
- Patients with hereditary/idiopathic angioedema or a history of angioedema related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor (see Warnings and Precautions, General).
- Patients with ascites.
- Patients hypersensitive to thiazides and other sulfonamide-derived drugs, because of the hydrochlorothiazide component.
- Patients with anuria
- Women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraception (see Warnings and Precautions, Special Populations, Pregnant Women and Adverse Reactions)
- Nursing women (see Warnings and Precautions, Special Populations, Nursing Women).
- Combination with aliskiren-containing drugs in patients with:
- diabetes mellitus (type 1 or type 2) or
- moderate to severe renal impairment (GFR < 60 ml/min/1.73m2) (see Warnings and Precautions, Dual Blockade of the Renin-Angiotensin System (RAS) and Renal, and Drug Interactions: Dual Blockade of the Renin- Angiotensin-System (RAS) with ACE inhibitors, ARBs or aliskiren-containing drugs).
- Patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the Lapp lactase deficiency as INHIBACE PLUS contains lactose (see Warnings and Precautions, Sensitivity/Resistance)
Warnings and Precautions
Serious Warnings and Precautions
The use of INHIBACE PLUS (cilazapril and hydrochlorothiazide) is contraindicated during pregnancy (see Contraindications). When used in pregnancy, angiotensin converting enzyme (ACE) inhibitors can cause injury or even death of the developing fetus. Pregnant women should be informed of the potential hazards to the fetus and must not take INHIBACE PLUS during pregnancy. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is detected, INHIBACE PLUS should be discontinued as soon as possible and, if appropriate, alternative therapy should be started (see Warnings and Precautions).
Angioedema has been reported in patients treated with angiotensin-converting enzyme inhibitors including INHIBACE PLUS (cilazapril and hydrochlorothiazide).
Angioedema has been associated with ACE inhibitors, with a reported incidence of 0.1- 0.5%. Angioedema due to ACE inhibitors can present as recurrent episodes of facial swelling, which resolve on withdrawal, or as acute oropharyngeal edema and potentially life-threatening airway obstruction, which requires emergency treatment. Angioedema associated with laryngeal edema and/or shock may be fatal. If angioedema occurs, INHIBACE PLUS should be promptly discontinued and appropriate therapy instituted without delay. A variant form is angioedema of the intestine, which tends to occur within the first 24-48 hours of treatment.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at an increased risk of angioedema while receiving an ACE inhibitor (see Contraindications).
Concomitant use of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors or dipeptidyl peptidase IV (DPP-IV) inhibitors may lead to an increased risk for angioedema. Caution should be used when using mTOR inhibitors or DPP-IV inhibitors concomitantly with ACE inhibitors (see Drug Interactions, Drug-Drug Interactions).
Aortic Stenosis/Hypertrophic Cardiomyopathy
As with other ACE inhibitors, INHIBACE PLUS should be used with caution in patients with obstructive cardiac disorders (e.g. mitral stenosis, aortic stenosis, hypertrophic cardiomyopathy), since cardiac output cannot increase to compensate for systemic vasodilation, and there is a risk of severe hypotension.
There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.
Patients should start treatment with INHIBACE PLUS only after they have been stabilized on each component given at the same dose as in the combined product. First-dose hypotension is most likely to occur in patients whose renin-angiotensin-aldosterone system is activated, such as in renovascular hypertension or other causes of renal hypoperfusion, sodium or volume depletion, or previous treatment with other vasodilators and in patients with dietary salt restriction, dialysis, diarrhea, or vomiting. These conditions can co-exist, particularly in severe heart failure.
Because of the potential fall in blood pressure in these patients, therapy with INHIBACE PLUS should be started under very close medical supervision, and patients should be followed closely for the first two weeks of treatment. Patients at risk for hypotension should start treatment with INHIBACE PLUS with a low initial dose and careful titration. Similar caution should be taken for patients with angina pectoris or cerebrovascular disease, in whom hypotension can cause myocardial or cerebral ischaemia.
Hypotension should be treated by placing the patient supine and volume expansion. INHIBACE PLUS may be continued once the patient is volume replete, but should be given at a lower dose or discontinued if hypotension persists.
Dual Blockade of the Renin-Angiotensin System (RAS)
There is evidence that co-administration of angiotensin converting enzyme (ACE) inhibitors, such as the cilazapril component in INHIBACE PLUS, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR < 60 ml/min/1.73m2). Therefore, the use of INHIBACE PLUS in combination with aliskiren-containing drugs is contraindicated in these patients (see Contraindications).
Further, co-administration of ACE inhibitors, including the cilazapril component of INHIBACE PLUS, with other agents blocking the RAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia.
A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of INHIBACE PLUS, has been reported.
Such possibility should be considered as part of the differential diagnosis of the cough.
Endocrine and Metabolism
Thiazides may increase serum uric acid levels and may precipitate acute gout. INHIBACE PLUS should be used with caution in patients with a history of gout.
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Thiazides have been shown to increase excretion of magnesium; this may result in hypomagnesemia.
Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests of parathyroid function.
Increases in cholesterol, triglyceride and glucose levels may be associated with thiazide diuretic therapy.
Hyperglycemia may occur with thiazide diuretics in diabetic patients. Dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.
Administration of ACE inhibitors to patients with diabetes may potentiate the blood glucose-lowering effect of oral hypoglycemic agents or insulin, especially in patients with renal impairment. In such patients, glucose levels should be carefully monitored during initiation of treatment with INHIBACE PLUS.
ACE inhibitors are less effective as antihypertensives in black-skinned patients of African descent. Black-skinned patients also have a higher risk of angioedema.
Thrombocytopenia, neutropenia and agranulocytosis have been caused by both ACE inhibitors and thiazides. Bone marrow depression has been caused by ACE inhibitors. Cases of leucopenia and neutropenia have rarely been reported in patients treated with ACE inhibitors. Periodic monitoring of white blood cell counts should be considered in patients with collagen vascular disease and renal disease such as systemic lupus erythematosus and scleroderma, or in patients receiving immunosuppressive therapy, especially when they also have impaired renal function.
Hydrochlorothiazide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.
Autoimmune hemolytic anemia has been reported with thiazides.
Patients with Impaired Liver Function
Hepatitis (hepatocellular and/or cholestatic), jaundice, elevations of liver enzymes and/or serum bilirubin have occurred during therapy with cilazapril in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug.
Cases of liver function disorders, such as increased values of liver function tests (transaminases, bilirubin, alkaline phosphatase, gamma GT) and cholestatic hepatitis have been reported. Patients receiving cilazapril who develop jaundice or marked elevations of hepatic enzymes should discontinue cilazapril and receive appropriate medical follow-up.
There are no adequate studies in patients with cirrhosis and/or liver dysfunction. INHIBACE PLUS should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.
In patients with liver cirrhosis (but without ascites) who require therapy for hypertension, INHIBACE PLUS should be initiated with great caution because significant hypotension may occur. In patients with ascites, INHIBACE PLUS is not recommended.
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.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease and liver function should be monitored closely since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Anaphylactoid Reactions During Membrane Exposure
Hemodialysis: Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., polyacrylonitrile [PAN], AN 69) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Anaphylactoid Reactions During Low Density Lipoproteins (LDL) Apheresis
Patients receiving ACE inhibitors during (LDL apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Anaphylactoid Reactions During Desensitization
There have been reports of patients experiencing sustained life threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.
Cilazapril use must be stopped before the start of desensitization therapy and must not be replaced by a beta-blocker.
Nitritoid Reactions - Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and symptomatic hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including INHIBACE PLUS (see Drug Interactions).
Acute Myopia and Secondary Angle-Closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss.
The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulphonamide or penicillin allergy.
In patients undergoing major surgery or during anesthesia with agents that produce hypotension, cilazapril blocks angiotensin II formation, secondary to compensatory renin release. This may result in arterial hypotension which can be corrected by volume expansion.
Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease the diuretic should be discontinued.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with ACE inhibitors may produce increases in blood urea nitrogen and/or serum creatinine and has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. Although these alterations are usually reversible upon discontinuation of cilazapril and/or diuretic therapy, cases of severe renal dysfunction and, rarely, acute renal failure have been reported. In susceptible patients, concomitant diuretic use may further increase risk.
Use of INHIBACE PLUS should include appropriate assessment of renal function.
When treated with cilazapril, patients with renal artery stenosis have an increased risk of renal insufficiency, including acute renal failure. Therefore, caution should be exercised in these patients.
In the patient populations as described above, renal function should be monitored during the first weeks of therapy. If renal failure occurs, treatment should be discontinued.
Reduced dosages may be required for patients with renal impairment depending on their creatinine clearance (see Dosage and Administration, Dosage Adjustment in Patients with Renal Impairment).
Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (i.e. moderate or severe renal insufficiency).
The use of ACE inhibitors - including the cilazapril component of INHIBACE PLUS - or ARBs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR < 60 ml/min/1.73m2). (See Contraindications and Drug Interactions, Dual Blockade of the Renin-Angiotensin-System (RAS) with ACE inhibitors, ARBs or aliskiren containing drugs).
Hypersensitivity to Hydrochlorothiazide
Sensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma.
Exacerbation or activation of systemic lupus erythematosus has been reported in patients treated with hydrochlorothiazide.
INHIBACE PLUS tablets contain lactose. Therefore, patients with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine (see Contraindications).
ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes) or potassium-sparing diuretics, and especially aldosterone antagonists, hyperkalemia can occur. Potassium-sparing diuretics should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored.
In clinical trials, elevated serum potassium (greater than 5.5 mEq/L) was observed in approximately 0.7% of hypertensive patients receiving cilazapril alone. In most cases these were isolated values which resolved despite continued therapy, however, in one case the patient discontinued treatment. In clinical trials, hyperkalemia was rarely seen in patients using INHIBACE PLUS. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia (see Drug Interactions and Adverse Reactions). Frequent monitoring of serum potassium may be advisable if these risk factors are present.
Thiazides increase potassium excretion and can cause hypokalemia. Hypokalemia may also occur in patients receiving INHIBACE PLUS, although to a lesser extent than that seen in patients receiving thiazide monotherapy. In patients receiving INHIBACE PLUS, the hypokalemic effect of hydrochlorothiazide alone is usually attenuated by the effect of cilazapril. Thiazides may decrease urinary calcium excretion and cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism.
Thiazides may also cause hyponatremia and dehydration. The risk of hyponatremia is greater in women, patients with hypokalemia or low sodium/solute intake, and in the elderly.
Electrolytes and renal function should be monitored in patients receiving INHIBACE PLUS.
ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. The use of INHIBACE PLUS is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the fetus and must not take INHIBACE PLUS during pregnancy (see contraindications). 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 INHIBACE PLUS should be stopped immediately, and, if appropriate, alternative therapy should be started.
Fetal exposure to ACE inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly, spina bifida) and of kidney malformations.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (hypotension, hyperkalemia, neonatal skull hypoplasia, intrauterine growth restriction, anuria, renal tubular dysplasia, reversible or irreversible renal failure and death). Oligohydramnios reported with the use of ACE inhibitors presumably resulted from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound examination of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension.
Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.
Dialysis clearance was estimated to be 2.4 L/h for cilazapril and 2.2-2.8 L/h for cilazaprilat. There is limited experience with hydrochlorothiazide during pregnancy. Thiazides cross the placenta. There have been reports of neonatal jaundice, thrombocytopenia and electrolyte imbalances after maternal use. Reductions in maternal blood volume could also adversely affect placental perfusion.
In fertility and general reproduction performance testing in rats, dosing with 50 mg/kg/day of cilazapril resulted in greater implantation losses, less viable fetuses, smaller pups, and dilatation of the renal pelvis in the pups. No teratogenic effects and no adverse effects on postnatal pup development were observed in rats and cynomolgus monkeys during embryotoxicity testing. In the rats, however, at a dose of 400 mg/kg/day, renal cavitation was observed in the pups. In peri- and post-natal toxicity testing in rats, dosing with 50 mg/kg/day resulted in greater pup mortality, smaller pups, and delayed unfolding of the pinna. On administration of 14C-cilazapril to pregnant mice, rats and monkeys, radioactivity was measured in the fetuses.
No teratogenicity was observed when pregnant mice were treated orally (gavage) with up to 2,400 mg/kg/day (400 mg/kg/day CLZ and 2,000 mg/kg/day HCTZ) of a 1:5 cilazapril/hydrochlorothiazide combination from gestation days 6 through 15. In fetuses from dams treated with 300 mg/kg/day (50 mg/kg/day CLZ and 250 mg/kg/day HCTZ), there was an increased incidence of reduced frontal bone ossification and at 2,400 mg/kg/day (400 mg/kg/day CLZ and 2,000 mg/kg/day HCTZ) there was an increased incidence of reduced frontal and parietal bone ossification, misaligned sternebrae and sternebrae variants, as well as an increased incidence of dilated renal pelvises. All these effects are considered to represent developmental delays (see Toxicology, Table 12).
No teratogenicity was observed when pregnant rats were treated orally (gavage) with up to 37 mg/kg/day (6 mg/kg/day CLZ and 31 mg/kg/day HCTZ) of a 1:5 cilazapril/hydrochlorothiazide combination from gestation day 7 through 17. At 96 (16 mg/kg/day CLZ and 80 mg/kg/day HCTZ) and 240 mg/kg/day (40 mg/kg/day CLZ and 200 mg/kg/day HCTZ), fetal body weight was decreased resulting in decreased or absent ossification of a variety of bones in litters of dams given 240 mg/kg/day (see Toxicology, Table 12).
Animal data show the presence of cilazaprilat in rat milk. However, no information is available regarding the safety of cilazapril during breast-feeding in humans. The presence of concentrations of ACE inhibitor have been reported in human milk. Use of ACE inhibitors is not recommended during breast-feeding. INHIBACE PLUS must not be administered to nursing mothers (see Contraindications) and alternative treatments with better established safety profiles during breast-feeding are preferable. Furthermore, thiazides do appear in human milk.
In rats, it has been shown that after the oral administration of cilazapril, cilazaprilat is excreted in milk at concentrations resembling those in plasma.
Ability to Drive and Use Machines
Occasionally dizziness and fatigue may occur, especially when starting therapy (see Adverse Reactions).
The safety and effectiveness of the use of INHIBACE PLUS in children have not been established. Therefore, use in this age group is not recommended.
Although clinical experience has not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out (see Indications and Clinical Use, Actions and Clinical Pharmacology and Dosage and Administration).
Adverse Drug Reaction Overview
INHIBACE PLUS (cilazapril and hydrochlorothiazide) has been evaluated for safety in 4,102 individuals (3,992 patients treated for essential hypertension and 110 normal volunteers enrolled in pharmacokinetic studies). In controlled clinical trials, 1,097 patients received the combination, cilazapril and hydrochlorothiazide, 225 received placebo, 437 received cilazapril alone and 340 received hydrochlorothiazide alone.
The most serious adverse reactions reported included hypotension (0.3%) and angioedema (0.1%). The most frequent adverse reactions reported for the cilazapril/hydrochlorothiazide combination were: headache (5.5%), dizziness (3.9%), fatigue (2.8%), coughing (2.6%), and somnolence (1.2%). Discontinuation of treatment due to adverse events occurred in 2.7% of patients.
Adverse events that have occurred have been those that were previously reported with cilazapril or hydrochlorothiazide when used separately for the treatment of hypertension.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
See table 1 for common adverse reactions (≥1%) reported by hypertensive patients treated with INHIBACE PLUS. The frequencies of ADRs from clinical trials for patients treated with INHIBACE, hydrochlorothiazide alone, and placebo alone in controlled clinical trials are also tabulated below. For comparison, adverse reactions tabulated for patients treated with cilazapril alone are as reported in the Product Monograph for INHIBACE (cilazapril) tablets.
|Body System / Adverse Reaction||Cilazapril (N=2586)||Cilazapril plus Hydro chlorothiazide (N=1097)||Hydro chlorothiazide (N=340)||Placebo (N=225)|
Less Common Clinical Trial Adverse Drug Reactions (<1%)
Adverse reactions reported by patients treated with INHIBACE PLUS at a frequency <1% are as follows:
Palpitation (0.9%), Chest Pain (0.4%), Tachycardia (0.3%), Angina Pectoris (0.3%), Hypotension (0.3%), Postural Hypotension (0.1%), Oedema Peripheral (0.3%), Oedema Dependent (0.2%), Extrasystoles (0.2%), Myocardial Infarction (0.2%). Reported ≤0.1% were: Atrial Fibrillation, Bradycardia.
Hypoaesthesia (0.3%), Paresthesia (0.3%), Vertigo (0.2%), Impotence (0.4%), Mouth Dry (0.3%), Sweating Increased (0.4%), Anxiety (0.2%), Depression (0.3%), Insomnia (0.1%), Nervousness (0.2%), Confusion (0.3%), Libido Decreased (0.2%). Reported ≤0.1% were: Libido Increased, Crying Abnormal, Paroniria, Dreaming Abnormal, Depersonalization, Neurosis.
Rhinitis (0.7%), Upper Respiratory Tract Infection (0.1%), Pharyngitis (0.2%), Sinusitis (0.2%), Bronchitis (0.1%), Dyspnea (0.4%).
Abdominal Pain (0.7%), Dyspepsia (0.7%), Diarrhea (0.5%), Flatulence (0.2%), Constipation (0.3%). Reported ≤0.1% were: Anorexia, Melena, Vomiting.
Rash (0.8%), Pruritus (0.4%). Reported ≤0.1% were: Dermatitis, Angioedema, Dry Skin.
Back Pain (0.6%), Leg Cramps (0.6%), Arthralgia (0.3%), Myalgia (0.4%).
Asthenia (0.6%), Malaise (0.3%), Hot Flushes (0.2%). Reported ≤0.1% were: Pain, Allergy, Face Oedema, Fever, Weight Increase, Rigors, Hypothermia, Polyuria, Nocturia, Flushing, Peripheral Ischemia, Cerebrovascular Disorder, Vasodilation, Vision Abnormal, Diplopia, Tinnitis, Ear Blockage, Purpura, Bleeding Time Increased, Gout, Thirst, Leukorrhea.
Abnormal Hematologic and Clinical Chemistry Findings
One thousand and ninety-seven patients received the combination test treatment. Clinically relevant laboratory abnormalities were reported most frequently for placebo. Laboratory abnormalities occurring in ≥1% of these patients were assessed as comparable with placebo except for the following parameters: low absolute neutrophil count, low potassium, low cholesterol-HDL, high glucose, high uric acid, high phosphorus and WBC in urine quantitative. Except for low cholesterol-HDL, all the above laboratory parameters were reported at equivalent or higher incidence for cilazapril alone or hydrochlorothiazide alone. Definitive evaluation of the effect of INHIBACE PLUS on cholesterol-HDL was not possible because controlled diet was not included in the design of this placebo-controlled trial.
Clinically relevant changes in neutrophil count (1.5% of patients), white blood cell count (0.3% of patients) and low hemoglobin count (0.3% of patients) were observed. These abnormalities were comparably reported for placebo (1.3%, 0.4%, and 0.9%, respectively).
Liver Function Tests
Clinically relevant changes in the values associated with liver function occurred in up to 0.6% of patients as follows: High SGPT (0.6%) and high SGOT (0.4%).
Clinically relevant changes in renal function test results occurred in 0.4% of patients as follows: High BUN (0.4%).
Decreased serum sodium (<130 mEq/L) reported in 0.3% of patients, upon further review was not observed to be clinically relevant as two patients experienced no clinical symptoms and the third incidence of decreased serum sodium was caused by laboratory sample mishandling.
Leukopenia and Neutropenia
Neutropenia was observed in 1% (11/1,097) of patients administered cilazapril/hydrochlorothiazide during the controlled clinical trials. These eleven patients had neutropenia with a neutrophil count <1,000. Ten of these patients had no clinical symptoms associated with these reported findings. In many of these cases, the findings were transient and believed to be due to laboratory handling problems. Some patients had a neutrophil count between 1,000 and 2,000 but none were associated with clinically serious adverse experiences. None of the patients evaluated during the study developed leukopenia (defined as a leukocyte count of <2,000).
Post-Market Adverse Drug Reactions
The following adverse reactions have been seen in association with cilazapril and/or other ACE inhibitors alone, hydrochlorothiazide and/or other thiazide-type diuretics alone, and in those receiving combined therapy.
|Frequency categories are as follows1:|
|Very common ≥ 1/10|
|Common ≥ 1/100 and < 1/10|
|Uncommon < 1/100|
1 Estimates of frequency are based on the proportion of patients reporting each adverse reaction during Inhibace Plus clinical trials that included a total combined population of 1,097 patients. Adverse reactions that were not observed during Inhibace Plus clinical trials but have been reported in association with monotherapy with either component or with other ACE inhibitors or thiazide diuretics, or derived from post-marketing case reports, are classified as 'uncommon' (<1/100). The category 'uncommon' incorporates 'rare' (≥1/10'000 and <1/1'000) and 'very rare' (<1/10'000).
The frequency of adverse reactions attributable to cilazapril, occurring in patients receiving combination therapy (cilazapril+hydrochlorothiazide), may differ from that seen in patients receiving cilazapril monotherapy. Reasons may include (i) differences between the target populations treated with Inhibace Plus and Inhibace, (ii) differences in cilazapril dose, and (iii) specific effects of combination therapy.
Adverse reactions to cilazapril
The most common adverse effects with cilazapril include dry cough, rash, hypotension, dizziness, fatigue, headache, and nausea, dyspepsia and other gastrointestinal disturbances.
Blood and Lymphatic Systems Disorders
Blood disorders have been reported with ACE Inhibitors and include neutropenia and agranulocytosis (especially in patients with renal failure and those with collagen vascular disorders such as systemic lupus erythematosus and scleroderma), thrombocytopenia, and hemolytic anemia.
Uncommon:Neutropenia, agranulocytosis, thrombocytopenia, anemia
Pronounced hypotension may occur at the start of therapy with ACE inhibitors, particularly in patients with heart failure and in sodium- or volume depleted patients. Myocardial infarction and stroke have been reported and may relate to severe falls in blood pressure in patients with ischaemic heart disease or cerebrovascular disease. Other cardiovascular effects that have occurred include tachycardia, palpitations, and chest pain.
Uncommon:Myocardial infarction , tachycardia, palpitations, angina pectoris
Uncommon:Hypotension (sometimes severe, see Warnings and Precautions) Symptoms of hypotension may include syncope, weakness, dizziness and visual impairment.
Respiratory, Thoracic and Mediastinal Disorders
Common:Cough (sometimes severe)
As for other ACE inhibitors, isolated cases of pancreatitis, in some cases fatal, have been reported in patients treated with INHIBACE PLUS.
Single cases of liver function disorders, such as increased liver function tests (transaminases, bilirubin, alkaline phosphatase, gamma GT) and cholestatic hepatitis with or without necrosis, have been reported (see Warnings and Precautions).
Uncommon:Abnormal liver function test (including transaminases, bilirubin, alkaline phosphatase, gamma GT), cholestatic hepatitis with or without necrosis .
Immune System Disorders
As with other ACE inhibitors, angioneurotic edema has been reported in patients receiving cilazapril (see Warnings and Precautions). Since this syndrome can be associated with laryngeal edema, cilazapril should be discontinued and appropriate therapy instituted without delay when involvement of the face, lips, tongue, glottis and/or larynx occurs.
Uncommon:Angioedema (may involve the face, lips, tongue, glottis, larynx or gastrointestinal tract, see Warnings and Precautions), anaphylaxis (see Warnings and Precautions), lupus-like syndrome (symptoms may include vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies, increased erythrocyte sedimentation rate, eosinophilia and leukocytosis).
Nervous System Disorders
Uncommon:Dysgeusia, transient ischaemic attack, ischaemic stroke (may be related in some cases to hypotension in patients with underlying cerebrovascular disease)
Skin and Subcutaneous Tissue Disorders
Skin rashes (including pemphigus, Stevens-Johnson syndrome, erythema multiforme and toxic epidermal necrolysis) may occur; photosensitivity, alopecia, and other hypersensitivity reactions have also been reported. Other reported skin reactions include vasculitis, erythema multiforme and pseudoporphyria.
Uncommon:Toxic epidermal necrolysis, Stevens-Johnson syndrome, ,erythema multiforme, pemphigus, bullous pemphigoid, exfoliative dermatitis, psoriaform dermatitis, psoriasis (exacerbation), lichen planus, urticaria, vasculitis, photosensitivity reactions, rash, alopecia, onycholysis
Renal and Urinary Disorders
Cases of acute renal failure have been reported in patients with severe heart failure, renal artery stenosis or renal disorders (see Warnings and Precautions: Renal Impairment).
Uncommon:Renal impairment, acute renal failure, blood creatinine increased, blood urea increased, hyperkalemia, hyponatremia (see Warnings and Precautions, Renal).
General Disorders and Administration Site Conditions
Adverse Reactions to Hydrochlorothiazide
Blood and Lymphatic Disorders
Uncommon:Thrombocytopaenia, haemolytic anaemia, granulocytopenia
Uncommon:Lacrimation decreased, visual impairment
Uncommon:Dry mouth, sialoadenitis, loss of appetite
General Disorders and Administration Site Conditions
Immune System Disorders
Uncommon:Hypersensitivity (angioedema, anaphylaxis)
Metabolism and Nutrition Disorders
Uncommon:Hypokalemia, hyponatremia, hypochloraemia, hypomagnesaemia, hypercalcaemia, hypocalciuria, hypovolaemia/dehydration, metabolic alkalosis, hyperglycaemia, hyperuricaemia, gout, hypercholesterolaemia (increased total, LDL and VLDL cholesterol) hypertriglyceridaemia
Musculoskeletal and Connective Tissue Disorders
Nervous System Disorders
Uncommon:Sleep disorder, depression
Renal and Urinary Disorders
Uncommon:Interstitial nephritis, renal impairment
Reproductive System and Breast Disorders
Skin and Subcutaneous Tissue Disorders
Uncommon:Rash, photosensitivity, pseudoporphyria, cutaneous vasculitis
Respiratory, Thoracic and Mediastinal Disorders
Uncommon:Acute interstitial pneumonitis, acute pulmonary edema
Description of Selected Adverse Events
Hypotension may occur when starting treatment or increasing dose, especially in at-risk patients (see Warnings and Precautions). Symptoms of hypotension may include syncope, weakness, dizziness and visual impairment.
Renal impairment and acute renal failure are more likely in patients with severe heart failure, renal artery stenosis, pre-existing renal disorders or volume depletion (see Warnings and Precautions).
Hyperkalemia is most likely to occur in patients with renal impairment and those taking potassium sparing diuretics or potassium supplements.
The events of transient ischaemic attack and ischaemic stroke reported rarely in association with ACE inhibitors may be related to hypotension in patients with underlying cerebrovascular disease. Similarly, myocardial ischaemia may be related to hypotension in patients with underlying ischaemic heart disease.
Hypokalemia may occur in patients receiving INHIBACE PLUS, although less commonly than in patients receiving thiazide monotherapy.
The risk of hyponatremia is greater in women, patients with hypokalemia or low sodium/solute intake, and the elderly.
|Proper Name||Ref.||Effect||Clinical comment|
|Agents increasing serum potassium (potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes)||CT, C||Hyperkalemia may occur in some patients treated with INHIBACE PLUS. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium impairment (see Action and Clinical Pharmacology and Warnings and Precautions).||Therefore, the combination of cilazapril with agents increasing serum potassium (potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes) is not recommended (see Warnings and Precautions). If concomitant use is indicated severe hyperkalemia may occur they should be used with caution and with frequent monitoring of serum potassium.|
|Alcohol, barbiturates, or narcotics||C||Potentiation of orthostatic hypotension may occur.||Avoid alcohol, barbiturates or narcotics, especially with initiation of therapy.|
|Amantadine||Simultaneous administration of amantadine and hydrochlorothiazide may increase possible adverse effects of amantadine.|
|Amphotericin B||T||Amphotericin B increases the risk of hypokalemia induced by thiazide diuretics||Monitor serum potassium level.|
|Antidiabetic agents (e.g. insulin and oral hypoglycemic agents)||CT*||Concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. Diabetes mellitus which has been latent may become manifest during thiazide administration.||Monitor glycemic control, supplement potassium if necessary, to maintain appropriate serum potassium levels, and adjust diabetes medications as required.|
|Thiazide-induced hyperglycemia may compromise blood sugar control. Depletion of serum potassium augments glucose intolerance.|
|CT, CT*||Concomitant use of ACE inhibitors with DPP-IV inhibitors may lead to an increased risk for angioedema.||See Warnings and Precautions, Cardiovascular, Angioedema|
|Antihypertensive drugs||CT||Hydrochlorothiazide may potentiate the action of other antihypertensive drugs (e.g. guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACEI, ARB, and direct renin inhibitors).
Patients concomitantly taking ACE inhibitors and diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy.
|The possibility of hypotensive effects after the first dose of cilazapril can be minimized by either discontinuing the diuretic, or increasing the salt intake prior to initiation of treatment with cilazapril.|
|Antineoplastic drugs, including cyclophosphamide and methotrexate||C||Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.||Hematological status should be closely monitored in patients receiving this combination. Dose adjustment of cytotoxic agents may be required.|
|Bile acid sequestrants, eg. cholestyramine, colestipol||CT||Bile acid sequestrants bind thiazide diuretics in the gut and impair gastrointestinal absorption by 43-85%. Administration of thiazide 4 hours after a bile acid sequestrant reduced absorption of hydrochlorothaizide by 30-35%.||Give thiazide 2-4 hours before or 6 hours after the bile acid sequestrant. Maintain a consistent sequence of administration. Monitor blood pressure, and increase dose of thiazide, if necessary.|
|Calcium and vitamin D supplements||C||Thiazides decrease renal excretion of calcium and increase calcium release from bone.||Monitor serum calcium, especially with concomitant use of high doses of calcium supplements. Dose reduction or withdrawal of calcium and/or vitamin D supplements may be necessary.|
|Carbamazepine||C||Carbamazepine may cause clinically significant hyponatremia. Concomitant use with thiazide diuretics may potentiate hyponatremia.||Monitor serum sodium levels. Use with caution.|
|Corticosteroids, and adrenocorticotropic hormone (ACTH)||T||Intensified electrolyte depletion, particularly hypokalemia, may occur.||Monitor serum potassium, and adjust medications, as required.|
|Cyclosporine||Simultaneous administration of cyclosporine and hydrochlorothiazide may increase the risk of developing hyperuricemia and gout-like complications.|
|Digoxin||CT||No pharmacodynamic or pharmacokinetic interactions (and no increase in plasma digoxin concentrations) were observed when cilazapril therapy (5 mg once daily) was administered to healthy volunteers receiving digoxin (0.25 mg twice daily).
Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, can increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events.
|Concomitant administration of hydrochlorothiazide and digoxin requires caution. Since thiazide-induced hypokalaemia may occur during therapy with INHIBACE PLUS, which may increase the risk of arrhythmia associated with digoxin therapy, monitoring of potassium plasma levels is advised. Monitor electrolytes and digoxin levels closely. Supplement potassium or adjust doses of digoxin or thiazide, as required.|
|Drugs that alter GI motility, i.e., anti-cholinergic agents, such as atropine and prokinetic agents, such as metoclopramide, domperidone||CT, T||Bioavailability of thiazide diuretics may be increased by anticholinergic agents due to a decrease in gastrointestinal motility and gastric emptying. Conversely, prokinetic drugs may decrease the bioavailability of thiazide diuretics.||Dose adjustment of thiazide may be required.|
|Gold||C||Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.||Use with caution when INHIBACE PLUS is coadministered with gold salts.|
|Gout medications (allopurinol, uricosurics, xanthine oxidase inhibitors)||T, RC||Thiazide-induced hyperuricemia may compromise control of gout by allopurinol and probenecid. The co-administration of hydrochlorothiazide and allopurinol may increase the incidence of hypersensitivity reactions to allopurinol.||Dosage adjustment of gout medications may be required.|
|Iodine containing contrast media||In case of dehydration induced by hydrochlorothiazide, there is an increased risk of acute renal impairment, in particular when larger doses of iodine containing contrast media are administered.|
|Lithium||CT||Reversible increases in serum lithium concentrations have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors. Lithium toxicity, including CNS symptoms, ECG changes and renal failure, has occurred in patients taking ACE inhibitors. Proposed mechanisms include decreased renal elimination of lithium due to decreased aldosterone secretion or decreased renal function.||Lithium generally should not be given with diuretics or ACE inhibitors. Use of cilazapril with lithium is not recommended, but if the combination proves necessary, careful and frequent monitoring of serum lithium levels should be performed.|
|Medicinal products that could induce torsades de pointes||Hydrochlorothiazide may induce hypokalemia.||Due to the risk of hypokalemia, hydrochlorothiazide should be administered with caution when a patient is simultaneously being treated with medicinal products that could induce torsades de pointes such as:
– Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide)
– Class III antiarrhythmics (e.g. amiodarone, sotalol, defetilide, ibutilide)
– Some antipsychotics (e.g. thioridazine, chlorpromazine, trifluoperazine, sulpiride, tiapride, haloperidol, droperidol)
Other medicinal products (e.g. bepridil, cisapride, diphemanil, halofantrine, ketanserin, pentamidine, terfenadine)
|Nonsteroidal anti-inflammatory drugs (NSAID) including aspirin ≥ 3 g/day||CT||NSAID-related retention of sodium and water antagonises the diuretic and antihypertensive effects of thiazides.
When ACE inhibitors, including INHIBACE PLUS, are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE inhibitors, including INHIBACE PLUS, 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 introduction of therapy with cilazapril (2.5 mg once daily) in hypertensive patients receiving indomethacin (50 mg twice daily) did not result in a reduction in blood pressure. However, the introduction of therapy with indomethacin (50 mg twice daily) in hypertensive patients receiving cilazapril (2.5 mg once daily) did not attenuate the blood pressure lowering effects of cilazapril. The interaction does not appear to occur in patients treated with cilazapril prior to the administration of a NSAID. There was no evidence of a pharmacokinetic interaction between cilazapril and indomethacin.
NSAID-induced inhibition of renal prostaglandins leading to decreases of renal blood flow, along with thiazide-induced decreases in GFR may lead to acute renal failure. Patients with heart failure may be at particular risk.
|The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring for signs of worsening heart failure or renal function or loss of blood pressure control after initiation of concomitant therapy, and periodically thereafter.|
|Other antihypertensive agents||CT||An additive effect may be observed when INHIBACE PLUS is administered in combination with other blood pressure-lowering agents (e.g., diuretics, beta-adrenergic blocking drugs).
Agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) should be used with caution.
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
|These drugs should be introduced at a low initial dosage, and used with caution.
Close monitoring of blood pressure is advised and dose/regimen adjustment should be considered if necessary.
|Pressor amines (e.g., norepinephrine)||Possible decreased response to pressor amines may occur but not sufficiently to preclude their use.|
|Selective serotonin reuptake inhibitors (SSRIs, e.g. citalopram, escitalopram, sertraline)||T, C||Concomitant use with thiazide diuretics may potentiate hyponatremia.||Monitor serum sodium levels. Use with caution.|
|Skeletal muscle relaxants of the curare family, eg., tubocurare||C||Thiazide drugs may increase the responsiveness of some skeletal muscle relaxants, such as curare derivatives||Non-depolarizing muscle relaxants should not be administered simultaneously, due to possible intensification and prolongation of the muscular relaxing effect.|
|Tetracycline||C||Increased toxicity has been reported when given with thiazides.|
|Topiramate||CT||Additive hypokalemia. Possible thiazide-induced increase in topiramate serum concentrations.||Monitor serum potassium and topiramate levels. Use potassium supplements, or adjust topiramate dose as necessary.|
|Tricyclic antidepressants/antipsyc hotics/anesthetics/narcoti cs||C||Concomitant use of anesthetics during the course of general anesthesia, as well as tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see Warnings and Precautions).||Close monitoring of blood pressure is advised and dose/regimen adjustment should be considered if necessary.|
|Dual blockade of the Renin- Angiotensin- System (RAS) with ACE inhibitors, ARBs or aliskiren-containing drugs||CT||Dual Blockade of the Renin-Angiotensin-System (RAS) with ACE inhibitors, ARBs or aliskiren-containing drugs is contraindicated in patients with diabetes and/or renal impairment, and is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia.||See Contraindications and Warnings and Precautions, Dual Blockade of the Renin- Angiotensin- System (RAS).|
|mTOR inhibitors||C, RCS||Concomitant use of ACE inhibitors with mTOR inhibitors may lead to an increased risk for Angioedema.||See Warnings and Precautions, Cardiovascular, Angioedema|
Legend: C = Case Study; RCS = Retrospective Cohort Study; CT = Clinical Trial; T = Theoretical, CT*: Epidemiological studies.
Dosage and Administration
Dosage must be individualized. The fixed combination is not for initial therapy. The dose of INHIBACE PLUS (cilazapril and hydrochlorothiazide) should be determined by titration of the individual components.
Once the patient has been successfully titrated with the individual components as described below, INHIBACE PLUS may be substituted if the titrated doses and dosing schedule can be achieved by the fixed combination (see Indications and Clinicl Use and Warnings and Precautions). In some patients a twice daily administration may be required.
The tablets must not be chewed or crushed and should always be swallowed with a glass of water.
Recommended Dose and Dosage Adjustment
The recommended initial dose of INHIBACE is 2.5 mg once daily. Dosage should be adjusted according to the blood pressure response, generally at intervals of at least two weeks. The usual dose range for INHIBACE is 2.5 to 5 mg once daily. Minimal additional blood pressure lowering effects were achieved with a dose of 10 mg daily. A dose of 10 mg should not be exceeded.
In most patients, the antihypertensive effect of INHIBACE is maintained with a once daily dosing regimen. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily administration with the same total daily dose, or an increase in dose should be considered. If blood pressure is not adequately controlled with INHIBACE alone a non-potassium- sparing diuretic may be administered concomitantly. After the addition of a diuretic, it may be possible to reduce the dose of INHIBACE.
Concomitant Diuretic Therapy
In patients receiving diuretics, INHIBACE therapy should be initiated with caution, since they are usually volume depleted and more likely to experience hypotension following ACE inhibition. Whenever possible, all diuretics should be discontinued two to three days prior to the administration of INHIBACE to reduce the likelihood of hypotension (see Warnings and Precautions). If this is not possible because of the patient's condition, INHIBACE should be started at 0.5 mg once daily and the blood pressure closely monitored after the first dose until stabilized. Thereafter, the dose should be adjusted according to individual response.
Dosage in Elderly Patients (Over 65 Years)
INHIBACE treatment should be initiated with 1.25 mg (half of a 2.5 mg tablet) once daily or less, depending on the patient’s volume status and general condition. Thereafter, the dose of INHIBACE must be adjusted according to individual response.
Dosage Adjustment in Renal Impairment
See Table 3 for dose schedules recommended in patients with renal impairment.
|Creatinine Clearance||Initial Dose Of INHIBACE||Maximal Dose Of INHIBACE|
|> 40 mL/min||1 mg once daily||5 mg once daily|
|10-40 mL/min||0.5 mg once daily||2.5 mg once daily|
|< 10 mL/min||Not recommended.|
When concomitant diuretic therapy is required in patients with severe renal impairment a loop diuretic rather than a thiazide diuretic is preferred for use with cilazapril. Therefore, for patients with severe renal dysfunction (creatinine clearance < 10 mL/min) INHIBACE PLUS is not recommended.
Dosage Adjustment in Hepatic Impairment
Should patients with liver cirrhosis require treatment with INHIBACE, treatment should be initiated with caution at a dose of 0.5 mg once daily or less as significant hypotension may occur (see Warnings and Precautions).
Limited data are available with regard to overdosage in humans. Symptoms associated with overdosage of ACE inhibitors may include hypotension, which may be severe, circulatory shock, electrolyte disturbances including hyperkalaemia and hyponatremia, renal impairment with metabolic acidosis, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.
The recommended treatment of overdosage is intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. Specific therapy with angiotensinamide may be considered if conventional therapy is ineffective.
Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.
Hemodialysis removes cilazapril and cilazaprilat from the general circulation to a limited extent.
The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
|For management of a suspected drug overdose, contact your regional Poison Control Centre.|
Action and Clinical Pharmacology
Mechanism of Action
INHIBACE PLUS (cilazapril and hydrochlorothiazide) combines the action of an angiotensin converting enzyme (ACE) inhibitor, cilazapril, and a thiazide diuretic agent, hydrochlorothiazide for the treatment of hypertension. The anti-hypertensive effects of cilazapril and hydrochlorothiazide in combination are greater than the effect of either component administered alone resulting in a higher percentage of hypertensive patients responding satisfactorily to the combination.
Cilazapril suppresses the renin-angiotensin-aldosterone system and thereby reduces both supine and standing systolic and diastolic blood pressures. Renin is an enzyme that is released by the kidneys into the circulation to stimulate the production of angiotensin I, an inactive decapeptide. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II, a potent vasoconstrictor. Angiotensin II also stimulates aldosterone secretion, leading to sodium and fluid retention. After absorption, cilazapril, a pro-drug, is hydrolyzed to cilazaprilat, the active metabolite, which prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE. Following the administration of cilazapril, plasma ACE activity is inhibited more than 90% within two hours at therapeutic doses. Plasma renin activity (PRA) and angiotensin I concentrations are increased and angiotensin II concentrations and aldosterone secretion are decreased. The increase in PRA comes as a result of the loss of negative feedback on renin release caused by the reduction in angiotensin II. The decreased aldosterone secretion may lead to small increases in serum potassium along with sodium and fluid loss. In patients with normal renal function, serum potassium usually remains within the normal range during cilazapril treatment. Mean serum potassium values increased by 0.02 mEq/L in patients with a normal baseline serum creatinine and by 0.11 mEq/L in patients with a raised serum creatinine. In patients concomitantly taking potassium-sparing diuretics, potassium levels may rise.
ACE is identical to kininase II. Therefore, cilazapril may interfere with the degradation of the vasodepressor peptide bradykinin. The role that this plays in the therapeutic effects of cilazapril is unknown.
Hydrochlorothiazide is a diuretic and antihypertensive which interferes with the renal tubular mechanism of electrolyte reabsorption. It increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. While this compound is predominately a saluretic agent, in vitro studies have shown that it has a carbonic anhydrase inhibitory action which seems to be relatively specific for the renal tubular mechanism. It does not appear to be concentrated in erythrocytes or the brain in sufficient amounts to influence the activity of carbonic anhydrase in those tissues.
Hydrochlorothiazide is useful in the treatment of hypertension. It may be used alone or as an adjunct to other antihypertensive drugs. Hydrochlorothiazide does not affect normal blood pressure. The mechanism of its antihypertensive action is uncertain. Lowering of the sodium content of arteriolar smooth muscle cells and diminished response to norepinephrine have been postulated.
The antihypertensive effect of cilazapril is usually apparent within the first hour after administration, with maximum effect observed between three and seven hours after dosing. Supine and standing heart rates remain unchanged. Reflex tachycardia has not been observed. Small, clinically insignificant alterations of heart rate may occur.
At recommended doses, the antihypertensive effect of cilazapril is maintained for up to 24 hours. In some patients, blood pressure reduction may diminish toward the end of the dosage interval. Blood pressure should be assessed after two to four weeks of therapy, and dosage adjusted if required. The antihypertensive effect of cilazapril is maintained during long-term therapy. No rapid increase in blood pressure has been observed after abrupt withdrawal of cilazapril.
The blood pressure-lowering effect of cilazapril in black patients may be less pronounced than in non-blacks. Racial differences in response are no longer evident when cilazapril is administered in combination with hydrochlorothiazide.
In hypertensive patients with moderate to severe renal impairment, the glomerular filtration rate and renal blood flow remained in general unchanged with cilazapril.
Use of hydrochlorothiazide increases plasma renin activity and aldosterone secretion resulting in a decrease in serum potassium. Cilazapril, by blocking the angiotensin/aldosterone axis attenuates the potassium loss associated with diuretic use. Concomitant use with hydrochlorothiazide results in a greater reduction of blood pressure by complementary mechanisms.
Cilazapril Absorption & Distribution
Cilazapril is well absorbed after oral administration and rapidly converted by ester cleavage to the active form, cilazaprilat. Peak plasma concentrations, and times to peak plasma concentrations for cilazapril and cilazaprilat following the oral administration of 0.5 to 5 mg cilazapril are given below.
Maximum plasma concentrations of cilazaprilat are reached within two hours after administration of cilazapril.
Maximum ACE inhibition is greater than 90% after 1 to 5 mg cilazapril. Maximum ACE inhibition is 70 to 80% after 0.5 mg cilazapril. Dose proportionality is observed following the administration of 1 to 5 mg cilazapril. Apparent non-proportionality is observed at 0.5 mg reflective of the binding to ACE. The higher doses of cilazapril are associated with longer duration of maximum ACE inhibition.
The absolute bioavailability of cilazaprilat after oral administration of cilazapril is 57% based on urinary recovery data. (The absolute bioavailability of cilazaprilat after oral administration of cilazaprilat is 19%.) Ingestion of food immediately before the administration of cilazapril reduces the average peak plasma concentration of cilazaprilat by 29%, delays the peak by one hour and reduces the bioavailability of cilazaprilat by 14%. These pharmacokinetic changes have little influence on plasma ACE inhibition.
Cilazapril Metabolism & Excretion
Cilazaprilat is eliminated unchanged by the kidneys. The total urinary recovery of cilazaprilat after intravenous administration of 2.5 mg is 91%. Total clearance is 12.3 L/h and renal clearance is 10.8 L/h. The total urinary recovery of cilazaprilat following the oral administration of 2.5 mg cilazapril is 52.6%.
Half-lives for the periods 1 to 4 hours and 1 to 7 days after the intravenous administration of 2.5 mg cilazaprilat are 0.90 and 46.2 hours respectively. These data suggest the saturable binding of cilazaprilat to ACE. The early elimination phase corresponds to the clearance of free drug. During the terminal elimination phase, almost all of the drug is bound to enzyme. Following the oral administration of 0.5, 1, 2.5 and 5 mg cilazapril, terminal elimination phase half-lives for cilazaprilat are 48.9, 39.8, 38.5 and 35.8 h respectively.
After multiple dose, daily administration of 2.5 mg cilazapril for 8 days, pharmacokinetic parameter values for intact cilazapril after the last dose are similar to the first dose. For cilazaprilat, peak plasma concentrations are achieved at the same time but are 30% higher after the last dose. Trough plasma concentrations and areas under the curve are 20% higher. The terminal elimination phase half -life after the last dose is 53.8 h. The effective half-life of accumulation for cilazaprilat is 8.9 h.
Hydrochlorothiazide Absorption & Distribution
Onset of the diuretic action following oral administration occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6 to 12 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Hydrochlorothiazide Metabolism & Excretion
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When hydrochlorothiazide plasma levels have been followed for 24 hours, the plasma half-life has been observed to vary between 5.6-14.8 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours.
Concomitant administration of cilazapril and hydrochlorothiazide has little, or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities.
Following oral administration of INHIBACE PLUS, hydrochlorothiazide is rapidly absorbed. Maximum plasma concentrations are consistently achieved within 2 hours post dosing. The bioavailability of hydrochlorothiazide after oral dose is about 65% based on urinary recovery. It is eliminated largely unchanged by the kidney, with a half-life of 7 to 11 hours.
AUC (area under the curve) values increase proportionally for cilazaprilat and hydrochlorothiazide with increasing doses of cilazapril and hydrochlorothiazide in the combination dosage form. The pharmacokinetic parameters of cilazaprilat are not altered in the presence of increasing doses of the hydrochlorothiazide component. Concomitant administration of cilazapril with hydrochlorothiazide has no effect on the bioavailability of either cilazaprilat, cilazapril or hydro-chlorothiazide. Administration of cilazapril and hydrochlorothiazide in the presence of food delays cilazaprilat Tmax by 1.5 hours and reduces Cmax by 24% and delays hydrochlorothiazide Tmax by 1.4 hours and reduces Cmax by 14% with no effect on overall bioavailability for either as assessed by AUC(0→24) values, indicating that there is an influence on rates but not on the extents of absorption.
Special Populations and Conditions
Following the administration of 1 mg cilazapril to healthy elderly and young volunteers, the elderly group experienced greater peak plasma concentrations of cilazaprilat and areas under the curve (39% and 25%, respectively) and lower total clearance and renal clearance (20% and 28%, respectively) than the younger volunteers.
Hepatic Impairment: Following the administration of 1 mg cilazapril in patients with moderate to severe compensated liver cirrhosis, peak plasma concentrations of cilazapril and cilazaprilat are increased (57% and 28% respectively), attained 30 minutes and 45 minutes earlier, and total clearances are decreased (51% and 31% respectively), in comparison to healthy subjects. The renal clearance and early and terminal elimination phase half-lives of cilazaprilat are decreased 52%, 42% and 62% respectively.
In patients with renal impairment, peak plasma concentrations of cilazaprilat, times to peak plasma concentrations, early elimination phase half-lives, areas under the curve and 24-hour plasma concentrations all increase as creatinine clearance decreases. The changes in these parameters are small for patients with creatinine clearances of 40 mL/min or more. Cilazaprilat clearance (total and renal) decreases in parallel with creatinine clearance. Cilazaprilat is not eliminated in patients with complete renal failure. Hemodialysis reduces concentrations of both cilazapril and cilazaprilat to a limited extent.
Storage and Stability
Store 15-30°C. Keep container tightly closed.
Special Handling Instructions
The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater, and disposal through household waste should be avoided. Use established 'collection systems' if available in your location.
Dosage Forms, Composition and Packaging
INHIBACE PLUS 5/12.5 mg film-coated tablets contain 5 mg cilazapril, as cilazapril monohydrate and 12.5 mg hydrochlorothiazide.
Non-medicinal ingredients: cornstarch, hydroxypropyl methylcellulose, lactose, red iron oxide, sodium stearyl fumarate, talc, and titanium dioxide.
INHIBACE PLUS (cilazapril and hydrochlorothiazide) is available as film-coated tablets containing: 5 mg cilazapril and 12.5 mg hydrochlorothiazide available in blister packages of 28 tablets. The tablets are pale red, oval shaped single-scored biconvex imprinted CIL + on the top half and 5 + 12,5 on the bottom half of one side of the tablet.