Download Fosinopril + HCTZ

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.
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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
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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.
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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.
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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
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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
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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.
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