ENAP-CO Tablets COMPOSITION - Pharma Dynamics

SCHEDULING STATUS: S3
PROPRIETARY NAME (AND DOSAGE FORM):
ENAP-CO Tablets
COMPOSITION:
PACKAGE INSERT
Each ENAP-CO tablet contains 20 mg enalapril maleate and 12,5 mg hydrochlorothiazide.
PHARMACOLOGICAL CLASSIFICATION:
A 7.1.3 Vascular medicines - other hypotensives.
PHARMACOLOGICAL ACTION:
ENAP-CO (enalapril maleate and hydrochlorothiazide) is a combination of an angiotensin-converting
enzyme (ACE) inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide), which produces an
additive anti-hypertensive effect. The active metabolite, enalaprilat, is formed by hydrolyzation of
enalapril.
INDICATIONS:
ENAP-CO is indicated for the treatment of hypertension in patients stabilised on the individual
components administered at the same dosages.
CONTRA-INDICATIONS:
Anuria.
Hypersensitivity to any ingredient of this product. In patients with a history of angioneurotic oedema
relating to previous treatment with an ACE-inhibitor. Hypersensitivity to other sulphonamide-derived
medicines. Pregnant and breast-feeding mothers (see Warnings).
Concomitant use with lithium (see Interactions).
WARNINGS:
Should a woman become pregnant while receiving an ACE-inhibitor, the treatment must be stopped
promptly and switched to a different medicine.
Should a woman contemplate pregnancy, the doctor should institute alternative medication.
ACE-inhibitors can cause foetal and neonatal morbidity and mortality when administered to pregnant
women during the second and third trimesters. ACE-inhibitors pass through the placenta and can be
presumed to cause disturbance in foetal blood pressure regulatory mechanisms.
Oligohydramnios, which may result in limb contractures, craniofacial deformities and hypoplastic lung
development, as well as hypotension, hyperkalemia, oliguria and anuria in newborns have been
reported after administration of ACE-inhibitors in the second and third trimester. Cases of defective
skull ossification have been observed. Prematurity and low birth mass can occur. These adverse
effects to the embryo and foetus do not appear to have resulted from intra-uterine ACE-inhibitor
exposure limited to the first trimester.

The routine use of diuretics in otherwise healthy pregnant women is not indicated and exposes mother
and foetus to unnecessary hazard. Diuretics do not prevent development of toxaemia of pregnancy and
there is no satisfactory evidence that they are useful in the treatment of toxaemia. Thiazides cross the
placental barrier and appear in cord blood. Hazards include foetal and neonatal jaundice,
thrombocytopenia and possibly other adverse reactions which occur in the adult.
Infants whose mothers have taken ENAP-CO should be closely observed for hypotension, oliguria and
hyperkalaemia. There is no experience with the removal of the combination product, ENAP-CO, from
the neonatal circulation. Enalapril, which crosses the placenta, has been removed from the neonatal
circulation by peritoneal dialysis with some clinical benefit. There is no experience with the removal of
hydrochlorothiazide, which also crosses the placenta, from the neonatal circulation.
Both enalapril and thiazides appear in human milk. If use of the medicine is deemed essential, the
patient should stop nursing.
After administration of the initial dose, symptomatic hypotension may occur. Hypotension is more likely
in patients who have received prior diuretic therapy. Discontinue diuretic therapy for 2-3 days before
therapy with ENAP-CO is initiated. In patients with ischaemic heart or cerebrovascular disease, therapy
should be administered with extreme caution because an excessive fall in blood pressure could result in
a myocardial infarction or cerebrovascular accident.
Minor increases in blood urea and serum creatinine have developed in some hypertensive patients with
no apparent pre-existing renal disease when enalapril has been given concomitantly with a diuretic.
Should this occur during therapy with ENAP-CO, the combination should be discontinued.
Minor alterations of fluid and electrolyte balance may precipitate hepatic encephalopathy and coma,
therefore, ENAP-CO should be used with caution in patients with impaired hepatic function or
progressive liver disease.
DOSAGE AND DIRECTIONS FOR USE:
Hypertension
The usual dosage is one tablet, once a day. The dosage may be increased to a maximum of two
tablets, administered once daily, if necessary.
Dosage in Renal Insufficiency
The use of thiazides may not be appropriate in patients with renal impairment. Thiazides are ineffective
at creatinine clearance values of 30 ml/min or below (i.e. moderate or severe renal insufficiency).
Do not use ENAP-CO as initial therapy in any patient with renal insufficiency.
ENAP-CO may however be used in patients with creatinine clearance greater than 30 and less than 80
ml/minute, but only after the individual components have been successfully titrated.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
Dizziness and fatigue, the most common clinical side-effects, generally respond to dosage reduction.
Other side-effects include: muscle cramps, nausea, aesthenia, orthostatic effects including
hypotension, headaches, cough and impotence.
Less common side-effects which have been reported include:
Nervous System/Psychiatric
Insomnia, somnolence, paraesthesia, vertigo, nervousness.
Cardiovascular
Syncope, non-orthostatic hypotension, palpitations, tachycardia, chest pain.

Respiratory
Dyspnoea
Gastro-intestinal
Diarrhoea, vomiting, dyspepsia, abdominal pain, flatulence, constipation.
Hypersensitivity/Angioneurotic Oedema
Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see
Special Precautions).
Other
Renal dysfunction, renal failure, decreased libido, dry mouth, gout, tinnitus, arthralgia.
A symptom complex which may include fever, serositis, vasculitis, myalgia, arthralgia/arthritis, a positive
anti-nuclear antibody, elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis, has been
reported. Dermatologic manifestations, including skin rash and photosensitivity may occur.
Skin
Stevens-Johnson syndrome, rash, pruritus, diaphoresis.
Laboratory Test Findings
Cases of hyperglycaemia, hyperuricemia and hypokalemia have been recorded. In some patients,
increases in blood urea and serum creatinine, and elevations of liver enzymes and/or serum bilirubin
have occurred. These are usually reversible upon discontinuation of the combination medication.
Hyperkalemia and hyponatremia have been noted. Decreases in haemoglobin, haematocrit, platelets
and white cell count have been noted.
Reports of neutropenia, thrombocytopenia and bone marrow depression have been received, but no
direct casual relationship to the combination medication could be established.
Side-effects reported for one of the individual components that may also contribute to side-effects
encountered with this combination medication, include the following:
Hydrochlorothiazide
Anorexia, gastric irritation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialoadenitis,
xanthopsia, leukopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia, purpura,
photosensitivity, fever, urticaria, necrotizing angiitis (vasculitis), respiratory distress (including
pneumonitis and pulmonary oedema), interstitial nephritis, anaphylactic reaction, glycosuria, electrolyte
imbalance, including hyponatraemia, restlessness, muscle spasm, transient blurred vision.
Enalapril
Ileus, pancreatitis, hepatitis, either hepatocellular or cholestatic, jaundice, depression, confusion,
bronchospasm/asthma, sore throat and hoarseness, cardiac rhythm disturbances, angina pectoris,
myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high
risk patients, rhinorrhoea, photosensitivity, alopecia, flushing, taste alteration, anorexia, blurred vision,
urticaria, stomatitis, glossitis, oliguria, toxic epidermal necrolysis, erythema multiforme, exfoliative
dermatitis, pulmonary infiltrates, hepatic failure, pemphigus.
Special Precautions:
Anaphylactoid Reactions during Hymenoptera Desensitization
Less frequently, patients receiving ACE inhibitors during desensitization with hymenoptera venom have
experiences life-threatening anaphylactoid reactions. These reactions were avoided by temporarily
withholding ACE-inhibitor therapy prior to each desensitization.
Cough
The use of ACE-inhibitors has been associated with cough. The cough is of a non-productive and
persistent nature, which resolves after therapy is discontinued. ACE-inhibitor-induced cough should be
considered as part of the differential diagnosis of cough.

Elderly Use
No significant differences in efficacy and tolerability, were identified in elderly or younger hypertensive
patients when enalapril maleate and hydrochlorothiazide were administered concominantly.
Haemodialysis patients
The use of this combination medication is not indicated in patients requiring dialysis for renal failure (see
Dosage and Directions for Use). Anaphylactoid reactions have been reported in patients dialysed with
high-flux membranes (e.g. AN69®), receiving concomitant ACE-inhibitor treatment. A different type of
dialysis membrane or a different class of antihypertensive agent, should be considered when treating
such patients.
Hepatic Disease
Thiazide 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.
Hypersensitivity/Angioneurotic Oedema
In some patients, angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has
been reported. Discontinue treatment in such cases and monitor patients to ensure complete
resolution of symptoms. Where swelling is confined to the face and lips, the condition may resolve
without treatment. Antihistamine treatment has proved useful in relieving these symptoms.
Angioneurotic oedema associated with laryngeal oedema may be fatal. If involvement of the tongue,
glottis or larynx, which is likely to cause airway obstruction should occur, appropriate therapy such as
subcutaneous adrenaline solution 1:1 000 (0,3 ml to 0,5 ml) should be administered immediately.
A history of angioedema unrelated to ACE-inhibitor therapy may expose patients to increased risk of
developing angioedema while receiving an ACE-inhibitor. (See Contra-indications).
Thiazide therapy may cause sensitivity reactions in certain patients, with or without, a history of allergy or
bronchial asthma. Reports of exacerbation or activation of systemic lupus erythematosus have been
associated with the use of thiazides.
Hypotension and Electrolyte/Fluid imbalance
Some patients may develop symptomatic hypotension. Such patients should be monitored for clinical
signs of fluid or electrolyte imbalance, e.g. volume depletion, hyponatremia, hypochloremic alkalosis,
hypomagnesaemia or hypokalemia which may occur during intercurrent diarrhoea or vomiting. Serum
electrolytes should be periodically determined at appropriate intervals when treating these patients.
If hypotension occurs, the patient should be made to lie down and, if necessary, an intravenous infusion
of normal saline should be administered. A transient hypotensive response is not a contra-indication to
further doses. Provided blood volume and pressure have been restored effectively, reintroduction of
therapy using reduced doses can be considered; as an alternative, either of the components may be
administered as monotherapy.
Metabolic and Endocrine Effects
Glucose tolerance may be impaired by thiazide therapy. Dosage of antidiabetic agents including
insulin, may need to be adjusted. Thiazides may decrease urinary calcium excretion and cause
intermittent and slight elevation of serum calcium. It should be kept in mind, that marked
hypercalcinemia may be evidence of hidden hyperparathyroidism. Discontinue thiazides before
carrying out tests of parathyroid function.
In some cases, thiazide diuretic therapy may be associated with increases in cholesterol and triglyceride
levels.
In certain patients thiazide therapy may precipitate hyperuricemia and/or gout, enalapril may, however,
increase urinary uric acid and thus attenuate the hyperuricemic effect of hydrochlorothiazide.
Paediatric use
The safety and efficacy of the combination medication in children have not been established.
Renal Function Impairment

See Dosage in Renal Insufficiency under Dosage and Directions for Use.
Increases in blood urea and serum creatinine have been seen in some patients with bilateral renal
artery stenosis or stenosis of the artery to a solitary kidney, who were receiving treatment with ACEinhibitors;
these symptoms are reversible upon discontinuation of therapy.
Surgery/Anaesthesia
Enalapril is known to block angiotensin II formation secondary to compensatory renin release in patients
undergoing major surgery or during anaesthesia with agents that produce hypotension. Should
hypotension occur and be considered to be due to this mechanism, volume expansion can be used to
correct the fall in blood pressure.
Interactions:
Concurrent use of the following drugs may cause interactions with thiazide diuretics:
Anti-diabetic medicine (oral agents and insulin) - the dosage of the anti-diabetic medication may have
to be adjusted.
Alcohol, Barbiturates or Narcotics - may potentiate orthostatic hypotension.
Corticosteroids, ACTH - increased electrolyte depletion, particularly hypokalemia, may occur.
Non-steroidal Anti-inflammatory Agents - reduction of the diuretic, natriuretic and anti-hypertensive
effects of diuretics in certain patients.
Pressor Amines (e.g. adrenalin) - a decreased response to pressor amines may occur, but this is
generally not sufficient to preclude their use.
Other interactions:
Lithium
The combination of lithium and diuretics should be avoided. Renal clearance of lithium is reduced by
diuretic agents and ACE-inhibitors, exposing patients to a high risk of lithium toxicity. Refer to lithium
preparation package inserts before use of such preparations.
Non-depolarising Muscle Relaxants
Responsiveness to tubocurarine may be increased during thiazide therapy.
Other Antihypertensive Therapy
The combination of enalapril with ganglionic blocking agents or adrenergic blocking agents, should only
be considered if the patient can be kept under careful observation.
Serum Potassium
The effect of enalapril usually attenuates the depletion of potassium by thiazide diuretics.
Serum potassium levels may be significantly increased, particularly in patients with impaired renal
function if potassium supplements, potassium-sparing agents or potassium-containing salt substitutes,
are used.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
No specific information for the treatment of overdosage with the combination medication is available at
present. Treatment is symptomatic and supportive. The following measures have been suggested:
induction of emesis and/or gastric lavage, correction of dehydration, electrolyte imbalance and
hypotension using established procedures which should be introduced within 2 hours after ingestion.
Hydrochlorothiazide
Overdosage with thiazides is commonly associated with signs and symptoms caused by electrolyte

depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive
diuresis. Hypokalemia may accentuate cardiac arrhythmias if digitalis has also been administered.
Enalapril Maleate
Overdosage is primarily characterised by hypotension, which commences approximately six hours after
ingestion of tablets, resulting from blockade of the renin-angiotensin system, and stupor.
Haemodialysis can be used to remove enalaprilat from the general circulation.
IDENTIFICATION:
A round, white, flat, tablet with a bevelled edge, scored on one side.
PRESENTATION:
Available in blisters of 30 tablets.
STORAGE INSTRUCTIONS:
Store in a cool (below 25°C), dry place. Protect from light and moisture.
KEEP OUT OF REACH OF CHILDREN.
REGISTRATION NUMBER:
34/7.1.3/0088
NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharma Dynamics (Pty) Ltd
F02 Grapevine House
Steenberg Office Park
Westlake
7945
DATE OF PUBLICATION OF THIS PACKAGE INSERT:
7 February 2000

SKEDULERINGSTATUS: S3
EIENDOMSNAAM (EN DOSEERVORM):
ENAP-CO (tablet)
SAMESTELLING:
VOUBILJET
Elke ENAP-CO tablet bevat 20 mg enalaprielmaleaat en 12,5 mg hidrochloortiasied.
FARMAKOLOGIESE KLASSIFIKASIE:
A 7.1.3 Vaskulêre medisyne - ander hipotensiewe middels.
FARMAKOLOGIESE WERKING:
ENAP-CO (enalaprielmaleaat en hidrochloortiasied) is ‘n kombinasie van ‘n
angiotensienomsettingsensiem (AOE)-inhibeerder (enalaprielmaleaat) en ‘n diuretikum
(hidrochloortiasied), wat ‘n additiewe antihipertensiewe uitwerking bewerkstellig. Die aktiewe
metaboliet, enalaprilaat, word deur hidrolisering van enalapriel gevorm.
INDIKASIES:
ENAP-CO word aangedui vir die behandeling van hipertensie in pasiënte wat op die individuele
komponente wat teen dieselfde doserings toegedien word, gestabiliseer is.
KONTRA-INDIKASIES:
Anurie.
Hipersensitiwiteit teenoor enige komponent van hierdie produk. In pasiënte met ‘n geskiedenis van
angioneurotiese edeem verwant aan vorige behandeling met ‘n AOE-inhibeerder. Hipersentiwiteit
teenoor ander sulfonamied-afgeleide medisyne. Swanger en borsvoedende moeders (sien
Waarskuwings). Gelyktydige gebruik van litium (sien Interaksies).
WAARSKUWINGS:
Indien ‘n vrou sou swanger raak terwyl sy ‘n AOE-remmer ontvang, moet die behandeling
onmiddellik gestaak word en oorgeskakel word na alternatiewe medikasie.
Indien ‘n vrou swangerskap oorweeg, moet die geneesheer alternatiewe medikasie instel.
AOE-inhibeerders kan fetale en neonatale morbiditeit en mortaliteit veroorsaak wanneer dit toegedien
word aan swanger vroue gedurende die tweede en derde trimesters. AOE-inhibeerders kruis die
plasenta en kan vermoedelik versteuring van fetale bloeddrukreguleringsmeganismes veroorsaak.
Oligohidramnios, wat kontrakture van ledemate, kraniofasiale wanvormings en hipoplastiese
longontwikkeling tot gevolg mag hê, sowel as hipotensie, hiperkalemie, oligurie en anurie is in
pasgeborenes na toediening van AOE-inhibeerders gedurende die tweede en derde trimester,
aangemeld. Gevalle van gebrekkige skedel-ossifisering is waargeneem. Vroeggeboorte en lae
geboortegewig kan voorkom. Intra-uteriene AOE-inhibeerder blootstelling wat die eerste trimester
beperk was, het skynbaar nie hierdie nadelige uitwerkings op die embrio en fetus gehad nie.
Die roetine gebruik van diuretika in andersins gesonde swanger vrouens is nie aangedui nie en dit stel
die moeder en fetus aan onnodige gevaar bloot. Diuretika verhoed nie ontwikkeling van toksemie in
swangerskap en daar bestaan geen bevredigende bewyse dat hierdie middels nuttig in die behandeling
van toksemie kan wees nie. Tiasiede kruis die plasentale skans en verskyn in koordbloed. Gevare sluit
fetale en neonatale geelsug, trombositopenie en moontlik ook ander nadelige reaksies wat in
volwassenes voorkom, in.

Suigelinge van moeders wat ENAP-CO geneem het, behoort noukeurig vir hipotensie, oligurie en
hiperkalemie, dopgehou te word. Daar is geen ondervinding met die verwydering van die kombinasie
produk, ENAP-CO, uit die neonatale bloedsomloop beskikbaar nie. Enalapriel, wat die plasenta kruis,
is met ‘n mate van kliniese voordeel uit die neonatale bloedsomloop verwyder met behulp van
peritoneale dialise. Geen ondervinding met die verwydering van hidrochloortiasied wat ook die plasenta
kruis, uit die neonatale bloedsomloop is beskikbaar nie.
Beide enalapriel en tiasiede verskyn in menslike melk. Indien die gebruik van die medisyne as
essensieel beskou word, moet die pasiënt borsvoeding staak.
Na toediening van die eerste dosis, mag simptomatiese hipotensie voorkom. Hipotensie is meer geneig
om voor te kom in pasiënte wat vroeër diuretika-terapie ontvang het. Staak diuretika-terapie vir 2-3 dae
voor terapie met ENAP-CO begin word. In pasiënte met iskemiese hart- of serebrovaskulêre siekte,
behoort terapie met groot versigtigheid toegedien te word omdat ‘n oormatige val in bloeddruk moontlik
‘n miokardiale infarksie of serebrovaskulêre insident kan veroorsaak.
Klein toenames in bloedureum en serumkreatinien het in sommige hipertensiewe pasiënte met geen
duidelike vooraf-bestaande niersiekte voorgekom toe enalapriel saam met ‘n diuretikum toegedien is.
As dit tydens terapie met ENAP-CO sou voorkom, behoort die kombinasie gestaak te word.
Klein veranderings in vloeistof- en elektrolietbalans mag hepatiese ensefalopatie en koma presipiteer.
Dus behoort ENAP-CO met omsig in pasiënte met ingekorte lewerfunksie of progressiewe lewersiekte
gebruik te word.
DOSIS EN GEBRUIKSAANWYSINGS:
Hipertensie
Die gewone dosering is een tablet een keer per dag. Die dosering mag, indien nodig, tot ‘n maksimum
van twee tablette wat een keer per dag toegedien word, verhoog word.
Dosering in Nierontoereikendheid
In pasiënte met nierontoereikendheid mag die gebruik van tiasiede nie toepaslik wees nie. Tiasiede is
nie effektief by kreatinienopruimingswaardes van 30 ml/min of laer (d.i. matige tot ernstige
nierontoereikendheid).
Moenie ENAP-CO as aanvangsterapie in enige pasiënt met nierontoereikendheid gebruik nie.
ENAP-CO mag egter gebruik word in pasiënte met kreatinienopruiming wat hoër as 30, en laer as 80
ml/min is, maar slegs nadat die individuele komponente suksesvol getitreer is.
NEWE-EFFEKTE EN SPESIALE VOORSORGMAATREËLS:
Newe-effekte:
Duiseligheid en moegheid, die mees algemene kliniese newe-effekte, reageer gewoonlik tot
dosisvermindering. Ander newe-effekte sluit in: spierkrampe, naarheid, asthenia, ortostatiese
uitwerkings insluitend hipotensie, hoofpyne, hoes en impotensie.
Minder algemene newe-effekte wat gerapporteer is, sluit in:
Senuweestelsel/Psigiatries
Slaaploosheid, slaperigheid, parestesie, vertigo, senuagtigheid.
Kardiovaskulêr
Sinkopee, nie-ortostatiese hipotensie, hartkloppings, tagikardie, borspyn.
Respiratories
Dispnee.
Gastro-intestinaal
Diarree, braking, dispepsie, abdominale pyn, winderigheid, hardlywigheid.

Hipersensitiwiteit/Angioneurotiese Edeem
Angioneurotiese edeem van die gesig, ekstremiteite, lippe, tong, glottis en/of larinks is al gerapporteer
(sien Spesiale Voorsorgmaatreëls).
Ander
Renale disfunksie, nierversaking, verminderde libido, droë mond, jig, tinnitus, artralgie.
‘n Simptoomkompleks wat koors, serositis, vaskulitis, mialgie, artralgie/artritis, ‘n positiewe anti-nukleêre
teenliggaampie, verhoogde eritrosiet-sedimentasietempo, eosinofilie, en leukositose mag insluit, is
gerapporteer. Dermatologiese manifestasies, insluitend veluitslag of fotosensitiwiteit, mag ook
voorkom.
Vel
Stevens-Johnson-sindroom, veluitslag, pruritus, diaforese.
Laboratoriumtoetsbevindings
Gevalle van hiperglisemie, hiperurisemie en hipokalemie is al aangeteken. In sommige pasiënte is
verhogings in bloedureum en serumkreatinien, en verhoogde lewerensieme en/of
serumbilirubienvlakke waargeneem. Hierdie bevindings is normaalweg omkeerbaar na staking van die
gekombineerde terapie. Hiperkalemie en hiponatremie is waargeneem. Verminderings in
hemoglobien, hematokrit, plaatjies en wit seltelling is gerapporteer.
Berigte van neutropenie, trombositopenie en beenmurgonderdrukking is al ontvang, maar geen direkte
oorsaaklike verwantskap met die kombinasie medikasie kon vasgestel word nie.
Newe-effekte wat vir een van die individuele komponente geraporteer is, en ook mag bydra tot die
newe-effekte wat met hierdie kombinasie ondervind word, sluit die volgende in:
Hidrochloortiasied
Anoreksie, gastriese irritasie, geelsug (intrahepatiese cholestatiese geelsug), pankreatitis, sialadenitis,
xantopsie, leukopenie, agranulositose, aplastiese anemie, hemolitiese anemie, purpura,
fotosensitiwiteit, koors, urtikarie, nekrotiserende angiïtis (vaskulitis), respiratoriese nood (insluitend
longontsteking en pulmonale edeem), interstisiële nefritis, anafilaktiese reaksie, glikosurie,
elektrolietwanbalans, insluitend hiponatremie, rusteloosheid, spierspasma, verbygaande versteurde
visie.
Enalapriel
Ileus, pankreatitis, hepatitis, óf sellulêr óf cholestaties, geelsug, depressie, verwarring, brongospasma/
asma, seer keel en heesheid, versteurings van hart-ritme, angina pectoris, miokardiale infarksie óf
serebrovaskulêre insident, moontlik sekondêr tot oormatige hipotensie in hoë-risiko pasiënte, rinoree,
fotosensitiwiteit, alopesie, blosing, smaakveranderings, anoreksie, versteurde visie, urtikarie, stomatitis,
glossitis, oligurie, toksiese epidermale nekrolise, erythema multiforme, eksfoliatiewe dermatitis,
pulmonale infiltrate, hepatiese versaking, pemfigus.
Spesiale Voorsorgmaatreëls
Anafilaktoïed Reaksies tydens Hymenoptera Desensitisering
Minder dikwels het pasiënte wat AOE-inhibeerders tydens desensitisering met hymenoptera gif ontvang
het, lewensbedreigende anafilaktoïede reaksies ondervind. Hierdie reaksies is vermy deur AOEinhibeerderterapie
tydelik voor elke desensitisering te weerhou.
Hoes
Die gebruik van AOE-inhibeerders is al met hoes geassosieer. Die hoes is kenmerkend nie-produktief
en aanhoudend van aard, en dit verdwyn na staking van terapie. AOE-inhibeerder-geïnduseerde hoes
moet as deel van die differensiële diagnose van hoes, beskou word.
Gebruik in bejaardes
Geen beduidende verskille in doeltreffendheid en verdraagbaarheid is in bejaarde of jonger
hipertensiewe pasiënte uitgeken nie, toe enalaprielmaleaat en hidrochloortiasied gelyktydig toegedien
is.

Hemodialise Pasiënte
Die gebruik van hierdie kombinasie medikasie is nie aangedui in pasiënte wat dialise vir nierversaking
benodig nie (sien Dosis en Gebruiksaanwysings). Anafilaktoïede reaksies is in pasiënte gerapporteer
tydens dialise met hoë-vloei membrane (byvoorbeeld AN 69®) wat gelyktydig ‘n AOE-inhibeerder
ontvang het. ‘n Ander soort dialise membraan of ‘n ander klas antihipertensiewe middel moet oorweeg
word wanneer hierdie pasiënte behandel word.
Hepatiese Siekte
Tiasiede moet met omsig gebruik word in pasiënte met ingekorte lewerfunksie of progressiewe
lewersiekte, omdat klein veranderings in vloeistof- en elektrolietbalans, hepatiese koma mag
presipiteer.
Hipersensitiwiteit/Angioneurotiese Edeem
In sommige pasiënte is angioneurotiese edeem van die gesig, ekstremiteite, lippe, tong, glottis en/of
larinks gerapporteer. Staak behandeling in sulke gevalle en moniteer pasiënte om volkome verligting
van simptome te verseker. In gevalle waar die swelling tot die gesig en lippe beperk is, mag die
toestand sonder behandeling herstel. Antihistamienbehandeling was nuttig om hierdie simptome te
verlig. Angioneurotiese edeem wat met laringeale edeem geassosieer is, mag fataal wees. Indien
betrokkenheid van die tong, glottis of larinks, wat moontlik lugwegobstruksie kan veroorsaak, sou
voorkom, behoort gepaste terapie soos subkutane adrenalienoplossing 1:1 000 (0,3 ml tot 0,5 ml)
onmiddellik toegedien te word.
‘n Geskiedenis van angio-edeem, onverwant aan AOE-inhibeerderterapie, mag pasiënte aan ‘n groter
risiko vir angio-edeem blootstel terwyl hulle ‘n AOE-inhibeerder ontvang (sien Kontra-indikasies).
Tiasiedterapie mag sensitiwiteitsreaksies in sekere pasiënte, met óf sonder, ‘n geskiedenis van allergie
of brongiale asma, veroorsaak. Berigte van verergerings of aktiverings van sistemiese lupus
eritematose is al met die gebruik van tiasiede geassosieer.
Hipotensie en Elektroliet-/Vloeistofwanbalans
Sommige pasiënte mag simptomatiese hipotensie ontwikkel. Sulke pasiënte behoort vir kliniese tekens
van vloeistof- of elektrolietwanbalans gemoniteer te word, b.v. volume-uitputting, hiponatremie,
hipochloremiese alkalose, hipomagnesemie of hipokalemie wat tydens bykomende diarree of braking
mag voorkom. Serumelektroliete behoort periodiek op geskikte tussenposes gemoniteer te word
tydens behandeling van hierdie pasiënte.
Indien hipotensie voorkom, behoort die pasiënt in ‘n rugliggende posisie geplaas te word, en indien
nodig moet ‘n intraveneuse infusie van standaard soutoplossing toegedien word. ‘n Verbygaande
hipotensie reaksie is nie ‘n teenaanduidings vir addisionele dosisse nie. Op voorwaarde dat
bloedvolume en -druk effektief herstel is, kan her-instelling van terapie teen verminderde dosisse
oorweeg word; as alternatief kan een van die twee komponente as monoterapie toegedien word.
Metaboliese en Endokriene Uitwerkings
Glukosetoleransie mag deur tiasiedterapie ingekort word. Dit mag nodig blyk te wees om dosering van
antidiabetiese middels, insluitend insulien, aan te pas. Tiasiede mag urinêre kalsiumuitskeiding
verminder en wisselvallige en klein verhogings van serumkalsium veroorsaak. Dit moet in gedagte
gehou word dat uitgesproke hiperkalsemie ‘n teken van verborge hiperparatiroïedisme mag wees.
Staak tiasiede alvorens toetse vir paratiroïedfunksie uitgevoer word.
In sommige gevalle mag tiasied diuretika-terapie met verhogings in cholesterol- en trigliseriedvlakke
geassosieer wees.
In sekere pasiënte mag tiasiedterapie hiperurisemie en/of jig presipiteer, maar enalapriel mag egter
urinêre uriensuur verhoog en dus die hiperurisemiese uitwerking van hidrochloortiasied verswak.
Pediatriese gebruik
Die veiligheid en doeltreffendheid van die kombinasie medikasie in kinders is nog nie vasgestel nie.
Inkorting van Nierfunksie
Sien Dosering in Nierontoereikendheid onder Dosis en Gebruiksaanwysings.

Toenames in bloedureum en serumkreatinien is waargeneem in sommige pasiënte met bilaterale
renale arteriestenose of stenose van die arterie na ‘n enkele nier wat behandeling met AOEinhibeerders
ontvang het; hierdie simptome is omkeerbaar na staking van terapie.
Chirurgie/Narkose
Dit is bekend dat enalapriel angiotensien-II-vorming sekondêr tot kompensatoriese renienvrystelling
blokkeer in pasiënte wat majoor chirurgie ondergaan of gedurende narkose met middels wat hipotensie
veroorsaak. Indien hipotensie sou voorkom en dit word vermoed dat dit die gevolg van hierdie
meganisme is, kan volume-uitsetting gebruik word om die val in bloeddruk te korrigeer.
Interaksies:
Gelyktydige gebruik van die volgende geneesmiddels mag interaksies met tiasied-diuretika veroorsaak:
Antidiabetiese medisyne (orale middels en insulien) - dit mag nodig wees om die dosering van die antidiabetiese
medikasie aan te pas.
Alkohol, Barbiturate en Narkotika - mag ortostatiese hipotensie versterk.
Kortikosteroïede, AKTH - verhoogde elektroliet-uitputting, veral hipokalemie, mag voorkom.
Nie-steroïedale Anti-inflammatoriese Middels - vermindering van die diuretiese, natriuretiese en antihipertensiewe
uitwerkings van diuretika in sekere pasiënte.
Pressoramiene (bv. Adrenalien) - ‘n verminderde reaksie teenoor pressoramiene mag voorkom, maar
dit is gewoonlik nie van so ‘n aard dat dit hulle gebruik uitskakel nie.
Ander Interaksies:
Litium
Die kombinasie van litium en diuretika behoort vermy te word. Nieropruiming van litium word deur
diuretika en AOE-inhibeerders verminder, wat pasiënte aan ‘n hoë risiko vir litiumtoksisiteit blootstel.
Verwys na die voubiljette van litium-preparate alvorens sulke middels gebruik word.
Nie-depolariserende Spierverslappers
Reaksie tot tubokurarien mag tydens tiasiedterapie verhoog word.
Ander Antihipertensiewe terapie
Die kombinasie van enalapriel met ganglioniese blokkeerders of adrenergiese blokkeerders moet
alleen oorweeg word indien die pasiënte onder sorgvuldige toesig gehou kan word.
Serumkalium
Die uitwerking van enalapriel verswak gewoonlik die uitputting van kalium deur tiasied-diuretika.
Serumkaliumvlakke mag beduidend verhoog wees, veral in pasiënte met ingekorte nierfunksie indien
kaliumsupplemente, kaliumsparende middels, of kalium-bevattende soutvervangers, gebruik word.
Die toediening van enalapriel aan pasiënte met nierversaking mag lei tot ‘n verhoging in serumkalium.
‘n Beduidende toename in serumkalium mag voorkom met die gebruik van kaliumsupplemente of
kaliumsparende diuretika, of kalium-bevattende soutvervangers, veral in pasiënte met ingekorte
nierfunksie. Indien gelyktydige gebruik van bogenoemde middels nodig geag word, moet dit met sorg
en gereelde bepaling van serumkaliumvlakke gepaard gaan.
BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE VAN DIE BEHANDELING
DAARVAN:
Geen spesifieke inligting oor die behandeling van oordosering met die kombinasie medikasie is
beskikbaar nie. Behandeling is simptomaties en ondersteunend. Die volgende maatreëls word
voorgestel: induksie van emese en/of maagspoeling, korrigering vn dehidrasie, elektrolietwanbalans en
hipotensie deur gebruik te maak van bewese prosedures wat binne 2 uur na inname ingestel behoort te
word.

Hidrochloortiasied
Oordosering met tiasiede word algemeen geassosieer met tekens en simptome wat deur elektrolietuitputting
(hipokalemie, hipochloremie, hiponatremie) en dihidrasie veroorsaak word, en die gevolg is
van oormatige diurese. Hipokalemie mag hartaritmieë versterk indien digitalis ook toegedien is.
Enalaprielmaleaat
Oordosering word primêr gekenmerk deur hipotensie, wat ongeveer ses ure na inname van tablette
begin en die resultaat van blokkering van die renien-angiotensien sisteem is, en stupor. Hemodialise
kan gebruik word om enalaprilaat uit die algemene bloedsomloop te verwyder.
IDENTIFIKASIE:
‘n Ronde, wit, plat, afgeskuinste tablet, gekeep aan een kant.
AANBIEDING:
Beskikbaar in stulpverpakkings met 30 tablette.
BERGINGSAANWYSINGS:
Bewaar op ‘n koel (benede 25°C), droë plek. Beskerm teen lig en vog.
HOU BUITE BEREIK VAN KINDERS.
REGISTRASIENOMMER:
34/7.1.3/0088
NAAM EN BESIGHEIDSADRES VAN DIE APPLIKANT:
Pharma Dynamics (Edms) Bpk.
F02 Grapevine House
Steenberg Office Park
Westlake
7945
DATUM VAN PUBLIKASIE VAN HIERDIE VOUBILJET:
7 Februarie 2000