TABLET AMINOFILIN

FARMAKOPE INDONESIA V USP BP dan Martindale

Anhydrous Theophylline; Teofilin; Teofilina;
Tablet Aminofilin mengandung aminofilin Teofilinas; Teofillin;
setara dengan Teofillina; Teofylliini; Teofyllin; Theofylin;
tidak kurang dari 93,0% dan tidak lebih dari Théophylline; Theophyllinum.
107,0% 3,7-Dihydro-1,3-dimethylpurine-2,6(1H)-
teofilin anhidrat, C7H8NO2, dari jumlah yang dione; 1,3-
tertera Dimethylxanthine.
pada etiket [ Теофиллин
Baku pembanding Teofilin BPFI; lakukan C7H8N4O2 = 180.2.
pengeringan CAS — 58-55-9.
pada suhu 105º selama 4 jam sebelum ATC — R03DA04.
digunakan. ATC Vet — QR03DA04.
Identifikasi Pharmacopoeias. In Eur. (see p.vii), Jpn, US,
A. Maserasi sejumlah tablet setara dengan and Viet. Some
lebih pharmacopoeias include anhydrous and
kurang 500 mg aminofilin dengan 25 ml air hydrated theophylline in
dan saring; one monograph.
filtrat menunjukkan reaksi basa terhadap Ph. Eur. 6.2 (Theophylline). A white or
lakmus P. Pada almost white, crystalline
filtrat tambahkan 1 ml asam klorida 3 N, aduk powder. Slightly soluble in water; sparingly
dan soluble in dehydrated
dinginkan jika perlu, hingga terbentuk alcohol. It dissolves in solutions of alkali
endapan. Saring hydroxides, in ammonia,
dan simpan filtrat. Cuci endapan dengan and in mineral acids.
sedikit air yang USP 31 (Theophylline). It contains one
didinginkan dan keringkan pada suhu 105º molecule of water of hydration
selama 1 jam: or is anhydrous. It is a white, odourless,
endapan yang diperoleh menunjukkan crystalline powder.
Identifikasi B Slightly soluble in water, more soluble in hot
seperti tertera pada Aminofilin dan jika water; sparingly
dihablurkan soluble in alcohol, in chloroform, and in ether;
kembali dari air dan dikeringkan pada suhu freely soluble
105º selama in solutions of alkali hydroxides and in
1 jam, melebur antara 270º dari 274º. ammonia.
B. Filtrat yang diperoleh dari Identifikasi A Theophylline Hydrate (BANM)
menunjukkan Identifikasi C seperti tertera Teofilina monohidrato; Teofilinas
pada monohidratas; Teofylliinimonohydraatti;
Aminofilin. Teofyllinmonohydrat; Theofylin monohydrát;
Waktu hancur <1251> Tidak lebih dari 30 Theophylline
menit untuk Monohydrate; Théophylline monohydratée;
tablet salut enterik, lakukan penetapan seperti Theophyllinum
tertera monohydricum.
pada Tablet Salut Enterik. Теофиллина Гидрат
Disolusi <1231> C7H8N4O2,H2O = 198.2.
Media disolusi : 900 ml air. CAS — 5967-84-0.
Alat tipe 2 : 50 rpm ATC — R03DA04.
Waktu : 45 menit. ATC Vet — QR03DA04.
Prosedur Lakukan penetapan sejumlah teofilin Pharmacopoeias. In Chin., Eur. (see p.vii),
anhidrat, C7H8N4O2, yang larut dengan US, and Viet.
mengukur Some pharmacopoeias include anhydrous and
serapan alikuot, jika perlu diencerkan dengan hydrated theophylline
Media in one monograph.
disolusi dan serapan larutan baku Teofilin Ph. Eur. 6.2 (Theophylline Monohydrate;
BPFI dalam Theophylline Hydrate
media yang sama pada panjang gelombang BP 2008). A white or almost white, crystalline
serapan powder. Slightly
maksimum lebih kurang 269 nm. soluble in water; sparingly soluble in
Toleransi Dalam waktu 45 menit harus larut dehydrated alcohol. It dissolves
tidak in solutions of alkali hydroxides, in ammonia,
kurang dari 75 % (Q) C7H8NO2, dari jumlah and in mineral
yang tertera acids.
pada etiket. USP 31 (Theophylline). It contains one
Keseragaman sediaan <911> Memenuhi molecule of water of hydration
syarat. or is anhydrous. It is a white, odourless,
Prosedur penetapan keseragaman kandungan crystalline powder.
Masukkan satu tablet ke dalam labu tentukur Slightly soluble in water, more soluble in hot
250-ml, water; sparingly
tambahkan 200 ml air, kocok hingga hancur soluble in alcohol, in chloroform, and in ether;
sempurna. freely soluble
Tambahkan air sampai tanda. Saring dan in solutions of alkali hydroxides and in
buang 20 ml ammonia.
filtrat pertama. Ukur serapan larutan ini (jika Stability. Alcohol-free theophylline liquid
perlu repackaged in clear
diencerkan) dan larutan baku Teofilin BPFI or amber polypropylene oral syringes could be
lebih kurang stored at room
10 μg per ml, pada panjang gelombang temperature under continuous fluorescent
serapan lighting for at least
maksimum lebih kurang 269 nm terhadap air 180 days without significant change in the
sebagai concentration of
blangko. Hitung jumlah dalam mg teofilin theophylline.1 However, it was recommended
anhidrat, that solutions be
C7H8N4O2, dalam tablet yang digunakan protected from light because of the potential
dengan rumus: for discoloration.
   Extemporaneous oral preparations of
  theophylline 5 mg/mL in
 commercial suspension vehicles were found2
 to be stable for up
 to 90 days in amber plastic bottles stored at
 23° to 25°.
 1. Johnson CE, Drabik BT. Stability of
S alcohol-free theophylline
U liquid repackaged in plastic oral syringes. Am
A J Hosp Pharm
A 1989; 46: 980–1.
D 2. Johnson CE, et al. Stability of anhydrous
TC theophylline in extemporaneously
T adalah jumlah teofilin anhidrat dalam mg prepared alcohol-free oral suspensions. Am J
yang tertera Health-Syst Pharm 2005; 62: 2518–20.
pada etiket; D adalah kadar teofilin dalam μg Adverse Effects
per ml The adverse effects commonly encountered
larutan tablet, berdasarkan jumlah per tablet with theophylline
yang tertera and xanthine derivatives irrespective of the
pada etiket dan pengenceran yang dilakukan; route, are gastrointestinal irritation and
C adalah stimulation of
kadar Teofilin BPFI dalam μg per ml larutan the CNS. Serum concentrations of
baku AU theophylline greater
dan AS berturut-turut adalah serapan yang than 20 micrograms/mL (110 micromol/litre)
diperoleh dari are associated
Larutan uji dan Larutan baku. with an increased risk of adverse effects (but
Kandungan etilendiamin Antara 152 dan see
178 mg per g below).
teofilin anhidrat, C7H8N4O2, yang diperoleh Theophylline may cause nausea, vomiting,
pada abdominal
Penetapan kadar, Lakukan penetapan sebagai pain, diarrhoea, and other gastrointestinal
berikut: disturbances,
Timbang saksama sejumlah serbuk tablet insomnia, headache, anxiety, irritability,
seperti tertera restlessness,
pada Penetapan kadar setara dengan lebih tremor, and palpitations. Overdosage may also
kurang 350 lead to
mg aminofilin, masukkan ke dalam labu agitation, diuresis and repeated vomiting
Erlenmeyer 100 (sometimes
ml, tambahkan 20 ml air dan digesti pada suhu haematemesis) and consequent dehydration,
50º, cardiac
sambil sering dikocok selama 30 menit. arrhythmias including tachycardia,
Dinginkan, hypotension, electrolyte
saring ke dalam labu Erlenmeyer 250 ml dan
cuci
dengan air hingga air cucian bereaksi netral
terhadap
lakmus P. Kumpulkan filtrat dan cairan
cucian,
tambahkan jingga metil LP dan titrasi dengan
asam
klorida 0,1 N LV.
Tiap ml asam klorida 0,1 N
setara dengan 3,005 mg C2H8N2
Penetapan kadar Timbang dan serbukkan
tidak kurang
dari 20 tablet. Timbang saksama sejumlah
serbuk setara
dengan lebih kurang 2 g aminofilin, masukkan
ke dalam
labu tentukur 200-ml tambahkan campuran 50
ml air dan
15 ml amonium hidroksida 6 N, biarkan
selama 30 menit
dengan seringkali dikocok, bila perlu
hangatkan sampai
suhu lebih kurang 50º untuk membantu
kelarutan. Jika
dihangatkan, dinginkan campuran hingga suhu
ruang,
tambahkan air sampai tanda. Sentrifus lebih
kurang 50
ml campuran dan pipet beningan setara
dengan lebih
kurang 250 mg aminofilin, kedalam labu
disturbances including profound
hypokalaemia,
hyperglycaemia, hypomagnesaemia, metabolic
acidosis,
rhabdomyolysis, convulsions, and death.
Severe
toxicity may not be preceded by milder
symptoms.
Convulsions, cardiac arrhythmias, severe
hypotension,
or cardiac arrest may follow rapid intravenous
injection,
and fatalities have been reported. The drug is
too
irritant for intramuscular use. Proctitis may
follow repeated
use of suppositories.
◊ Adverse effects are uncommon at serum-
theophylline concentrations
of 5 to 10 micrograms/mL but become more
frequent at
15 micrograms/mL or above, and are greatly
increased in frequency
and severity at concentrations greater than
20 micrograms/mL.1-3 The severity of
toxicity is generally correlated
with age, underlying disease, and serum-
theophylline concentration,
but a distinction has been made between acute
and
chronic theophylline intoxication; symptoms
appear to occur at
Erlenmeyer a lower theophylline concentration in chronic
250 ml, dan encerkan dengan air hingga lebih toxicity than after
kurang 40 acute ingestion of large amounts.1,2,4,5
ml. Tambahkan 8 ml amonium hidroksida 6 N Young infants and the elderly
dan (over 60 years) appear to be at particular risk
lakukan Penetapan kadar seperti tertera pada from chronic
Injeksi intoxication with theophylline.6,7 Older
Aminofilin mulai dari ”Tambahkan 20,0 ml patients with chronic intoxication
perak nitrat may be at greater risk of major toxic effects,
0,1 N LV”. such as
Tiap ml perak nitrat 0,1 N arrhythmias, seizures, and death, than those
setara dengan18,02 mg C7H8N4O2 with acute intoxication.
Wadah dan penyimpanan Dalam wadah 5
tertutup rapat. Common clinical manifestations of
theophylline toxicity after
overdosage of aminophylline or theophylline
include nausea,
vomiting, diarrhoea, agitation, tremor,
hypertonicity, hyperventilation,
supraventricular and ventricular arrhythmias,
hypotension,
and seizures. Metabolic disturbances such as
hypokalaemia,
hyperglycaemia, hypophosphataemia,
hypercalcaemia,
metabolic acidosis, and respiratory alkalosis
often occur.1-3 Other
toxic effects reported include dementia,8 toxic
psychosis,9 symptoms
of acute pancreatitis,10 rhabdomyolysis11-13
with associated
renal failure,11 and acute compartment
syndrome.14
Serious toxic symptoms may not be preceded
by minor symptoms.
In acute intoxication with sustained-release
preparations
the onset of major toxic symptoms may be
delayed for up to 24
hours1 and prolonged monitoring of such
patients is required. Patients
have recovered despite serum-theophylline
concentrations
in excess of 200 micrograms/mL12,14 but
fatalities have occurred
with much lower serum
concentrations.10,15,16 Mortality in severe
poisoning may be as high as 10%.
1. Dawson AH, Whyte IM. The assessment
and treatment of theophylline
poisoning. Med J Aust 1989; 151: 689–93.
2. Minton NA, Henry JA. Acute and chronic
human toxicity of
theophylline. Hum Exp Toxicol 1996; 15:
471–81.
3. Hardy CC, Smith J. Adverse reactions
profile: theophylline and
aminophylline. Prescribers’ J 1997; 37: 96–
101.
4. Olson KR, et al. Theophylline overdose:
acute single ingestion
versus chronic repeated overmedication. Am J
Emerg Med
1985; 3: 386–94.
5. Shannon M. Life-threatening events after
theophylline overdose:
a 10-year prospective analysis. Arch Intern
Med1999;
159: 989–94.
6. Shannon M, Lovejoy FH. Effect of acute
versus chronic intoxication
on clinical features of theophylline poisoning
in children.
J Pediatr 1992; 121: 125–30.
7. Shannon M. Predictors of major toxicity
after theophylline
overdose. Ann Intern Med 1993; 119: 1161–7.
8. Drummond I. Aminophylline toxicity in the
elderly. BMJ 1982;
285: 779–80.
9. Wasser WG, et al. Theophylline madness.
Ann Intern Med 1981;
95: 191.
10. Burgan THS, et al. Fatal overdose of
theophylline simulating
acute pancreatitis. BMJ 1982; 284: 939–40.
11. Macdonald JB, et al. Rhabdomyolysis and
acute renal failure
after theophylline overdose. Lancet 1985; i:
932–3.
12. Rumpf KW, et al. Rhabdomyolysis after
theophylline overdose.
Lancet 1985; i: 1451–2.
13. Modi KB, et al. Theophylline poisoning
and rhabdomyolysis.
Lancet 1985; ii: 160–1.
14. Lloyd DM, et al. Acute compartment
syndrome secondary to
theophylline overdose. Lancet 1990; ii: 312.
15. Whyte KF, Addis GJ. Toxicity of
salbutamol and theophylline
together. Lancet 1983; ii: 618–19.
16. Davies RJ, Hawkey CJ. Fatal theophylline
toxicity precipitated
by in situ pulmonary artery thrombosis.
Postgrad Med J 1989;
65: 49–50.
Effects on carbohydrate metabolism.
Hyperglycaemia is
frequent in theophylline intoxication, and is
thought to be secondary
to theophylline-induced adrenal catecholamine
release.1,2
Whether the effects on blood glucose are
significant at more
modest serum concentrations of theophylline
is unclear, although
in 29 preterm infants, mean plasma-glucose
concentrations
were significantly higher after treatment with
intravenous
aminophylline and oral theophylline than in
those not treated.
Two of 15 treated infants developed clinically
significant hyperglycaemia
and glycosuria. It was recommended that
plasma-glucose
concentrations be monitored in preterm infants
receiving
theophylline.3
1. Kearney TE, et al. Theophylline toxicity
and the beta-adrenergic
system. Ann Intern Med 1985; 102: 766–9.
2. Shannon M. Hypokalemia, hyperglycemia
and plasma catecholamine
activity after severe theophylline intoxication.
J Toxicol
Clin Toxicol 1994; 32: 41–7.
3. Srinivasan G, et al. Plasma glucose changes
in preterm infants
during oral theophylline therapy. J Pediatr
1983; 103: 473–6.
Effects on electrolytes. Hypokalaemia is a
common metabolic
disturbance in theophylline intoxication, but it
has also been
reported1 in patients with plasma-theophylline
concentrations
within the therapeutic range. It is considered
to be secondary to
theophylline-induced adrenal catecholamine
release, with cellular
influx of potassium ions.2 It is recommended1
that plasmapotassium
is monitored during intravenous theophylline
therapy
particularly if other drugs predisposing to
hypokalaemia are also
given (see also Interactions, below).
Hypophosphataemia1,3 and
hyponatraemia1 can also occur at therapeutic
plasma-theophylline
concentrations. Hypomagnesaemia4 and
hypercalcaemia5
have occurred in theophylline overdose.
1. Zantvoort FA, et al. Theophylline and
serum electrolytes. Ann
Intern Med 1986; 104: 134–5.
2. Minton NA, Henry JA. Acute and chronic
human toxicity of theophylline.
Hum Exp Toxicol 1996; 15: 471–81.
3. Laaban J-P, et al. Hypophosphatemia
complicating management
of acute severe asthma. Ann Intern Med 1990;
112: 68–9.
4. Hall KW, et al. Metabolic abnormalities
associated with intentional
theophylline overdose. Ann Intern Med 1984;
101:
457–62.
5. McPherson ML, et al. Theophylline-
induced hypercalcemia.
Ann Intern Med 1986; 105: 52–4.
Effects on the heart. ARRHYTHMIAS.
Theophylline or aminophylline
can precipitate sinus tachycardia and
supraventricular
and ventricular premature contractions at
therapeutic serum-
theophylline concentrations1 and in
overdose.2,3
Multifocal atrial tachycardia has also been
 associated with
both theophylline overdose2 and serum-
theophylline concentrations
within the generally accepted therapeutic
range of 10
HN
NN
N
CH3
O CH3
O
N
NN
HN
CH3
O
O

OMEPRAZOLE

OMEPRAZOL Omeprazole (BAN, USAN, rINN)

H-168/68; Omepratsoli; Omeprazol; Omeprazolas; Oméprazole;
Omeprazole Omeprazolum. (RS)-5-Methoxy-2-(4-methoxy-3,5-dimethyl-
N
HN 2-pyridylmethylsulphinyl)benzimidazole.
S
O Омепразол
N C17H19N3O3S = 345.4.
CH3
H3C OCH3 CAS — 73590-58-6.
H3CO ATC — A02BC01.
1H-Benzimidazol,5-metoksi-2-[[(4-metoksi-3,5-dimetil- ATC Vet — QA02BC01.
Pharmacopoeias. In Chin., Eur. (see p.vii), and US.
2 Ph. Eur. 6.2 (Omeprazole). A white or almost white powder. It
piridinil)metil]sulfinil] exhibits polymorphism. Very slightly soluble in water; sparingly
5-Metoksi-2-[[(4-metoksi-3,5-dimetil-2 piridinil) metil] soluble in alcohol and in methyl alcohol; soluble in dichloromethane.
It dissolves in dilute solutions of alkali hydroxides.
sulfinil]benzimidazol [73590-58-6] Store in airtight containers at a temperature between 2° and 8°.
C17H19N3O3S BM 345,42 Protect from light.
Omeprazol mengandung tidak kurang dari 98,0% dan
tidak lebih dari 102,0% C17H19N3O3S, dihitung terhadap
zat yang telah dikeringkan.
Pemerian Serbuk putih hingga hampir putih, melebur
pada suhu 150º hingga 160º disertai penguraian.
Kelarutan Larut dalam diklorometan, agak sukar larut
dalam metanol dan dalam etanol; sangat sukar larut
dalam
air.
Baku pembanding Omeprazol BPFI; tidak boleh
dikeringkan sebelum digunakan. Simpan dalam wadah
tertutup rapat di tempat dingin, terhindar dari
kelembaban.
Identifikasi
A. Pada uji Kemurnian kromatografi Metode I, harga
Rf bercak utama Larutan identifikasi sama dengan harga
Rf bercak utama Larutan baku yang mengandung
Omeprazol BPFI 0,15 mg per ml.
B. Spektrum serapan inframerah zat yang didispersikan
dalam kalium bromida P, menunjukkan maksimum
hanya
pada bilangan gelombang yang sama seperti pada
Omeprazol BPFI.
Kesempurnaan melarut <901> Memenuhi syarat;
menggunakan larutan 20 mg per ml dalam metilen
klorida P.
Warna larutan Serapan tidak lebih dari 0,10;
ditetapkan
menggunakan larutan yang dibuat untuk uji
Kesempurnaan melarut pada panjang gelombang 440
nm
dalam sel 1-cm menggunakan metilen klorida P sebagai
blangko.
Susut pengeringan <1121> Tidak lebih dari 0,5%;
lakukan pengeringan dalam hampa udara pada suhu
60
selama 4 jam.
Sisa pemijaran <301> Tidak lebih dari 0,1%.
USP 31 (Omeprazole). A white to off-white powder. Very
slightly soluble in water; sparingly soluble in alcohol and in
methyl alcohol; soluble in dichloromethane. Store in airtight containers
at a temperature not exceeding 8°. Protect from moisture.
Omeprazole Magnesium (BANM, USAN, rINNM)
Magnesii Omeprazolum; Omeprazol magnésico; Oméprazole
magnésique; Oméprazole Magnesique; Omeprazolum magnesicum.
Магния Омепразол
C34H36MgN6O6S2 = 713.1.
CAS — 95382-33-5.
ATC — A02BC01.
ATC Vet — QA02BC01.
Pharmacopoeias. In US.
USP 31 (Omeprazole Magnesium). A white to off-white powder.
Very soluble in water and in dichloromethane; slightly soluble
in alcohol; sparingly soluble in methyl alcohol. Store in airtight
containers. Protect from light.
Omeprazole Sodium (BANM, USAN, rINNM)
Natrii Omeprazolum; Omepratsolinatrium; Omeprazol sódico;
Omeprazol sodná sůl monohydrát; Oméprazole sodique; Omeprazolnatrium;
Omeprazol-nátrium; Omeprazolo natrio druska;
Omeprazolum natricum; Omeprazolum Natricum Monohydricum.
Натрий Омепразол
C17H18N3NaO3S = 367.4.
CAS — 95510-70-6.
ATC — A02BC01.
ATC Vet — QA02BC01.
Pharmacopoeias. In Eur. (see p.vii).
Ph. Eur. 6.2 (Omeprazole Sodium). A white or almost white,
hygroscopic powder. Freely soluble in water and in alcohol; very
slightly soluble in dichloromethane; soluble in propylene glycol.
The pH of a 2% solution in water is 10.3 to 11.3. Store in airtight
containers. Protect from light.
Adverse Effects
Proton pump inhibitors are generally well tolerated,
and adverse effects are relatively infrequent. The adverse
effects reported most often with omeprazole and
other proton pump inhibitors have been headache, diarrhoea,
and skin rashes; they have sometimes been severe
enough to require stopping treatment. Other effects
include pruritus, dizziness, fatigue, constipation,
nausea and vomiting, flatulence, abdominal pain, arthralgia
and myalgia, urticaria, and dry mouth. Isolated
cases of photosensitivity, bullous eruption, erythema
multiforme, Stevens-Johnson syndrome, and toxic epidermal
necrolysis have occurred. Hypersensitivity reactions,
including fever, bronchospasm, angioedema,
and anaphylaxis have been reported. Effects on the
CNS include occasional insomnia, somnolence, and
vertigo; reversible confusional states, agitation, depression,
and hallucinations have occurred in severely
ill patients. Raised liver enzymes, and isolated cases
Logamberat <371> Metode III Tidak lebih dari 20 bpj. of hepatitis, jaundice, hepatic failure, and hepatic
encephalopathy, have been reported. Other adverse
effects reported rarely include paraesthesia, blurred
vision, alopecia, stomatitis, increased sweating, taste
disturbances, peripheral oedema, malaise, hyponatraemia,
blood disorders (including agranulocytosis, leucopenia,
and thrombocytopenia), gynaecomastia, impotence,
and interstitial nephritis.
Proton pump inhibitors may increase the risk of gastrointestinal
infections because of their acid suppressive
effects.
Early toxicological studies identified carcinoid-like tumours
of the gastric mucosa in rats given very high
doses of omeprazole over long periods; this is reviewed
in more detail under Gastrointestinal Tumours,
below.
Incidence of adverse effects. Prescription-event monitoring
for 16 205 patients prescribed omeprazole, 17 329 prescribed
lansoprazole, and 11 541 prescribed pantoprazole indicated that
adverse events were reported infrequently, with the most common
being gastrointestinal disturbances and headache. The incidences
of diarrhoea, the most commonly reported event, per
1000 days of exposure, were 0.18 for omeprazole, 0.39 for lansoprazole,
and 0.23 for pantoprazole. Despite the inherent biases
of such a cohort study, there did seem to be some evidence that
lansoprazole might be associated with a somewhat greater risk of
diarrhoea, particularly in the elderly.1
1. Martin RM, et al. The rates of common adverse events reported
during treatment with proton pump inhibitors used in general
practice in England: cohort studies. Br J Clin Pharmacol 2000;
50: 366–72.
Effects on the blood. There have been rare cases of leucopenia,
agranulocytosis, thrombocytopenia, and pancytopenia, with
omeprazole and other proton pump inhibitors such as lansoprazole
and pantoprazole.1-3 Auto-immune haemolytic anaemia has
also been reported with omeprazole.4
1. Holt TL, et al. Neutropenia associated with omeprazole. Med J
Aust 1999; 170: 141–2.
2. Zlabek JA, Anderson CG. Lansoprazole-induced thrombocytopenia.
Ann Pharmacother 2002; 36: 809–11.
3. Watson TD, et al. Pantoprazole-induced thrombocytopenia. Ann
Pharmacother 2006; 40: 758–61.
4. Butt MI, et al. Autoimmune haemolytic anaemia associated with
use of omeprazole. Br J Hosp Med 2007; 68: 108.
Effects on the cardiovascular system. Results and preliminary
analyses from 2 studies raised concerns about a possible increased
risk of myocardial infarction, cardiac failure, and cardiac-
related sudden death in patients taking omeprazole or
esomeprazole compared with patients who received surgery for
gastro-oesophageal reflux disease.1,2 However, an FDA safety
review found that patients who underwent surgery tended to be
younger and less likely to have a history of cardiac problems or
cardiac risk factors than those treated with one of the drugs.2 The
FDA concluded that long-term use of these drugs is not likely to
be associated with an increased risk of cardiac problems. 3 However,
while Health Canada4 considered that there was no evidence
to support such an increased risk with long-term use of
esomeprazole they were unable to make such a definitive conclusion
for omeprazole.
1. FDA. Early communication about an ongoing safety review: omeprazole
(Prilosec) esomeprazole (Nexium) (issued 9th August
2007). Available at: http://www.fda.gov/cder/drug/early_comm/
omeprazole_esomeprazole.htm (accessed 28/01/08)
2. FDA. Follow-up to the August 9, 2007, communication about
the ongoing safety review of omeprazole and esomeprazole (issued
10th December 2007). Available at: http://www.fda.gov/
cder/drug/early_comm/omeprazole_esomepazole_update.htm
(accessed 28/01/08)
3. FDA. FDA’s safety reviews of Prilosec and Nexium find no evidence
of increased rates of cardiac events (issued 10th December
2007). Available at: http://www.fda.gov/bbs/topics/NEWS/
2007/NEW01754.html (accessed 28/01/08)
4. Health Canada. Health Canada completes safety review of Losec
(omeprazole) and Nexium (esomeprazole) (issued 27 February
2008). Available at: http://www.hc-sc.gc.ca/ahc-asc/media/
advisories-avis/_2008/2008_34-eng.php (accessed 09/07/08)
Effects on the endocrine system. Up to December 1991,
WHO had received 30 reports of impotence or gynaecomastia
which might have been due to omeprazole;1 of these reports 15
were of impotence, 13 of gynaecomastia in men, and 2 of breast
enlargement in women. The Spanish Pharmacovigilance System
reported 24 cases of gynaecomastia in association with use of
proton pump inhibitors, including lansoprazole and rabeprazole,
between January 1982 and July 2006. In most of the cases, gynaecomastia
improved after stopping the drug.2 For reference to
a case-control study showing no statistical link between gynaecomastia
and omeprazole, see under Cimetidine, p.1717.
1. Lindquist M, Edwards IR. Endocrine adverse effects of omeprazole.
BMJ 1992; 305: 451–2.
2. Carvajal A, et al. Gynaecomastia associated with proton pump
inhibitors: a case series from the Spanish Pharmacovigilance
System. Drug Safety 2007; 30: 527–31.
Effects on the eyes. Visual disturbances associated with the
use of omeprazole have included 6 cases of irreversible blindness
or visual impairment in severely ill patients given the drug intravenously,
and 13 cases of visual disturbances associated with
oral use.1 As a result of concern about these effects the availability
of intravenous omeprazole was restricted in Germany; however,
the consensus appears to be that a causal link has not been
established between omeprazole and these ocular effects. Suggestions
that visual (and also auditory2) impairment could follow
drug-induced vasculitis2-4 appear to be contentious.1,5-7 A cohort
study involving 140 128 patients receiving antisecretory therapy,
33 988 of whom received omeprazole, found no evidence that
any of the drugs used was associated with a major increase in risk
of vascular or inflammatory disorders of the eye;8 however, the
statistical power of this study was not high.9
1. Creutzfeldt WC, Blum AL. Safety of omeprazole. Lancet 1994;
343: 1098.
2. Schönhöfer PS. Intravenous omeprazole and blindness. Lancet
1994; 343: 665.
3. Schönhöfer PS. Safety of omeprazole and lansoprazole. Lancet
1994; 343: 1369–70.
4. Schönhöfer PS, et al. Ocular damage associated with proton
pump inhibitors. BMJ 1997; 314: 1805.
5. Colin-Jones D. Safety of omeprazole and lansoprazole. Lancet
1994; 343: 1369.
6. Lessell S. Omeprazole and ocular damage. BMJ 1998; 316: 67.
7. Sachs G. Omeprazole and ocular damage. BMJ 1998; 316: 67–8.
8. García Rodríguez LA, et al. A cohort study of the ocular safety
of anti-ulcer drugs. Br J Clin Pharmacol 1996; 42: 213–16.
9. Merlo J, Ranstam J. Ocular safety of anti-ulcer drugs. Br J Clin
Pharmacol 1997; 43: 449.
Effects on the kidneys. Acute interstitial nephritis developed
in 2 elderly patients given omeprazole for the treatment of gastro-
oesophageal reflux disease.1,2 When the drug was stopped,
renal function improved rapidly in 1 patient, but recurred upon
rechallenge,1 while in the other renal function remained severely
affected for several months.2 It was postulated that this adverse
effect might have an allergic mechanism.2 In these cases interstitial
nephritis was associated with rash and eosinophilia; however,
a further 2 cases of acute interstitial nephritis associated with
omeprazole therapy in elderly patients 3,4 did not exhibit these
symptoms. In another report, associated rash without eosinophiluria
was seen.5
The Australian Adverse Drug Reactions Advisory Committee
(ADRAC)6 stated in April 2003 that it had received 18 biopsyconfirmed
reports of interstitial nephritis associated with the use
of omeprazole. These patients had presented with symptoms including
weight loss, malaise, fever, and nausea; polyuria and
polydipsia occurred in one case. Most patients had raised plasma-
urea and/or plasma-creatinine concentrations. ADRAC had
also received 2 reports of interstitial nephritis associated with
rabeprazole.6 A case report (in March 2005) of 2 cases of interstitial
nephritis associated with the omeprazole isomer esomeprazole
noted that, by October 2004, the manufacturer had reported
being aware of some 15 cases worldwide possibly
associated with the drug, and at least 200 associated with omeprazole.
7 Acute interstitial nephritis has also been associated
with the use of pantoprazole in an elderly woman for the treatment
of gastro-oesophageal reflux disease.8
1. Ruffenach SJ, et al. Acute interstitial nephritis due to omeprazole.
Am J Med 1992; 93: 472–3.
2. Christensen PB, et al. Renal failure after omeprazole. Lancet
1993; 341: 55.
3. Assouad M, et al. Recurrent acute interstitial nephritis on rechallenge
with omeprazole. Lancet 1994; 344: 549.
4. Jones B, et al. Acute interstitial nephritis due to omeprazole.
Lancet 1994; 344: 1017–18.
5. Kuiper JJ. Omeprazole-induced acute interstitial nephritis. Am J
Med 1993; 95: 248.
6. Adverse Drug Reactions Advisory Committee (ADRAC). Interstitial
nephritis with the proton pump inhibitors. Aust Adverse
Drug React Bull 2003; 22: 3. Also available at: http://
www.tga.health.gov.au/adr/aadrb/aadr0304.htm (accessed
07/05/04)
7. Geevasinga N, et al. Acute interstitial nephritis secondary to esomeprazole.
Med J Aust 2005; 182: 235–6.
8. Ra A, Tobe SW. Acute interstitial nephritis due to pantoprazole.
Ann Pharmacother 2004; 38: 41–5.
Effects on the liver. Raised liver enzymes have occurred with
omeprazole and other proton pump inhibitors, and there have
been isolated cases of hepatotoxicity. For a study suggesting a
relatively low incidence of acute liver injury in patients receiving
 omeprazole see Cimetidine, p.1717.
References.
1. Jochem V, et al. Fulminant hepatic failure related to omeprazole.
Am J Gastroenterol 1992; 87: 523–5.
2. Kourg SI, et al. Omeprazole and the development of acute hepatitis.
Eur J Emerg Med 1998; 5: 467–9.
Effects on the musculoskeletal system. Progressive muscular
weakness suggestive of myopathy developed in a 78-yearold
patient given oral omeprazole.1 After 4 weeks of treatment
the patient required assistance in walking and rising from squatting.
Weakness resolved on withdrawal of the drug, but returned
on rechallenge. Acute myopathy has also been reported after a
single infusion of omeprazole.2 Analysis of the WHO adverse
drug reaction database in March 2005 revealed 868 reports associating
proton pump inhibitors with myalgia, of which 292 cases
had symptoms indicative of muscle disorders including polymyositis
and rhabdomyolysis.3 Reports implicated omeprazole, pantoprazole,
lansoprazole, esomeprazole, and rabeprazole, and it
was suggested that myopathy was probably a class effect. The
mechanism might involve induction of auto-immune antibodies.
A report of 5 cases of arthralgia, sometimes associated with
swelling of the affected joints, in patients receiving omeprazole, 4
also noted that some reported cases of omeprazole-associated
headache were accompanied by arthralgia or myalgia. In another
case5 arthralgia in a patient with a hereditary myopathy

ALLOPURINOL

ALOPURINOL Allopurinol (BAN, USAN, rINN)

Allopürinol; Allopurinoli; Allopurinolum; Allopurynol; Alopurinol;
Allopurinole Alopurinolis; BW-56-158; HPP; NSC-1390.
NH
N
N
Аллопуринол
N C5H4N4O = 136.1.
O
H CAS — 315-30-0 (allopurinol); 17795-21-0 (allopurinol
1H-Pirazol[3,4-d]pirimidin-4-ol [315-30-0] sodium).
ATC — M04AA01.
C6H4O BM 136,11 ATC Vet — QM04AA01.
Alopurinol mengandung tidak kurang dari 98,0% dan Description. Allopurinol is a tautomeric mixture of 1H-pyrazolo[
3,4-d]pyrimidin-4-ol and 1,5-dihydro-4H-pyrazolo[3,4-
tidak lebih dari 101,0%, C5H4N4O, dihitung terhadap d]pyrimidin-4-one.
zat Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, and US.
Ph. Eur. 6.2 (Allopurinol). A white or almost white powder.
yang telah dikeringkan. Very slightly soluble in water and in alcohol; dissolves in dilute
Pemerian Serbuk halus; putih hingga hampir putih; solutions of alkali hydroxides.
USP 31 (Allopurinol). A fluffy white to off-white powder having
berbau lemah. only a slight odour. Very slightly soluble in water and in alcohol;
Kelarutan Sangat sukar larut dalam air dan dalam
etanol; larut dalam larutan kalium dan dalam natrium
hidroksida; praktis tidak larut dalam kloroform dan
dalam eter.
Baku pembanding Alopurinol BPFI; lakukan
pengeringan dalam hampa udara suhu 105° selama 5
jam
sebelum digunakan; 3-amino-4-karboksamidopirazol
Hemisulfat BPFI; lakukan pengeringan dalam hampa
udara pada suhu 105° selama 3 jam sebelum digunakan.
Identifikasi Spektrum serapan inframerah zat yang
didispersikan dalam kalium bromida P, menunjukkan
maksimum pada panjang gelombang yang sama seperti
pada Alopurinol BPFI.
Susut pengeringan <1121> Tidak lebih dari 0,5%;
lakukan pengeringan dalam hampa udara pada suhu
105º
selama 5 jam.
Kemurnian kromatografi Tidak lebih dari 0,2%;
lakukan penetapan secara Kromatografi lapis tipis
seperti
tertera pada Kromatografi <931>.
Fase gerak Kocok 200 ml n-butanol P dan 200 ml
amonium hidroksida 6 N, buang lapisan bawah dan
tambahkan 20 ml n butanol P pada lapisan atas.
Larutan baku Timbang saksama sejumlah 3-amino-4
karboksamidopirazol Hemisulfat BPFI, larutkan dalam
amonium hidroksida 6 N hingga kadar 50 μg per ml.
Larutan uji Timbang saksama lebih kurang 250 mg
zat, larutkan dalam campuran amonium hidroksida 6
Nnatrium
hidroksida 1 N (9:1) hingga 10,0 ml, campur.
Prosedur Totolkan masing-masing secara terpisah 10
l Larutan baku dan Larutan uji pada lempeng
kromatografi selulosa setebal 0,16 mm yang
mengandung indikator fluoresensi. Masukkan lempeng
ke dalam bejana yang berisi Fase gerak, biarkan
merambat hingga 1 cm di bawah ujung lempeng, angkat
practically insoluble in chloroform and in ether; soluble in solutions
of potassium and sodium hydroxides.
Incompatibility. Allopurinol sodium as a 3 mg/mL solution in
0.9% sodium chloride was visually incompatible with amikacin
sulfate, amphotericin B, carmustine, cefotaxime sodium, chlormethine
hydrochloride, chlorpromazine hydrochloride, cimetidine
hydrochloride, clindamycin phosphate, cytarabine, dacarbazine,
daunorubicin hydrochloride, diphenhydramine hydrochloride,
doxorubicin hydrochloride, doxycycline hyclate,
droperidol, floxuridine, gentamicin sulfate, haloperidol lactate,
hydroxyzine hydrochloride, idarubicin hydrochloride, imipenem
with cilastatin sodium, methylprednisolone sodium succinate,
metoclopramide hydrochloride, minocycline hydrochloride, nalbuphine
hydrochloride, netilmicin sulfate, ondansetron hydrochloride,
pethidine hydrochloride, prochlorperazine edisilate,
promethazine hydrochloride, sodium bicarbonate, streptozocin,
tobramycin sulfate, and vinorelbine tartrate.1
1. Trissel LA, Martinez JF. Compatibility of allopurinol sodium
with selected drugs during simulated Y-site administration. Am J
Hosp Pharm 1994; 51: 1792–9.
Adverse Effects
The most common adverse effect of allopurinol is skin
rash. Rashes are generally maculopapular or pruritic,
sometimes purpuric, but more serious hypersensitivity
reactions may occur and include exfoliative rashes, the
Stevens-Johnson syndrome, and toxic epidermal
necrolysis. It is therefore recommended that allopurinol
be withdrawn immediately if a rash occurs (see
Precautions, below). Further symptoms of hypersensitivity
include fever and chills, lymphadenopathy, leucopenia
or leucocytosis, eosinophilia, arthralgia, and
vasculitis leading to renal and hepatic damage and,
very rarely, seizures. These hypersensitivity reactions
may be severe, even fatal, and patients with hepatic or
renal impairment are at special risk.
Hepatotoxicity and signs of altered liver function may
also be found in patients who are not hypersensitive.
Haematological effects include thrombocytopenia,
aplastic anaemia, agranulocytosis, and haemolytic
anaemia.
Many other adverse effects have been noted rarely and
include paraesthesia, peripheral neuropathy, alopecia,
gynaecomastia, hypertension, taste disturbances, nausea,
vomiting, abdominal pain, diarrhoea, headache,
malaise, drowsiness, vertigo, and visual disturbances.
Patients with gout may have an increase in acute attacks
on beginning treatment with allopurinol, although
attacks usually subside after several months.
Incidence of adverse effects. A Boston Collaborative Drug
Surveillance Program involving 29 524 hospitalised patients
found that, with the exception of skin reactions, 33 of 1835 patients
treated with allopurinol (1.8%) had adverse effects. These
dan keringkan di udara, amati di bawah cahaya effects were dose-related and the most frequent were haematological
(11 patients, 0.6%), diarrhoea (5 patients, 0.3%), and drug
ultraviolet; intensitas bercak lain selain bercak utama fever (5 patients, 0.3%). Hepatotoxicity was reported in 3 patients
dari Larutan uji tidak lebih besar dari bercak utama (0.2%). Two patients developed possible hypersensitivity
reactions to allopurinol.1
Larutan baku. A further analysis involving 1748 outpatients indicated no instances
Cemaran senyawa organik mudah menguap <471> of acute blood disorders, skin diseases, or hypersensitivity
that warranted hospital treatment. Liver disease, although
Metode V Memenuhi syarat. found, was not considered to be associated with allopurinol.
Pelarut Gunakan dimetil sulfoksida P.
Penetapan kadar Timbang saksama lebih kurang 100
mg zat, larutkan dalam 30 ml dimetilformamida P.
Hangatkan bila perlu. Titrasi dengan tetrabutil
amonium
hidroksida 0,1 N LV, amati titik akhir secara
potensiometri menggunakan sistem elektrode
kacakalomel,
jaga agar tidak terjadi penyerapan karbon
dioksida dari udara. Lakukan penetapan blangko.
Tiap ml tetrabutilamonium hidroksida 0,1 N
setara dengan 13,61 mg C5H4N4O
Wadah dan penyimpanan Dalam wadah tertutup baik.
TABLET ALOPURINOL
Allopurinole Tablet
Tablet Alopurinol mengandung Alopurinol, C5H4N4O,
tidak kurang dari 93,0% dan tidak lebih dari 107,0%
dari
jumlah yang tertera pada etiket.
Baku pembanding Alopurinol BPFI; lakukan
pengeringan dalam hampa udara pada suhu 105
selama
5 jam sebelum digunakan.
Identifikasi Timbang sejumlah serbuk tablet setara
dengan 50 mg alopurinol, gerus dengan 10 ml natrium
hidroksida 0,1 N, saring. Asamkan filtrat dengan asam
asetat 1 N, diamkan 10 - 15 menit agar terjadi
pengendapan yang cukup, kumpulkan endapan yang
terbentuk. Cuci endapan dengan 3 ml etanol mutlak P
sedikit demi sedikit dan akhirnya cuci dengan 4 ml eter
P. Biarkan kering di udara selama 15 menit, keringkan
pada suhu 105 selama 3 jam: endapan yang diperoleh
memenuhi Identifikasi seperti tertera pada Alopurinol.
Disolusi <1231>
Media disolusi : 900 ml asam klorida 0,1 N.
Alat tipe 2 : 75 rpm.
Waktu : 45 menit.
Prosedur : Lakukan penetapan jumlah, C5H4N4O,
yang terlarut dengan mengukur serapan alikuot, jika
perlu diencerkan dengan asam klorida 0,1 N dan
serapan
larutan baku Alopurinol BPFI dalam media yang sama
pada panjang gelombang serapan maksimum lebih
kurang 250 nm.
Toleransi Dalam waktu 45 menit harus larut tidak
kurang dari 75% (Q) C5H4N4O, dari jumlah yang tertera
pada etiket.
Keseragaman sediaan <911> Memenuhi syarat.
Penetapan kadar Lakukan penetapan dengan cara
Kromatografi cair kinerja tinggi seperti tertera pada
Kromatografi <931>.

PHENYTOIN

FENITOIN Phenytoin (BAN, USAN, rINN)

Difenilhidantoína; Diphenylhydantoin; Fanantina; Fenantoína;
Phenytoin Fenitoin; Fenitoína; Fenitoinas; Fenytoiini; Fenytoin; Fenytoina;
NH
N Phenantoinum; Phénytoïne; Phenytoinum. 5,5-Diphenylhydantoin;
H
O 5,5-Diphenylimidazolidine-2,4-dione.
O Фенитоин
5,5-Difenilhidantoin [57-41-0] C15H12N2O2 = 252.3.
CAS — 57-41-0.
C15H12N2O2 BM 252,27 ATC — N03AB02.
Fenitoin mengandung tidak kurang dari 98,0% dan ATC Vet — QN03AB02.
Pharmacopoeias. In Eur. (see p.vii), Int., Jpn, US, and Viet.
tidak Ph. Eur. 6.2 (Phenytoin). A white or almost white, crystalline
lebih dari 102,0% C15H12N2O2, dihitung terhadap zat powder. Practically insoluble in water; sparingly soluble in alcohol;
yang telah dikeringkan. very slightly soluble in dichloromethane. It dissolves in dilute
solutions of alkali hydroxides.
Pemerian Serbuk; putih; tidak berbau. Melebur pada USP 31 (Phenytoin). A white, odourless powder. Practically
suhu lebih kurang 295°. insoluble in water; soluble in hot alcohol; slightly soluble in cold
alcohol, in chloroform, and in ether. Store in airtight containers.
Kelarutan Praktis tidak larut dalam air; larut dalam Phenytoin Sodium (BANM, rINNM)
etanol panas; sukar larut dalam etanol dingin, klorofrom Diphenin; Fenitoin Sodyum; Fenitoína sódica; Fenitoin-nátrium;
dan eter. Fenitoino natrio druska; Fenytoiininatrium; Fenytoin sodná sůl;
Baku pembanding Fenitoin BPFI; Tidak boleh
dikeringkan. Simpan dalam wadah tertutup rapat.
Kejernihan dan warna larutan Larutkan 1,0 g zat
dalam campuran 5 ml natrium hidroksida 1 N dan 20
ml air: larutan jernih dan tidak lebih tua dari kuning
pucat.
Identifikasi Spektrum serapan inframerah zat yang
didispersikan dalam kalium bromida P menunjukkan
maksimum hanya pada bilangan gelombang yang sama
seperti pada Fenition BPFI.
Susut pengeringan <1121> Tidak lebih dari 1,0%;
lakukan pengeringan pada suhu 105° selama 4 jam.
Logamberat <371> Metode III Tidak lebih dari 20 bpj.
Batas benzofenon Tidak lebih dari 0,1%. Lakukan
penetapan dengan cara Kromatografi cair kinerja tinggi
seperti tertera pada kromatografi.
Fase gerak dan Larutan uji Buat seperti tertera pada
Kemurnian kromatografi.
Larutan baku Timbang saksama sejumlah
benzofenon, larutkan dalam metanol P, jika perlu
encerkan secara kuantitatif dan bertahap dengan
metanol P hingga kadar lebih kurang 1,0 g per ml.
Sistem kromatografi Gunakan sistem yang sama
seperti tertera pada Kemurnian kromatografi kecuali:
suntikkan Larutan baku tiga kali dan rekam
kromatogram dan ukur respons puncak seperti tertera
pada Prosedur: simpangan baku relatif pada
penyuntikan ulang tidak lebih dari 5,0%.
Prosedur Suntikkan secara terpisah sejumlah volume
sama (lebih kurang 20 l) Larutan baku dan Larutan
uji
ke dalam kromatograf, rekam kromatogram dan ukur
respons semua puncak. Waktu retensi relatif fenitoin
dan
benzofenon masing-masing lebih kurang 0,25 dan 1,0.
Hitung persentase benzofenon dalam zat uji dengan
rumus:
 
Fenytoina sodowa; Fenytoinnatrium; Natrii Phenytoinum; Phénytoïne
sodique; Phenytoinum natricum; Soluble Phenytoin.
Натрий Фенитоин
C15H11N2NaO2 = 274.2.
CAS — 630-93-3.
ATC — N03AB02.
ATC Vet — QN03AB02.
Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, and US.
Ph. Eur. 6.2 (Phenytoin Sodium). A white or almost white,
slightly hygroscopic, crystalline powder. Soluble in water and in
alcohol; practically insoluble in dichloromethane. Store in airtight
containers.
USP 31 (Phenytoin Sodium). A white, odourless powder. Is
somewhat hygroscopic and on exposure to air gradually absorbs
carbon dioxide. Freely soluble in water, the solution usually being
somewhat turbid due to partial hydrolysis and absorption of
carbon dioxide; soluble in alcohol; practically insoluble in chloroform
and in ether. Store in airtight containers.
Incompatibility. Phenytoin sodium only remains in solution
when the pH is considerably alkaline (about 10 to 12) and there
have been reports of loss of clarity or precipitation of phenytoin
crystals when solutions of phenytoin sodium for injection have
been mixed with other drugs1-6 or added to intravenous infusion
fluids,7-10 while binding has been reported after addition to
enteral nutrition solutions.11 A phenytoin precipitate has blocked
implanted central venous access devices after the inadvertent admixture
of phenytoin sodium with glucose 5% or glucose in sodium
chloride (pH 4);12,13 the blockage can be successfully
cleared by the local instillation of sodium bicarbonate 8.4% to
increase the pH of the medium.
1. Misgen R. Compatibilities and incompatibilities of some intravenous
solution admixtures. Am J Hosp Pharm 1965; 22: 92–4.
2. Patel JA, Phillips GL. A guide to physical compatibility of intravenous
drug admixtures. Am J Hosp Pharm 1966; 23:
409–11.
3. Klamerus KJ, et al. Stability of nitroglycerin in intravenous admixtures.
Am J Hosp Pharm 1984; 41: 303–5.
4. Hasegawa GR, Eder JF. Visual compatibility of dobutamine hydrochloride
with other injectable drugs. Am J Hosp Pharm
1984; 41: 949–51.
5. Gayed AA, et al. Visual compatibility of diltiazem injection
with various diluents and medications during simulated Y-site
injection. Am J Health-Syst Pharm 1995; 52: 516–20.
6. Trissel LA, et al. Compatibility of propofol injectable emulsion
with selected drugs during simulated Y-site administration. Am
J Health-Syst Pharm 1997; 54: 1287–92.
7. Bauman JL, et al. Phenytoin crystallization in intravenous fluids.
Drug Intell Clin Pharm 1977; 11: 646–9.
8. Bauman JL, Siepler JK. Intravenous phenytoin (concluded). N
Engl J Med 1977; 296: 111.
9. Cloyd JC, et al. Concentration-time profile of phenytoin after
admixture with small volumes of intravenous fluids. Am J Hosp
Pharm 1978; 35: 45–8.
10. Giacona N, et al. Crystallization of three phenytoin preparations
in intravenous solutions. Am J Hosp Pharm 1982; 39: 630–4.
11. Miller SW, Strom JG. Stability of phenytoin in three enteral nutrient
formulas. Am J Hosp Pharm 1988; 45: 2529–32.
12. Akinwande KI, Keehn DM. Dissolution of phenytoin precipitate
with sodium bicarbonate in an occluded central various access
device. Ann Pharmacother 1995; 29: 707–9.
 13. Tse CST, Abdullah R. Dissolving phenytoin precipitate in central
 venous access device. Ann Intern Med 1998; 128: 1049.
  Adverse Effects
Adverse effects are fairly frequent in patients receiving
 phenytoin, but some remit with dose reduction or continued
 use. Often reported are CNS-related effects
(such as headache, dizziness, tremor, transient nervousness,
 and insomnia), and gastrointestinal disturbances
 including nausea, vomiting, and constipation.
Tenderness and hyperplasia of the gums often occur,
 particularly in younger patients. Acne, hirsutism, and
S
U coarsening of the facial features may be associated
with phenytoin therapy, and may be particularly undesirable
r in adolescents and women.
r Phenytoin toxicity may be manifested as a syndrome
D of cerebellar, vestibular, and ocular effects, notably
nystagmus, diplopia, slurred speech, and ataxia.
100 C Mental confusion, sometimes severe, may occur, and
C adalah kadar benzofenon dalam g per ml Larutan dyskinesias and exacerbations of seizure frequency
baku; D adalah kadar fenitoin dalam g per ml have been noted. Hyperglycaemia has been associated
with toxic concentrations.
Larutan Overdosage may result in hypotension, coma, and respiratory
uji; rU dan rS berturut-turut adalah respons puncak depression. Hypotension and CNS depression
benzofenon yang diperoleh dari Larutan uji dan may also follow intravenous dosage, if too rapid, as
Larutan may cardiac arrhythmias and impaired cardiac conduction.
Solutions for injection are very alkaline and may
baku. result in irritation at the injection site or phlebitis. A
Kemurnian kromatografi Total cemaran tidak lebih syndrome of distal limb oedema, discoloration, and
dari 0,9%, tidak termasuk benzofenon. pain (‘purple glove syndrome’) has been reported occasionally.
Fase gerak Buat seperti tertera pada Penetapan kadar. Prolonged therapy may produce subtle effects on
mental function and cognition, especially in children.
Larutan baku Timbang saksama sejumlah Fenitoin In addition there is some evidence that phenytoin interferes
BPFI, larutkan dalam metanol P, jika perlu $encerkan with vitamin D and folate metabolism. Rickets
secara kuantitatif dan bertahap dengan metanol P and osteomalacia have occurred in a few patients not
exposed to adequate sunlight, although the causal role
hingga kadar lebih kurang 10 g per ml.
of phenytoin is debatable. A proportion of patients develop
Larutan uji Gunakan Larutan uji A, seperti tertera peripheral neuropathies, usually mild, and occasional
pada Penetapan kadar. cases of megaloblastic anaemia have been seen.
Larutan resolusi Buat larutan benzoin dalam metanol Mild hypersensitivity reactions are common, with skin
rashes, often morbilliform, sometimes accompanied
P hingga kadar lebih kurang 10 g per ml. Larutkan 10 by fever. Bullous, exfoliative, or purpuric rashes may
mg Fenitoin BPFI dalam 10,0 ml larutan benzoin. be symptoms of rare but severe reactions such as lupus
Sistem kromatografi Lakukan seperti tertera pada erythematosus, erythema multiforme, Stevens-Johnson
Kromatografi <931>. Kromatograf cair kinerja tinggi syndrome, or toxic epidermal necrolysis. Eosinophilia,
lymphadenopathy, hepatitis, polyarteritis
dilengkapi dengan detektor 220 nm dan kolom 4,6 mm nodosa, and blood disorders such as aplastic anaemia,
x leucopenia, thrombocytopenia, and agranulocytosis,
25 cm berisi bahan pengisi L1 dengan ukuran partikel 5 have occurred rarely; some of these conditions may
m. Laju alir lebih kurang 1,5 ml per menit. Lakukan also represent hypersensitivity reactions.
kromatografi terhadap Larutan resolusi, rekam
kromatogram dan ukur respons puncak seperti tertera
pada Prosedur: waktu retensi relatif fenitoin dan
benzoin berturut-turut adalah lebih kurang 0,75 dan 1,0
dan resolusi, R, tidak kurang dari 1,5.
Prosedur Suntikkan secara terpisah sejumlah volume
sama (lebih kurang 20 l) Larutan baku dan Larutan
uji
GENTAMYCIN
GENTAMISIN SULFAT
Gentamycin Sulfate
Gentamisin sulfat [1405-41-0]
Gentamisin Sulfat adalah garam sulfat atau campuran
dari antibiotik yang dihasilkan oleh pembiakan
Micromonospora purpurea. Potensi setara dengan tidak
kurang dari 590 μg per mg gentamisin, dihitung
terhadap
zat yang telah dikeringkan.
- 482 -
Pemerian Serbuk; putih sampai kekuning-kuningan.
Hypoprothrombinaemia of the newborn after use of
phenytoin during pregnancy has been reported. Congenital
malformations have been seen in the offspring
of mothers receiving phenytoin during pregnancy (see
under Precautions, below).
Effects on the blood. AGRANULOCYTOSIS. Fatal agranulocytosis
has been reported1 in a patient 17 years after starting
therapy with phenytoin and primidone. In the report it was
stated that since 1963 the UK CSM had received reports of 3
previous cases of fatal agranulocytosis associated with
phenytoin and none associated with primidone. The most
likely cause was considered to be a direct toxic effect of
phenytoin although other possible mechanisms included the
ability of both drugs to produce folate deficiency. For a discussion
of the effect of antiepileptics on serum folate, see below.
1. Laurenson IF, et al. Delayed fatal agranulocytosis in an epileptic
taking primidone and phenytoin. Lancet 1994, 344: 332–3.
FOLIC ACID DEFICIENCY. Antiepileptic therapy has long been
associated with folate deficiency: early studies suggested that
more than half of all patients on long-term therapy with drugs
such as phenytoin, phenobarbital, and primidone had subnormal
serum-folate concentrations.1,2 Megaloblastic haematopoiesis
is often present,3 but clinical megaloblastic anaemia
appears to be rare.
The relative importance of individual antiepileptics in causing
folate deficiency and macrocytosis has been difficult to establish,
because of the tendency to use combination regimens; with
greater emphasis on single drug therapy there is evidence that
monotherapy may produce less significant changes.4,5 Despite
suggestions that carbamazepine has relatively little effect on folic
acid concentrations, its effects have been found to be comparable
with those of phenytoin;5 however, valproate had little or no effect
on red cell folate concentrations.
Gentamicin Sulfate (USAN, pINNM)
Gentamicin sulfát; Gentamicin Sulphate (BANM); Gentamicine,
sulfate de; Gentamicini sulfas; Gentamicino sulfatas; Gentamicinsulfat;
Gentamicin-szulfát; Gentamisiinisulfaatti; Gentamisin Sülfat;
Gentamycyny siarczan; NSC-82261; Sch-9724; Sulfato de gentamicina.
Гентамицина Сульфат
CAS — 1403-66-3 (gentamicin); 1405-41-0 (gentamicin
sulfate).
ATC — D06AX07; J01GB03; S01AA11; S02AA14;
S03AA06.
ATC Vet — QD06AX07; QJ01GB03; QS01AA11;
QS02AA14; QS03AA06.
(gentamicin)
NOTE. GNT is a code approved by the BP 2008 for use on single
unit doses of eye drops containing gentamicin sulfate where the
Kelarutan Larut dalam air; tidak larut dalam etanol,
aseton, kloroform, eter dan benzen.
Baku pembanding Gentamisin Sulfat BPFI; lakukan
pengeringan dalam hampa udara dengan tekanan tidak
lebih dari 5 mmHg pada suhu 110º selama 3 jam
sebelum digunakan. Gunakan segera zat yang telah
dikeringkan dan lakukan pengerjaan dalam lingkungan
udara kering. Simpan dalam wadah tertutup rapat,
terlindung cahaya, di tempat dingin. Endotoksin BPFI
[Catatan Bersifat pirogenik, penanganan vial dan
isinya
harus hati-hati untuk menghindari kontaminasi.].
Rekonstitusi semua isi, gunakan larutan dalam waktu
14
hari. Simpan vial yang belum dibuka dan larutan dalam
lemari pendingin.
Identifikasi
A. Spektrum serapan inframerah zat yang
didispersikan dalam kalium bromida P menunjukkan
maksimum hanya pada bilangan gelombang yang sama
seperti pada Gentamisin Sulfat BPFI.
B. Menunjukkan reaksi Sulfat seperti tertera pada Uji
Identifikasi Umum <291>.
Rotasi jenis <1081> Antara +107º dan +121º, dihitung
terhadap zat yang telah dikeringkan; lakukan penetapan
menggunakan larutan yang mengandung 10 mg per ml.
pH <1071> Antara 3,5 dan 5,5; lakukan penetapan
menggunakan larutan (1 dalam 25).
Susut pengeringan <1121> Tidak lebih dari 18,0%;
lakukan pengeringan dalam hampa udara dengan
tekanan tidak lebih dari 5 mmHg pada suhu 110º
selama
3 jam.
Sisa pemijaran <301> Tidak lebih dari 1,0%.
Metanol Tidak lebih dari 1,0%. Lakukan penetapan
dengan cara Kromatografi gas seperti tertera pada
Kromatografi <931>.
Larutan baku internal Pipet 2,5 ml n-propil alkohol P,
individual container may be too small to bear all the appropriate
labelling information.
Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, US, and
Viet.
Ph. Eur. 6.2 (Gentamicin Sulphate). A mixture of the sulfates of
antimicrobial substances produced by Micromonospora purpurea,
the main components being gentamicins C1, C1a, C2, C2a,
and C2b. It contains 20 to 40% of gentamicin C1, 10 to 30% of
gentamicin C1a; the sum of gentamicins C2, C2a, and C2b is 40
to 60%. The potency is not less than 590 units/mg, calculated
with reference to the anhydrous substance. A white or almost
white hygroscopic powder. Freely soluble in water; practically
insoluble in alcohol. A 4% solution in water has a pH of 3.5 to
5.5. Store in airtight containers.
USP 31 (Gentamicin Sulfate). The sulfate salt, or a mixture of
such salts, of antibiotic substances produced by the growth of
Micromonospora purpurea. The content of gentamicin C1 is between
25 and 50%, the content of gentamicin C1a is between 10
and 35%, and the sum of the contents of gentamicin C2a and
gentamicin C2 is between 25 and 55%. It has a potency equivalent
to not less than 590 micrograms of gentamicin per mg, calculated
on the dried basis. A white to buff powder. Freely soluble
in water; insoluble in alcohol, in acetone, in chloroform, in ether,
and in benzene. pH of a 4% solution in water is between 3.5 and
5.5. Store in airtight containers.
Incompatibility. The aminoglycosides are inactivated in vitro
by various penicillins and cephalosporins via an interaction with
the beta-lactam ring, the extent of inactivation depending on temperature,
concentration, and duration of contact. The different
aminoglycosides vary in their stability, with amikacin apparently
the most resistant and tobramycin the most susceptible to inactivation;
gentamicin and netilmicin are of intermediate stability.
The beta lactams also vary in their ability to produce inactivation,
with ampicillin, benzylpenicillin, and antipseudomonal penicillins
such as carbenicillin and ticarcillin producing marked inactivation.
Inactivation has also been reported with clavulanic acid.
Gentamicin is also incompatible with furosemide, heparin, sodium
bicarbonate (the acid pH of gentamicin solutions may liberate
carbon dioxide), and some solutions for parenteral nutrition.
Interactions with preparations having an alkaline pH (such as
sulfadiazine sodium), or drugs unstable at acid pH (for example
erythromycin salts), might reasonably be expected.
Given their potential for incompatibility, gentamicin and other
aminoglycosides should not generally be mixed with other drugs
in syringes or infusion solutions nor given through the same intravenous
line. When aminoglycosides are given with a beta
lactam, they should generally be given at separate sites.
General references.
1. Henderson JL, et al. In vitro inactivation of gentamicin, tobramycin,
and netilmicin by carbenicillin, azlocillin, or mezlocillin.
Am J Hosp Pharm 1981; 38: 1167–70.
2. Tindula RJ, et al. Aminoglycoside inactivation by penicillins and
cephalosporins and its impact on drug-level monitoring. Drug
Intell Clin Pharm 1983; 17: 906–8.
3. Navarro AS, et al. In-vitro interaction between dibekacin and
penicillins. J Antimicrob Chemother 1986; 17: 83–9.
4. Courcol RJ, Martin GR. Comparative aminoglycoside inactivation

ke dalam labu tentukur 500-ml, encerkan dengan air
sampai tanda. Larutan ini mengandung n-propil alkohol
0,50%(v/v).
Larutan baku Pipet 1,25 ml metanol P dan 1,25 ml
npropil
alkohol P, ke dalam labu tentukur 500-ml,
encerkan dengan air sampai tanda. Larutan
mengandung
metanol 0,25% (v/v) dan n-propil alkohol 0,25%(v/v).
Larutan kontrol Timbang lebih kurang 500 mg zat dan
larutkan dalam 2 ml air.
Larutan uji Timbang lebih kurang 500 mg zat dan
larutkan dalam 1 ml Larutan baku internal dan
tambahkan 1 ml air.
Sistem kromatografi Lakukan seperti tertera pada
Kromatografi <931>. Kromatograf gas dilengkapi
dengan detektor ionisasi nyala dan kolom 4 mm x 1,5
m berisi bahan pengisi S3. Pertahankan suhu kolom
pada
suhu tetap antara 120° dan 140°, suhu injektor dan
detektor dipertahankan pada suhu tetap tidak kurang
dari
50° lebih tinggi dari suhu kolom. Gunakan nitrogen P
sebagai gas pembawa dengan kecepatan alir tetap,
antara
30 dan 40 ml per menit. Lakukan kromatografi terhadap
Larutan baku dan Larutan kontrol, rekam kromatogram
dan ukur respons puncak seperti tertera pada Prosedur:
resolusi, R, antara puncak n-propil alkohol dan metanol
tidak kurang dari 1,0; jika ada puncak dengan waktu
retensi yang sesuai dengan waktu retensi n-propil
alkohol dari Larutan kontrol, gunakan respons puncak
tersebut untuk mengkoreksi respons puncak n-propil
alkohol dari Larutan uji.
Prosedur Suntikkan secara terpisah, menggunakan
siring dengan pengisap politef, sejumlah volume sama
(lebih kurang 2 l) Larutan baku dan Larutan uji ke
dalam kromatograf, rekam kromatogram, ukur respons
by potassium clavulanate. J Antimicrob Chemother 1986;
17: 682–4.
Stability. There was an average 16% potency loss of gentamicin
sulfate from solutions containing 10 and 40 mg/mL when stored
at 4° or 25° in plastic disposable syringes for 30 days, and a
brown precipitate formed in several. Storage in glass disposable
syringes for 30 days produced an average 7% potency loss,
which was considered acceptable, but storage for longer resulted
in precipitate formation in some cases and was not recommended.
1
1. Weiner B, et al. Stability of gentamicin sulfate injection following
unit dose repackaging. Am J Hosp Pharm 1976; 33: 1254–9.
Adverse Effects
The aminoglycosides can produce irreversible, cumulative
ototoxicity. This affects both the cochlea (manifest
as hearing loss, initially of higher tones, and which,
because speech recognition relies greatly on lower frequencies,
may not be at first apparent) and the vestibular
system (manifest as dizziness or vertigo). The incidence
and relative toxicity with different
aminoglycosides is a matter of some dispute, but
netilmicin is probably less cochleotoxic than gentamicin
or tobramycin, and amikacin more so. Netilmicin
also exhibits less vestibular toxicity than gentamicin,
tobramycin, or amikacin, while streptomycin
produces a high incidence of vestibular damage. Vestibular
damage is more common than hearing loss in
patients receiving gentamicin.
Reversible nephrotoxicity may occur and acute renal
failure has been reported, often in association with the
use of other nephrotoxic drugs. Renal impairment is
usually mild, although acute tubular necrosis and interstitial
nephritis have occurred. Decreased glomerular
filtration rate is usually seen only after several days,
and may even occur after therapy has stopped. Electrolyte
disturbances (notably hypomagnesaemia, but also
hypocalcaemia and hypokalaemia) have occurred. The
nephrotoxicity of gentamicin is reported to be largely
due to the gentamicin C2 component.
Although particularly associated with high plasma
concentrations, many risk factors have been suggested
for ototoxicity and nephrotoxicity in patients receiving
aminoglycosides—see Precautions below.
Aminoglycosides possess a neuromuscular-blocking
action and respiratory depression and muscular paralysis
have been reported, notably after absorption from
serous surfaces. Neomycin has the most potent action
and several deaths have been associated with its use.
Hypersensitivity reactions have occurred, especially
after local use, and cross-sensitivity between
aminoglycosides may occur. Very rarely, anaphylactic
puncak n-propil alkohol dan metanol. Hitung persentase
metanol dalam zat dengan rumus:
 
 Infrequent effects reported for gentamicin include
reactions to gentamicin have occurred. Some hypersensitivity
reactions have been attributed to the presence
of sulfites in parenteral formulations, and endotoxic
shock has also been reported.
blood dyscrasias, purpura, nausea and vomiting, stomatitis,
and signs of liver dysfunction such as increased
serum-aminotransferase values and increased
serum-bilirubin concentrations. Neurotoxicity has occurred,
with both peripheral neuropathies and central
symptoms being reported including encephalopathy,
confusion, lethargy, hallucinations, convulsions, and
mental depression.
Atrophy or fat necrosis has been reported at injection
sites. There have been isolated reports of meningeal irritation,
arachnoiditis, polyradiculitis, and ventriculitis
after intrathecal, intracisternal, or intraventricular use
of aminoglycosides. Subconjunctival injection of gentamicin
may lead to pain, hyperaemia, and conjunctival
oedema, while severe retinal ischaemia has followed
intra-ocular injection.
Effects on the ears. Reviews and references to aminoglycoside-
induced ototoxicity.
1. Cone LA. A survey of prospective, controlled clinical trials of
gentamicin, tobramycin, amikacin, and netilmicin. Clin Ther
1982; 5: 155–62.
2. Kahlmeter G, Dahlager JI. Aminoglycoside toxicity—a review
of clinical studies published between 1975 and 1982. J Antimicrob
Chemother 1984; 13 (suppl A): 9–22.
3. Brummett RE, Fox KE. Aminoglycoside-induced hearing loss in
humans. Antimicrob Agents Chemother 1989; 33: 797–800.
4. Mattie H, et al. Determinants of efficacy and toxicity of
aminoglycosides. J Antimicrob Chemother 1989; 24: 281–93.
5. Schacht J. Aminoglycoside ototoxicity: prevention in sight?
Otolaryngol Head Neck Surg 1998; 118: 674–7.
6. Nakashima T, et al. Vestibular and cochlear toxicity of
aminoglycosides—a review. Acta Otolaryngol 2000; 120:
904–11.
7. Darlington CL, Smith PF. Vestibulotoxicity following aminoglycoside
antibiotics and its prevention. Curr Opin Investig Drugs
2003; 4: 841–6.
8. Rizzi MD, Hirose K. Aminoglycoside ototoxicity. Curr Opin
Otolaryngol Head Neck Surg 2007; 15: 352–7.
Effects on the kidneys. Reviews and references to aminoglycoside-
induced nephrotoxicity.
1. Cone LA. A survey of prospective, controlled clinical trials of
gentamicin, tobramycin, amikacin, and netilmicin. Clin Ther
1982; 5: 155–62.
2. Lietman PS, Smith CR. Aminoglycoside nephrotoxicity in humans.
Rev Infect Dis 1983; 5 (suppl 2): S284–93.
3. Kahlmeter G, Dahlager JI. Aminoglycoside toxicity—a review
of clinical studies published between 1975 and 1982. J Antimicrob
Chemother 1984; 13 (suppl A): 9–22.
4. Kohlhepp SJ, et al. Nephrotoxicity of the constituents of the
gentamicin complex. J Infect Dis 1984; 149: 605–14.
5. Mattie H, et al. Determinants of efficacy and toxicity of
aminoglycosides. J Antimicrob Chemother 1989; 24: 281–93.
6. Appel GB. Aminoglycoside nephrotoxicity. Am J Med 1990; 88
(suppl 3C): 16S–20S.
7. Bertino JS, et al. Incidence of and significant risk factors for
aminoglycoside-associated nephrotoxicity in patients dosed by
using individualized pharmacokinetic monitoring. J Infect Dis
1993; 167: 173–9.
8. Swan SK. Aminoglycoside nephrotoxicity. Semin Nephrol
1997; 17: 27–33.
9. Baciewicz AM, et al. Aminoglycoside-associated nephrotoxicity
in the elderly. Ann Pharmacother 2003; 37: 182–6.
10. Rougier F, et al. Aminoglycoside nephrotoxicity. Curr Drug
Targets Infect Disord 2004; 4: 153–62.
11. Martínez-Salgado C, et al. Glomerular nephrotoxicity of
aminoglycosides. Toxicol Appl Pharmacol 2007; 223: 86–98.
Endotoxin reactions. Reports of endotoxin reactions associated
with intravenous gentamicin have been received by the CDC
and the FDA in the USA.1 Although endotoxin concentrations in
the injections used were within USP limits, giving a single daily
dose rather than divided doses was thought to have resulted in
toxic serum concentrations of endotoxins.1,2
1. CDC. Endotoxin-like reactions associated with intravenous gentamicin—
California, 1998. MMWR 1998; 47: 877–80.
2. Krieger JA, Duncan L. Gentamicin contaminated with endotoxin.
N Engl J Med 1999; 340: 1122.
Gentamicin C1
Gentamicin C2
Gentamicin C1a
R1 = R2 = CH3
R1 = CH3, R2 = H
R1 = R2 = H
O
R1
HN R2
O
H2N H2N
HO
O
HO O
NH
OH
CH3
H3C
NH2