PROPOSED ANNOTATED PROFESSIONAL INFORMATION
Reference
1
SCHEDULING STATUS: Medicines and
related
2
S0 Pack of 20 tablets Substances Act,
1965 (Act 101 of
3
1965), as
amended.
4
S1 Pack of 100 tablets
5
1. NAME OF THE MEDICINE:
6
[PRODUCT NAME], tablet [Sec. 1.2.1]
7
8
2. QUALITATIVE AND QUANTITATIVE COMPOSITION:
9
Each tablet contains 500 mg paracetamol. [Sec. 3.2.P.1]
10
Sugar free
Professional
11
For full list of excipients, see section 6.1 Information
Guideline
12
2.16_Jul19_v2
13
3. PHARMACEUTICAL FORM
14
Tablet
15
White, round, flat, beveled edge tablets, plain on one side and [Sec.3.2.P.5.1]
16
break line on the other side.
17
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
18
4. CLINICAL PARTICULARS:
19
4.1 Therapeutic indications
20
The relief of mild to moderate pain and fever such as [Ref. 1.3.1.2: std-
1, page 1, line
21
headaches, toothache and pain associated with colds and flu. 24-26]
22
23
4.2 Posology and method of administration
24
Posology
25
Children 6 – 12 years: ½ - 1 tablet every 6 hours. Not
26
more than 4 doses to be taken in
27
any24-hour period.
28
Children over 12 years: 1 tablet every 4 – 6 hours. Not
29
more than 4 tablets to be taken in
30
any 24-hour period.
31
Adults: 1 – 2 tablets every 4 – 6 hours.
32
Not more than 8 tablets to be
33
taken in any 24-hour period.
34
DO NOT EXCEED THE RECOMMENDED DOSE
35
36
Paediatric population:
[Ref. 1.3.1.2: std-
37
Children under 6 years: Not recommended. 1, page 2, line 20-
26]
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
38
Method of administration
39
[PRODUCT NAME] should be taken orally. The tablets should
40
be swallowed with liquid and should not be chewed.
41
42
4.3 Contraindications
43
[PRODUCT NAME] is contraindicated in the following:
44
• Hypersensitivity to paracetamol, or any of the other
[Ref. 1.3.1.2: std-
45
ingredients in [PRODUCT NAME]. 1, page 1, line 29-
32]
46
• Severe liver function impairment.
47
48
4.4 Special warnings and precautions for use
49
• Consult a doctor or pharmacist if pain or fever persists or
50
gets worse at the recommended dosage, or if new
51
symptoms occur.
52
• Do not use [PRODUCT NAME] continuously without
53
consulting a medical practitioner:
54
Pain – for more than 7 days in adults (5 days for
55
children); and
56
Fever – for more than 3 days.
57
• Dosages in excess of those recommended may cause
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
58
severe liver damage.
59
• Patients suffering from hepatitis or alcoholism, or
60
recovering from any form of liver disease should not take
61
excessive quantities of [PRODUCT NAME].
62
• Caution is recommended in patients with moderate renal
63
failure and patients on dialysis, as plasma concentrations
64
of [PRODUCT NAME] and its conjugates are increased. [Ref. 1.3.1.2: std-
1, Page 1, line
65
• Use with caution in renal impairment, chronic 34-44]
66
malnutrition or dehydration.
67
• Caution should be exercised in patients with glutathione
68
depleted states, as the use of paracetamol may increase
69
the risk of metabolic acidosis. [Ref. 1.3.1.2: std-
2, age 1, line 35-
70
• Use with caution in patients with glutathione depletion 37]
71
due to metabolic deficiencies.
72
[PRODUCT NAME] contains paracetamol which may be fatal
73
in overdose. In the event of overdosage or suspected [Ref. 1.3.1.2: std-
1, Page 1, line
74
overdose and notwithstanding the fact that the person may be 45-47]
75
asymptomatic, the nearest doctor, hospital or Poison Centre
76
must be contacted immediately.
77
78
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
79
4.5 Interaction with other medicines and other forms of
80
interaction
81
Hepatotoxic medicines: Increased risk of hepatotoxicity.
[Ref. 1.3.1.2: std-
82
Enzyme-inducing medicines: Increased risk of hepatotoxicity 1, Page 1, line 49]
83
and possible decrease in therapeutic effects of [PRODUCT
84
NAME].
85
Metoclopramide: Absorption of [PRODUCT NAME] may be
86
accelerated.
87
Probenecid: Pre-treatment with probenecid can decrease
88
[PRODUCT NAME] clearance, and increase its half-life.
89
Cholestyramine: Absorption of [PRODUCT NAME] is reduced if
90
given within one hour of cholestyramine.
91
Salicylates: Prolonged concurrent use of [PRODUCT NAME]
92
with salicylates increases the risk of adverse renal effects.
93
Antibiotics: Chronic use of isoniazid, an antibiotic medicine often
94
prescribed for tuberculosis, may increase the risk of liver
95
damage when combined with [PRODUCT NAME], even at [Ref. 1.3.1.2: std-
1, Page 2, line 1-
96
recommended doses. 12]
97
Warfarin: The anticoagulant effect of warfarin and other
98
coumarins may be enhanced by prolonged regular daily use of
99
paracetamol with increased risk of bleeding; occasional doses [Ref. 1.3.1.2: std-
2, Page 2, line 3-
100
have no significant effect. 4
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
101
102
4.6 Fertility, pregnancy and lactation
103
Pregnancy
104
[PRODUCT NAME] is generally considered safe for use in
105
pregnant patients, if used infrequently (not daily or on most
106
days).
107
Breastfeeding
108
[PRODUCT NAME] is distributed into breastmilk, in amounts too
109
small to be considered harmful to a breast-fed infant. No
[Ref. 1.3.1.2: std-
110
significant adverse effects have been seen in breast-fed infants 1, page 2, line
13-18]
111
whose mothers received paracetamol.
112
Fertility
113
There is no data on adverse effects on male or female fertility.
114
115
4.7 Effects on ability to drive and use machines
[Ref. 1.3.1.2: std-
116
None 2, page 2, line
11-12]
117
118
4.8 Undesirable effects
119
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
120
System Organ Adverse reaction Frequency
121
Class
122
Blood and Neutropenia, Less
[Ref. 1.3.1.2: std-
123
lymphatic system pancytopenia, frequent 1, page 2, line
35-36]
124
disorders leucopenia,
125
thrombocytopenia, [Ref. 1.3.1.2: std-
2, page 2, line
126
agranulocytosis 23-24]
127
Immune system Anaphylaxis. Less [Ref. 1.3.1.2: std-
2, page 2, line
128
disorders Hypersensitivity frequent 25]
129
reactions
130
(characterised by
131
urticaria, dyspnoea
132
and hypotension) [Ref. 1.3.1.2: std-
1, page 2, line
133
Angioedema 33-34]
134
Respiratory, Bronchospasm Less
[Ref. 1.3.1.2: std-
135
thoracic and frequent 2, page 2, line
31-32]
136
mediastinal
137
disorders
138
Hepatobiliary Hepatic dysfunction Less [Ref. 1.3.1.2: std-
2, page 2, line
139
disorders: frequent 33]
140
Skin and Skin rashes. Skin Less
141
subcutaneous rashes are usually frequent [Ref. 1.3.1.2: std-
1, page 2, line
142
30-32]
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
143
tissue disorder erythematous or
144
urticarial, but
145
sometimes more
146
serious and may be
147
accompanied by fever
148
and mucosal lesions.
149
150
Reporting of suspected adverse reactions
151
Reporting suspected adverse reactions after authorisation of Professional
Information
152
the medicine is important. It allows continued monitoring of the Guideline
2.16_Jul19_v2
153
benefit/risk balance of the medicine. Healthcare professionals
154
are asked to report any suspected adverse reactions to
155
SAHPRA via the “6.04 Adverse Medicine Reaction
156
Reporting Form”, found online under SAHPRA’s publications:
157
https://www.sahpra.org.za/Publications/Index/8.
158
159
4.9 Overdose:
160
Prompt treatment is essential. In the event of an overdosage,
161
consult a doctor immediately, or take the person directly to a
162
hospital. A delay in starting treatment may mean that the
163
antidote is given too late to be effective. Evidence of liver
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
164
damage is often delayed until after the time for effective
165
treatment has lapsed.
166
Susceptibility to paracetamol toxicity is increased in patients
167
who have taken repeated high doses (greater than 5 – 10 g/day)
168
of paracetamol for several days, in chronic alcoholism, chronic
169
liver disease, AIDS, malnutrition, and with the use of medicines
170
that induce liver microsomal oxidation such as barbiturates,
171
isoniazid, rifampicin, phenytoin and carbamazepine.
172
Symptoms of paracetamol overdosage in the first 24 hours
173
include pallor, nausea, vomiting, anorexia and possibly
174
abdominal pain. Mild symptoms during the first two days of
175
acute poisoning, do not reflect the potential seriousness of the
176
overdosage.
177
Liver damage may become apparent 12 to 48 hours, or later
178
after ingestion, initially by elevation of the serum transaminase
179
and lactic dehydrogenase activity, increased serum bilirubin
180
concentration and prolongation of the prothrombin time. Liver
181
damage may lead to encephalopathy, coma and death.
182
Acute renal failure with acute tubular necrosis may develop even
183
in the absence of severe liver damage. Abnormalities of glucose
184
metabolism and metabolic acidosis may occur. Cardiac
185
arrhythmias have been reported.
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
186
After maternal overdosage during pregnancy, foetal metabolism
187
of paracetamol that crosses the placenta can produce
188
hepatotoxic metabolites, causing foetal hepatotoxicity.
189
Treatment for paracetamol overdosage:
190
Although evidence is limited it is recommended that any adult
191
person who has ingested 5 - 10 grams or more of paracetamol
192
(or a child who has had more than 140 mg/kg) within the
193
preceding four hours, should have the stomach emptied by
194
lavage (emesis may be adequate for children) and a single dose
195
of 50 g activated charcoal given via the lavage tube. Ingestion of
196
amounts of paracetamol smaller than this may require treatment
197
in patients susceptible to paracetamol poisoning (see above). In
198
patients who are stuperose or comatose endotracheal intubation
199
should precede gastric lavage in order to avoid aspiration.
200
201
N-acetylcysteine should be administered to all cases of
202
suspected overdose as soon as possible preferably within eight
203
hours of overdosage, although treatment up to 36 hours after
204
ingestion may still be of benefit, especially if more than 150
205
mg/kg of paracetamol was taken.
206
IV: An initial dose of 150 mg/kg N-acetylcysteine in 200 ml
207
dextrose injection given intravenously over 15 minutes,
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
208
followed by an infusion of 50 mg/kg in 500 ml dextrose injection
209
over the next four hours, and then 100 mg/kg in 1 000 ml
210
dextrose injection over the next sixteen hours. The volume of
211
intravenous fluid should be modified for children.
212
Oral: Although the oral formulation is not the treatment of
213
choice, 140 mg/kg dissolved in water may be administered
214
initially, followed by 70 mg/kg every four hours for seventeen
215
doses.
216
A plasma paracetamol level should be determined four hours
217
after ingestion in all cases of suspected overdosage. Levels
218
done before four hours may be misleading.
219
Patients at risk of liver damage, and hence requiring continued
220
treatment with N-acetylcysteine, can be identified according to
221
their 4-hour plasma paracetamol level. The plasma paracetamol
222
level can be plotted against time since ingestion in the
223
nomogram below.
224
225
226
227
228
229
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
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231
232
233
234
235
236
237
238
* Nomogram reproduced from the Guidelines for the
239 Management of Acute Paracetamol Overdose produced
by the Medicines Information Centre, UCT.
240
241
The nomogram should be used only in relation to a single acute
242
ingestion. Those, whose plasma paracetamol levels are above
243
the “normal treatment line”, should continue N-acetylcysteine
244
treatment with 100 mg/kg IV over sixteen hours repeatedly until
245
recovery. Patients with increased susceptibility to liver damage
246
as identified above, should continue treatment if concentrations
247
are above the “high risk treatment line” (refer to paracetamol [Ref. 1.3.1.2: std-
1, page 2, line
248
nomogram above). Prothrombin index correlates best with 38-53, page 3,
line 1-37]
249
survival.
250
Monitor all patients with significant ingestions for at least ninety-
251
six hours.
Page 13 of 18
PROPOSED ANNOTATED PROFESSIONAL INFORMATION
Hepatic tests must be carried out at the beginning of treatment
and repeated every 24 hours. In most cases hepatic
transaminases return to normal in one to two weeks with full
restitution of the liver function. In very severe cases, however,
liver transplantation may be necessary.
252
5. PHARMACOLOGICAL PROPERTIES
253
5.1 Pharmacodynamic properties
254
Pharmacological classification: A 2.7 Antipyretics or antipyretic
255
and anti-inflammatory analgesics
256
ATC Code: N02BE01
257
[Ref. 1.3.1.2: std-
258
Paracetamol has analgesic and antipyretic activity. 1, page 1, line 12-
15]
259
260
5.2 Pharmacokinetic properties
261
Absorption:
262
Paracetamol is readily absorbed from the gastrointestinal tract,
263
with peak plasma concentrations occurring approximately 10 –
264
60 minutes after oral doses.
265
Distribution:
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
266
Paracetamol is distributed into most body tissues. It crosses
267
the placenta and is present in breast milk.
268
Biotransformation:
269
Paracetamol is mainly metabolised in the liver, following two
270
major hepatic pathways: glucuronic acid conjugation and
271
sulphuric acid conjugation.
272
Elimination:
273
The metabolites of paracetamol are mainly excreted in the
274
urine. Less than 5 % is excreted as unchanged paracetamol.
[Ref. 1.3.1.2: std-
275
The elimination half-life of paracetamol varies from about 1 – 3 1, page1, line 16-
23]
276
hours.
277
278
5.3 Preclinical safety data
279
Conventional studies using the currently accepted standards [Ref. 1.3.1.2: std-
2, page 3, line 35-
280
for the evaluation of toxicity to reproduction and development 36]
281
are not available.
282
283
6 PHARMACEUTICAL PARTICULARS
284
6.1 List of excipients [Sec.3.2.P.1]
285
Colloidal anhydrous silica, dioctyl sodium sulphosuccinate,
286
magnesium stearate, maize starch, polyvinylpyrrolidone
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
287
288
6.2 Incompatibilities
289
Not applicable
290
291
6.3 Shelf life
292
4 years (proposed) [Sec. 3.2.P.8.1]
293
294
6.4 Special precautions for storage [Sec. 3.2.P.8]
295
Store at or below 30 °C.
296
Protect from light and moisture.
297
Store in the original package/container.
298
Keep the blister in the carton until required for use
299
300
6.5 Nature and contents of container
301
[PRODUCT NAME] is packed in a blister comprising of plain [Sec.3.2.P.7]
302
aluminium foil with VMCH coating and clear transparent PVC
303
film and placed in a preprinted carton along with a patient
304
information leaflet.
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PROPOSED ANNOTATED PROFESSIONAL INFORMATION
305
Pack sizes: 20 and 100 tablets
306
Not all pack sizes may be marketed.
307
308
6.6 Special precautions for disposal
309
No special requirements.
310
311
7 HOLDER OF CERTIFICATE OF REGISTRATION
312
Oethmaan Biosims (Pty) Ltd
313
207A Sherwood House
314
Greenacres Office Park
315
c/o Victory and Rustenberg Roads
316
Victory Park
317
Johannesburg
318
2195
319
320
8 REGISTRATION NUMBER(S):
321
To be allocated
322
Page 17 of 18
PROPOSED ANNOTATED PROFESSIONAL INFORMATION
323
9 DATE OF FIRST AUTHORISATION
324
Date of registration: To be advised
325
326
10 DATE OF REVISION OF THE TEXT
327
Not applicable
328
Page 18 of 18
