Summary for UKPID
Mefenamic acid
Dr Alan Worsley Bsc(hons) PhD MRPharmS
National Poisons Information Service (Newcastle Centre)
Regional Drug & Therapeutics Centre
Wolfson Building
Claremont Place
Newcastle upon Tyne
NE1 4LP
UK
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
SUMMARY
Mefenamic acid
Type of product
A non steroidal anti-inflammatory drug.
Ingredients
Mefenamic acid Tablets 500mg
Capsules 250mg & 500mg
Paediatric Suspension 50mg/5ml
Toxicity
The fatal dose is not known. The minimum amount which has been
reported to cause convulsions is 2.5g in a 12 year old girl.
Features
Convulsions are the main feature of acute overdosage. Most
patients have only one fit but some have several. Convulsions may
be preceeded by agitation and twitching.
Vomiting and diarrhoea may occur but are seldom a serious
problem. In most cases all features of acute toxicity will have
been resolved with 12 hours.
Rarely, acute renal failure and hypoprothrombinaemia may develop.
Management
1. Give oral activated charcoal to adults who have ingested more
than 2.5g
2. Do not use emetics due to the possible rapid onset of
convulsions.
3. Children who have ingested more than 25mg/kg should be given
activated charcoal.
4. Single, brief convulsions do not require treatment, but if they
are prolonged or recurrent, they should be controlled with
intravenous diazepam.
5. Observe the patients for at least 12 hours.
6. Other measures as indicated by the patients clinical conditions.
References
Smolinske SC et al
Toxic effects of non steroidal anti-inflammatory drugs in overdose.
Drug safety (1990) 5: 252-274
McKillop G & Canning GP
A case of intravenous and oral mefenamic acid poisoning.
Scot Med J (1987) 32 : 81-82
Shipton EA & Muller FO
Severe mefenamic acid poisoning. A case report.
SA Med J (1985) 67: 823-4
Court H & Volans GN
Poisoning after overdosage with non steroidal anti-inflammatory drugs.
Adv Drug. React. Pois. Rev. (1984) 3: 1-21
Gossinger H et al
Coma in mefenamic acid poisoning
Lancet (1982) 2: 384
Balali-Mood et al
Mefenamic acid overdosage
Lancet (1981) 1: 1354-6
Name
MEFENAMIC ACID
proprietary name:- Ponstan, Ponstan Forte
Chemical group/family
Non steroidal Anti-inflamatory
BNF 10.1.1
Reference Number1
(CAS) 61-68-7 (mefenamic acid)
Manufacturer/supplier2
(generic)
Parke-Davies
Lambert Court,
Chestnut Ave,
Eastliegh,
Hants.
SO53 3ZQ
Tel 01703 620500
Presentation
mefenamic acid 250mg, 500mg tablets
mefenamic acid 50mg/5ml oral suspension
Physico-chemical properties: (Dollery)3
N-(2,3-Xylyl) anthranilic acid
Molecular weight: 241.3
pKa 4.2
Solubility
in alcohol 1 in 185
in water practically insoluble
Hazard /risk classification
none
USES
Indications2
Mild to moderate pain in rheumatoid arthritis (including juvenile
arthritis), osteoarthritis, and related conditions.
Dysmenorrhoea and menorrhagia.
Therapeutic Dosage (BNF)6
Oral
Adults 500mg three times daily
Child over 6 months 25mg/kg daily in divided doses for not longer
than 7 days except in juvenile arthritis.
Contraindications
Gastro-intestinal ulceration or bleeding.
History of hypersensitivity precipitated by aspirin or other NSAIDs.
Also specifically inflamatory bowel disease; blood tests required
during long term treatment.
Porphyria.
Precautions
Caution should be used in patients with GI upset/ bleeding, asthma and
patients with renal and hepatic impairment.
Pharmacokinetics
Oral absorption >90%
Presystemic metabolism 0
Volume of distribution 1.3l/kg
Plasma half life
range 3-4h
plasma protein binding 99%
Adverse effects
Drowsiness, dizziness, skin rashes, diarrhoea, thrombocytopaenia,
haemolytic anaemia.
Pregnancy4
Mefenamic acid was used as a tocolytic in a double blinded randomised
human study. Compared to controls, preterm delivery occured less in
the mefenamic acid group (15% vs 40% p<0.005), and birth weights were
higher. No adverse effects were observed in the newborns exposed in
utero to mefenamic acid (Mital P et al J R Soc Health 1992 ;112:
214-6).
Constriction of the ductus arteriosus in utero is a pharmacological
consequence arising from the use of prostaglandin synthesis inhibitors
during pregnancy, as is inhibition of labour, prolongation of
pregnancy, and suppression of renal function. Persisitent pulmonary
hypertension of the newborn may occur if these agents are used in the
3rd trimester close to delivery ( Levin DL Semin.Perinatol.
1980;4:35-44). Women attempting to conceive should not use any
prostaglandin synthetase inhibitor, including mefenamic acid , because
of the findings in a variety of animal models that indicate these
agents block blastocyst implantation (Matt DW et al. Reproductive
toxicology. 2nd Edn. New York Raven Press.1995:175-93, Dawood MY. Am J
Obstet Gynecol. 1993; 169:1255-65 )
Breast Milk4
Small amounts of mefenamic acid are excreted into breast milk and
absorbed by the nursing infant (Buchanan RA et al. Curr Ther Res Clin
Exp. 1968;10:592-6). Ten nursing mothers were given mefenamic acid
500mg oral loading dose, followed by 250mg three times daily. The
averages of mean daily concentrations of mefenamic acid in maternal
plasma and milk were 0.94 microg/ml and 0.17microg/ml, respectively,
corresponding to a milk:plasma ration of 0.18. The mean infant blood
concentration of mefenamic acid was 0.08 microg/ml.
Interactions5
Lithium
Excretion of lithium may be reduced by concurrent use of mefenamic
acid.
Oral anticoagulants
Slight potentiation of oral anticoagulants is documented but rarely
significant.
Albumen bound drugs
Mefenamic acid binds strongly to plasma proteins and competition for
non-specific binding sites on plasma albumen may occur.
MECHANISM OF POISONING6
NSAIDs probably act by inhibiting prostaglandin synthesis.
Prostaglandins (Pgs) are believed to cause vasodilation, increased
vascular permeability, and increased sensitivity of nerve endings to
other inflammatory mediators. By reversible inhibitio of the enzyme
cyclo-oxygenase, NSAIDs block the conversion of the arachidonic acid
found in the cell membrane phospholipids into various PGs.
Since PGs appear to maintain the gastric mucosal barrier, NSAID
inhibition of PG synthesis may be the cause of the gastritis, peptic
ulceration, and gastrointestinal bleeding observed with NSAIDs.
NSAIDs cause sodium retention, especially in patients with underlying
sodium retaining states such as congestive heart failure. Although the
mechanism is not entirely clear, the inhibition of PG synthesis plays
a leading role. These compounds redistribute renal blood flow away
from the superficial cortical glomeruli to the juxtamedullary
glomeruli, which have a greater capacity to absorb sodium.
EPIDEMIOLOGY OF POISONING
There are no data available on the epidemiology of poisoning with
mefanamic acid. Cumulative data is available on the non steroidal
anti-inflammatory drugs in general. Mefanamic acid is often prescribed
to adolescent women for gynaecological problems, endometreosis etc.
Overdose with this drug has often been associated with this section of
the population.
MECHANISM OF ACTION/TOXICITY
Range of toxicity (Poisindex)
Toxic Levels
Mean plasma mefenamic acid levels at hospital admission were higher in
patients with seizures (73+/- 46mcg/mL) than in patients without
seizures (38+/-24mcg/mL)
Fatal Level
Not Known
FEATURES OF POISONING
Summary
Acute overdose
Most cases of NSAID overdose develop no effects or mild effects
consisting of lethargy and gastrointestinal upset. However convulsions
are a feature of acute overdosage with mefenamic acid and occur in
about one third of cases.
Low gradew fever, hypotension, and sinus tachycardia have been noted
in both overdose, and therapeutic use of NSAIDs.
Metabolic acidosis occurs rarely in overdose, usually in conjunction
with seizures.
HYPOTHERMIA
A 4 year old, concurrently taking cephalexin, noscapine, and mefenamic
acid, experienced hypothermia to 34.8 degrees C, and irregular
respirations 3 hours after ingesting 4ml of mefenamic syrup. rewarming
with an electric blanket resulted in a temperature of 36 degrees C 7
hours later (Anon 1989).
NEUROLOGICAL
Seizures have been reported in up to 38% of cases, with a mean onset
of 4.4hours (range 0.5 to 12 hours), often preceded by muscle
twitching. The lowest dose reported to cause seizures was 2.5g, and
the lowest plasma level reported was 46mcg/ml. Other neurological
findings include dyskinesias (one case), agitation and restlessness
(one case ), altered mental status, and coma (two cases).
The mean time from ingestion to seizures is 4.4 hours, with a range of
0.56 to 12 hours.
Seizures
1. Incidence. In 29 patients with significant ingestion i.e plasma
concentration greater than 10mcg/ml, seizures occured in 11 (38%)7.
2. Onset. The mean time from ingestion to seizure is 4.4hours, witha
range of 0.56 to 12hours8.
3. Dose. Lowest dose ingested to cause seizures was 2.5g in a 12yr
old. Four patients ingesting 5g or less had seizures8.
GASTROINTESTINAL
Nausea, vomiting, epigastric pain, erosive oesophagitis, pancreatitis
and gastrointestinal bleeding have been associated with therapeutic
and/or overdose of NSAIDs10.
Vomiting.
Case report 1. Haematemesis, vomiting and diarrhoea were reported
folowing oral ingestion of 20 tablet (5 g) in a 22 year old, followed
by an intravenous injection of 2.25g mefenamic acid mixed with
water11.
Case report 2. Vomiting, abdominal pain and diarrhoea lasted 18 hours
in a 30 yr old patient after ingesting 12.5g mefenamic acid12.
Diarrhoea.
Diarrhoea and steatorrhoea have been reported with chronic therapeutic
use13.
Diarrhoea due to proctitis or ileocolitis was reported in 4 patients
taking mefenamic acid in doses of 500mg two to three times daily for 6
weeks or longer 14,15.
Pancreatitis.
Case report. Pancreatitis was reported in a 32 year old after use of
mefanamic acid 250mg four times daily16.
GENITOURINARY
Acute renal failure, uraemia and nephrotic syndrome have occurred with
both acute overdose and chronic ingestion of most NSAIDs.
Renal failure.
Renal failure is not a prominent acute overdose symptom 17,18,19,
however it has been reported in one case12.
Reversible renal failure (non-oliguric) has been reported with
administration of 12 to 15 g of mefenamic acid over 4 to 5 days 7,20.
Irreversible renal interstitial nephritis has occured with chronic use
21.
Renal Papillary Necrosis.
Case report. Renal papillary necrosis has been described in a 47 yr
old who ingested mefenamic acid for 10 years and a 58 year old who
took 10 capsules per week for 10 years 22.
Interstitial Fibrosis.
Case report. A child aged 13 with a history of focal segmental
glomerulosclerosis developed renal impairment 8 months after mefenamic
acid 750mg per day. Fibrosis was suspected, but not confirmed by
biopsy 23.
IMMUNOLOGIC
Anaphylactoid reactions have been associated with therapeutic
ingestion of mefenamic acid, tolmetin, sulindac, ketorolac,
fenoxopren, naproxen, but have not bee reported following acute
overdose.
MANAGEMENT
1. Dose of activated charcoal within 1-2 hours of ingestion, or
empty the stomach.
2. Treatment is systematic and supportive.
3. Seizures-administer diazepam 5-10mg I/V every 15minutes PRN up to
30mg
4. Monitor vital signs
5. Hypotension- administer IV fluids
6. Monitor for sins of gastrointestinal ulceration and haemorrhage.
7. There is no evidence to suggest that enhanced elimination is of
benefit.
ANALYSIS
Plasma NSAID levels are insufficiently studied to be clinically
useful. Monitor the patients acid-base balance. Fluid and electrolyte
imbalances have been reported.
ABSTRACTS
Case Reports
1. A 19yr old female took 12.5g mefenamic acid and developed status
epilepticus three hours later. She received 10ml paraldehyde i/m
and recovered 24.
2. A study of 54 patients who ingested 1.5g to 50g mefenamic acid 1
to 18 hours prior to hospital admission, reported that of the 29
patients whose plasma concentrations were greater than 10mcg/ml,
14 were symptom free. Muscle twitching was observed in 15
patients and grand mal seizure in 11 patients. One to eleven
hours after ingestion the plasma concentration of mefenamic acid
ranged from 11 to 148mcg/ml. Patients with twitching and seizures
generally had concentrations above a line joining 100mcg/ml at 2
hour post ingestion and 15mcg/ml at 15hours. Three patients had
seizures at serum levels below this line.
Author
Dr Alan Worsley Bsc(hons) PhD MRPharmS
National Poisons Information Service (Newcastle Centre)
Regional Drug & Therapeutics Centre
Wolfson Building
Claremont Place
Newcastle upon Tyne
NE1 4LP
UK
This monograph was produced by the staff of the Newcastle Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Peer review was undertaken by the Directors of the UK National Poisons
Information Service.
Last updated September 1997
REFERENCES
1. Martindale : The Extra Pharmacopoeia. 30th Edition JEF (Ed)
Pharmaceutical Press. 1993
2. ABPI data sheet Compendium. Datapharm publications Ltd. 1995-6
3. Therapeutic Drugs. Dollery C (Ed). Churchill Livingstone. 1991
4. Briggs G G et al. Drugs in pregnancy and lactation. Update Vol 8
No2 June 1995. Williams and Wilkins Ltd.
5. British National Formulary. No32 (sept 1996) section 10.1
6. Nonsteroidal Anti-inflammtory Drug Monograph. Medical toxicology.
Ellenhorn MJ & Barceloux DG (Eds) Elsevier. 1988
7. Bali-Mood M, Proudfoot AT, Critchley JAJH et al. Mefenamic acid
overdose. Lancet (1981); 1:1354-56
8. Court H et Volans GN. Poisoning after overdose with non-steroidal
and anti-inflammatory drugs. Adv Drug React Ac Pois
Rev(1984);3:1-21
9. Gossinger H, Hruby K, Haubenstock A et al. Coma in mefenamic acid
poisoning. Lancet (1982);2:384
10. De Caestecker JS et Heading RC. Iatrogenic oesophageal ulceration
with massive haemorrhage and stricture formation. Br J Clin Pract
(1988);42:212-214
11. McKillop G et Canning GP. A case of intravenous and oral
mefenamic acid poisoning. Scot Med J.(1987);32:81-82
12. Turnbull AJ, Campbell P et Hughes JA . Mefenamic acid
nephropathy-acute renal failure in overdose (letter). B M J
(1988);296:646
13. Isaacs PET, Sladen GE et Filipe I. mefenamic acid enteropathy. J
Clin Pathol (1987);40:1221-1227
14. Phillips MS, Fehilly B Stewart S et al. Enteritis and colitis
associated with mefenamic acid (letter). BMJ (1983);287:1626
15. Rampton DS et Tapping PJ. Enteritis and colitis associated with
mefenamic acid (letter). BMJ (1983);287:1627
16. Van Walraven AA, Edels M et Fong S. Pancreatitis caused by
mefenamic acid (letter). Can Med Assoc J (1982);126:894
17. Venning V, Dixon AJ et Oliver DO. Mefenamic acid nephropathy.
Lancet (1980);2:745-746
18. Malik S, Arthurton I, Griffith ID. Mefenamic acid nephropathy.
Lancet (1980);2:746
19. Robertson CE, Ford MJ et Van Someren V. Mefenamic acid
nephropathy. Lancet (19800;2:232-233
20. Reynolds JEF (Ed);Martindale:The Extra Pharmacopoeia(1990)
21. Boletis J, Williams AJ, Shortland JR et al. Irreversible renal
failure following mefenamic acid. Nephron(1989);51:575-576
22. Segasothy M, Thyaparan A, Kamal A et al. Mefenamic acid
nephropathy. Nephron(19870;45;156-157
23. Itami N, Akutsu Y, Yasoshima K et al. Progressive renal failure
despite discontinuation of mefenamic acid. Nephron
(1990);54:281-282
24. Young R J. Mefenamic acid poisoning and epilepsy. BMJ (1979); 2:
672
See Also:
Toxicological Abbreviations