Drugs List

Therapeutic Indications

Uses

Treatment of osteo- or rheumatoid arthritis in patients at risk of ulcer

Contraindications

Children under 18 years
Coronary artery bypass graft
Females attempting to conceive
Breastfeeding
Cerebrovascular disorder
Galactosaemia
Gastrointestinal haemorrhage
Gastrointestinal perforation
Gastrointestinal ulcer
Ischaemic heart disease
New York Heart Association class II failure
Peripheral arterial circulatory disorder
Pregnancy
Severe hepatic impairment
Severe renal impairment

Precautions and Warnings

Allergic disposition
Elderly
Females of childbearing potential
Predisposition to fluid retention
Risk factors for cardiovascular disorder
Asthma
Coagulopathy
Congestive cardiac failure
Crohn's disease
Glucose-galactose malabsorption syndrome
Haematological disorder
Hepatic cirrhosis
Hepatic impairment
History of asthma
History of gastrointestinal bleeding
History of gastrointestinal ulceration
History of peptic ulcer
Hypertension
Lactose intolerance
Nephrotic syndrome
Renal impairment
Severe dehydration
Ulcerative colitis

May mask fever
May mask symptoms or signs of infections
May precipitate bronchospasm in patients with asthma or allergy
Advise ability to drive/operate machinery may be affected by side effects
Contains lactose
Exclude pregnancy prior to initiation of treatment
Discontinue if signs of gastro-intestinal bleeding occur
Discontinue treatment immediately if pregnancy is suspected
May inhibit platelet aggregation - observe for signs of bleeding
Monitor blood pressure
Monitor hepatic function on long term therapy
Monitor renal function on long term therapy
Perform blood counts on prolonged use of this treatment
Discontinue if signs of gastro-intestinal ulceration occur
High dose/long term use may increase risk of arterial thrombotic events
May prolong bleeding time
Severe gastro-intestinal side effects may occur without warning
Discontinue treatment if skin rash or other allergic reaction occurs
Maintain treatment at the lowest effective dose
Female: Ensure adequate contraception during treatment
Advise patients to report any new or worsening cardiovascular symptoms

Elderly patients have increased frequency of adverse reactions, especially gastrointestinal bleeding and perforation which may be fatal. These patients should commence treatment on the lowest dose available and be monitored for gastrointestinal bleeding for 4 weeks following initiation of therapy.

Patients with renal or hepatic impairment and the elderly should be kept under surveillance, since the use of NSAIDs may result in deterioration of renal function. The lowest effective dose should be used and renal function monitored.

If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (eosinophilia, rash, etc.) treatment should be discontinued. Hepatitis may occur without prodromal symptoms.

Diclofenac sodium may reversibly inhibit platelet aggregation. Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

Pregnancy and Lactation

Pregnancy

Diclofenac plus misoprostol is contraindicated during pregnancy.

The manufacturer states that women of childbearing potential must be informed about the risk of teratogenicity and that treatment must be discontinued if pregnancy is suspected.

Diclofenac
First trimester exposure to NSAIDs has been associated with an increased risk spontaneous abortions and of birth defects (notably cardiac septal defects). There is conflicting evidence, however, from various studies and the risk appears to be low.

When an NSAID is considered essential, a more established drug such as ibuprofen may be considered. Diclofenac should be used with caution in the first and second trimesters. Schaefer (2007) considers that use of NSAIDs in early pregnancy does not require termination of pregnancy or invasive diagnostic procedures.

Diclofenac is a prostaglandin synthetase inhibitor and may have the following effects during the second and third trimesters:
- Pulmonary and cardiac toxicity in the foetus/newborn (pulmonary hypertension with preterm closing of the ductus arteriosus). The risk exists from the beginning of the sixth month and increases if administration is close to full term.
- Functional renal injury in the foetus. From the twelfth week: oligohydramnios (usually reversible after the end of treatment) or anamnios (particularly with prolonged exposure). Following birth, renal failure may persist (especially with late and prolonged exposure).
- Inhibition of uterine contractions with delayed onset and prolongation of labour.
- Increased possibility of bleeding in mother and child.
- Increased risk of maternal oedema formation.
- When used in the peri-natal period, necrotising enterocolitis and intraventricular haemorrhages have been reported in very pre-term and very low birth weight infants.

Use of any NSAID is considered contraindicated during the third trimester of pregnancy.

Misoprostol
Misoprostol is a potent uterine stimulant that induces abortion in early pregnancy after oral administration. It has also been associated with birth defects. The teratogenic mechanism appears to be related to the induction of uterine contractions that deform the embryo, resulting in vascular disruption, haemorrhage and cell death (Briggs, 2011).

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Diclofenac plus misoprostol use is contraindicated during lactation.

Diclofenac
In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations.

When an NSAID is considered necessary during breastfeeding ibuprofen or flurbiprofen would be the drugs of choice although occasional use of diclofenac is permissible.

The secretion in maternal milk following oral administration is minimal and probably too low to affect the infant. Diclofenac has a short half-life of 1.1 hours and a number of active metabolites although the clinical significance of these is not known.

Misoprostol
At the time of writing no studies describing the use of misoprostol during breastfeeding have been located. The manufacturer considers the drug to be contraindicated during breastfeeding because of the potential for severe, drug induced diarrhoea in the infant (Briggs, 2011)

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Acute renal insufficiency
Agranulocytosis
Altered uterine contractions
Anaphylactic reaction
Angioedema
Anorexia
Anxiety
Aplastic anaemia
Arterial thrombosis
Aseptic meningitis
Asthma
Bronchospasm
Cardiac failure
Chest pain
Chills
Constipation
Convulsions
Decrease in haemoglobin
Depression
Diarrhoea
Disorientation
Dizziness
Drowsiness
Dry mouth
Dyspepsia
Dyspnoea
Eructation
Erythema multiforme
Exacerbation of Crohn's disease
Exfoliative dermatitis
Facial oedema
Fever
Flatulence
Fulminant hepatitis
Gastritis
Gastro-intestinal perforation
Gastrointestinal bleeding
Glossitis
Haematemesis
Haematuria
Haemolytic anaemia
Hair loss
Headache
Hepatitis
Hypersensitivity reactions
Hypertension
Hypotension
Incomplete abortion
Increase of liver transaminases
Insomnia
Intermenstrual bleeding
Interstitial nephritis
Irritability
Jaundice
Leucopenia
Melaena
Memory disturbances
Menorrhagia
Mood changes
Mouth ulcers
Nausea
Nephrotic syndrome
Nightmares
Oedema
Oesophageal lesions
Palpitations
Papillary necrosis
Paraesthesia
Peptic ulceration
Photosensitivity
Pneumonitis
Premature birth
Proteinuria
Pruritus
Psychosis
Purpura
Rash
Renal failure
Retained placenta
Serum bilirubin increased
Shock
Stevens-Johnson syndrome
Stomatitis
Taste disturbances
Thrombocytopenia
Tinnitus
Tongue oedema
Toxic epidermal necrolysis
Tremor
Ulcerative colitis
Urticaria
Uterine rupture
Vaginal bleeding
Vasculitis
Vesiculation
Visual disturbances
Vomiting

Presentation

Modified release formulations of diclofenac sodium and misoprostol

Drugs List

Therapeutic Indications

Uses

Treatment of osteo- or rheumatoid arthritis in patients at risk of ulcer

Dosage

Adults

Elderly

Contraindications

Children under 18 years
Coronary artery bypass graft
Females attempting to conceive
Breastfeeding
Cerebrovascular disorder
Galactosaemia
Gastrointestinal haemorrhage
Gastrointestinal perforation
Gastrointestinal ulcer
Ischaemic heart disease
New York Heart Association class II failure
Peripheral arterial circulatory disorder
Pregnancy
Severe hepatic impairment
Severe renal impairment

Precautions and Warnings

Allergic disposition
Elderly
Females of childbearing potential
Predisposition to fluid retention
Risk factors for cardiovascular disorder
Asthma
Coagulopathy
Congestive cardiac failure
Crohn's disease
Glucose-galactose malabsorption syndrome
Haematological disorder
Hepatic cirrhosis
Hepatic impairment
History of asthma
History of gastrointestinal bleeding
History of gastrointestinal ulceration
History of peptic ulcer
Hypertension
Lactose intolerance
Nephrotic syndrome
Renal impairment
Severe dehydration
Ulcerative colitis

May mask fever
May mask symptoms or signs of infections
May precipitate bronchospasm in patients with asthma or allergy
Advise ability to drive/operate machinery may be affected by side effects
Contains lactose
Exclude pregnancy prior to initiation of treatment
Discontinue if signs of gastro-intestinal bleeding occur
Discontinue treatment immediately if pregnancy is suspected
May inhibit platelet aggregation - observe for signs of bleeding
Monitor blood pressure
Monitor hepatic function on long term therapy
Monitor renal function on long term therapy
Perform blood counts on prolonged use of this treatment
Discontinue if signs of gastro-intestinal ulceration occur
High dose/long term use may increase risk of arterial thrombotic events
May prolong bleeding time
Severe gastro-intestinal side effects may occur without warning
Discontinue treatment if skin rash or other allergic reaction occurs
Maintain treatment at the lowest effective dose
Female: Ensure adequate contraception during treatment
Advise patients to report any new or worsening cardiovascular symptoms

Elderly patients have increased frequency of adverse reactions, especially gastrointestinal bleeding and perforation which may be fatal. These patients should commence treatment on the lowest dose available and be monitored for gastrointestinal bleeding for 4 weeks following initiation of therapy.

Patients with renal or hepatic impairment and the elderly should be kept under surveillance, since the use of NSAIDs may result in deterioration of renal function. The lowest effective dose should be used and renal function monitored.

If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (eosinophilia, rash, etc.) treatment should be discontinued. Hepatitis may occur without prodromal symptoms.

Diclofenac sodium may reversibly inhibit platelet aggregation. Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

Pregnancy and Lactation

Pregnancy

Diclofenac plus misoprostol is contraindicated during pregnancy.

The manufacturer states that women of childbearing potential must be informed about the risk of teratogenicity and that treatment must be discontinued if pregnancy is suspected.

Diclofenac
First trimester exposure to NSAIDs has been associated with an increased risk spontaneous abortions and of birth defects (notably cardiac septal defects). There is conflicting evidence, however, from various studies and the risk appears to be low.

When an NSAID is considered essential, a more established drug such as ibuprofen may be considered. Diclofenac should be used with caution in the first and second trimesters. Schaefer (2007) considers that use of NSAIDs in early pregnancy does not require termination of pregnancy or invasive diagnostic procedures.

Diclofenac is a prostaglandin synthetase inhibitor and may have the following effects during the second and third trimesters:
- Pulmonary and cardiac toxicity in the foetus/newborn (pulmonary hypertension with preterm closing of the ductus arteriosus). The risk exists from the beginning of the sixth month and increases if administration is close to full term.
- Functional renal injury in the foetus. From the twelfth week: oligohydramnios (usually reversible after the end of treatment) or anamnios (particularly with prolonged exposure). Following birth, renal failure may persist (especially with late and prolonged exposure).
- Inhibition of uterine contractions with delayed onset and prolongation of labour.
- Increased possibility of bleeding in mother and child.
- Increased risk of maternal oedema formation.
- When used in the peri-natal period, necrotising enterocolitis and intraventricular haemorrhages have been reported in very pre-term and very low birth weight infants.

Use of any NSAID is considered contraindicated during the third trimester of pregnancy.

Misoprostol
Misoprostol is a potent uterine stimulant that induces abortion in early pregnancy after oral administration. It has also been associated with birth defects. The teratogenic mechanism appears to be related to the induction of uterine contractions that deform the embryo, resulting in vascular disruption, haemorrhage and cell death (Briggs, 2011).

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Diclofenac plus misoprostol use is contraindicated during lactation.

Diclofenac
In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations.

When an NSAID is considered necessary during breastfeeding ibuprofen or flurbiprofen would be the drugs of choice although occasional use of diclofenac is permissible.

The secretion in maternal milk following oral administration is minimal and probably too low to affect the infant. Diclofenac has a short half-life of 1.1 hours and a number of active metabolites although the clinical significance of these is not known.

Misoprostol
At the time of writing no studies describing the use of misoprostol during breastfeeding have been located. The manufacturer considers the drug to be contraindicated during breastfeeding because of the potential for severe, drug induced diarrhoea in the infant (Briggs, 2011)

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Acute renal insufficiency
Agranulocytosis
Altered uterine contractions
Anaphylactic reaction
Angioedema
Anorexia
Anxiety
Aplastic anaemia
Arterial thrombosis
Aseptic meningitis
Asthma
Bronchospasm
Cardiac failure
Chest pain
Chills
Constipation
Convulsions
Decrease in haemoglobin
Depression
Diarrhoea
Disorientation
Dizziness
Drowsiness
Dry mouth
Dyspepsia
Dyspnoea
Eructation
Erythema multiforme
Exacerbation of Crohn's disease
Exfoliative dermatitis
Facial oedema
Fever
Flatulence
Fulminant hepatitis
Gastritis
Gastro-intestinal perforation
Gastrointestinal bleeding
Glossitis
Haematemesis
Haematuria
Haemolytic anaemia
Hair loss
Headache
Hepatitis
Hypersensitivity reactions
Hypertension
Hypotension
Incomplete abortion
Increase of liver transaminases
Insomnia
Intermenstrual bleeding
Interstitial nephritis
Irritability
Jaundice
Leucopenia
Melaena
Memory disturbances
Menorrhagia
Mood changes
Mouth ulcers
Nausea
Nephrotic syndrome
Nightmares
Oedema
Oesophageal lesions
Palpitations
Papillary necrosis
Paraesthesia
Peptic ulceration
Photosensitivity
Pneumonitis
Premature birth
Proteinuria
Pruritus
Psychosis
Purpura
Rash
Renal failure
Retained placenta
Serum bilirubin increased
Shock
Stevens-Johnson syndrome
Stomatitis
Taste disturbances
Thrombocytopenia
Tinnitus
Tongue oedema
Toxic epidermal necrolysis
Tremor
Ulcerative colitis
Urticaria
Uterine rupture
Vaginal bleeding
Vasculitis
Vesiculation
Visual disturbances
Vomiting

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: May 2015

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press Accessed on 22 May 2015.

Summary of Product Characteristics: Arthrotec 50 tablets. Pfizer Ltd. Revised September 2018.
Summary of Product Characteristics: Arthrotec 75 tablets. Pfizer Ltd. Revised Sptember 2018.

Summary of Product Characteristics: Masidemen 50mg/200microgram modified release tablets. Actavis UK Ltd. Revised February 2014.
Summary of Product Characteristics: Masidemen 75mg/200microgram modified release tablets. Actavis UK Ltd. Revised February 2014.

Summary of Product Characteristics: Misofen 50mg/200microgram modified release tablets. Morningside Healthcare Ltd. Revised February 2014.
Summary of Product Characteristics: Misofen 75mg/200microgram modified release tablets. Morningside Healthcare Ltd. Revised February 2014.

'PRAC recommends the same cardiovascular precautions for diclofenac as for selective COX-2 inhibitors'
European Medicines Agency (EMA) 14th June 2013
Available at: www.ema.europe.eu
Last accessed: 11 May, 2015

MHRA Drug Safety Update June 2013
Available at: https://www.mhra.gov.uk
Last accessed: 22 May, 2015

The drug database for acute porphyria (NAPOS)
Available at: https://www.drugs-porphyria.org
Diclofenac sodium + misoprostol Last revised: 1 August, 2013
Last accessed: 22 May, 2015

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Diclofenac Last revised: 30 January, 2015
Last accessed: 22 May, 2015

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Misoprostol Last revised: 6 March, 2014
Last accessed: 22 May, 2015