Drugs List

Therapeutic Indications

Uses

Ascites and oedema associated with hepatic cirrhosis
Congestive cardiac failure
Diuresis (potassium sparing) in nephrosis
Diuresis (potassium sparing) required due to corticosteroid therapy
Diuresis (potassium sparing) required due to oestrogen therapy
Prompt diuresis especially where potassium conservation is important

Contraindications

Acute renal failure
Addison's disease
Anuria
Breastfeeding
Electrolyte imbalance
Galactosaemia
Hyperkalaemia
Hypovolaemia
Long QT syndrome
Pre-coma associated with hepatic cirrhosis
Pregnancy
Renal damage secondary to nephrotoxic agents
Renal impairment - creatinine clearance below 30ml/minute/1.73m sq
Renal impairment associated with hepatic coma
Renal impairment secondary to hepatotoxic agents
Severe hypokalaemia
Severe hyponatraemia
Torsade de pointes

Precautions and Warnings

Children under 18 years
Elderly
Family history of long QT syndrome
Hypoproteinaemia
Predisposition to hypotension
Predisposition towards electrolyte imbalance
Benign prostatic hyperplasia
Diabetes mellitus
Glucose-galactose malabsorption syndrome
Gout
Hepato-renal syndrome
History of torsade de pointes
Hypotension
Lactose intolerance
Systemic lupus erythematosus
Urinary obstruction

Adjustment of hypoglycaemic therapy may be necessary in diabetes mellitus
Correct electrolyte disorders before treatment
Correct hypotension before initiating treatment
May exacerbate or activate systemic lupus erythematosus
Advise ability to drive/operate machinery may be affected by side effects
Correct hypovolaemia prior to administration
Contains lactose
Consider monitoring ECG in patients at risk of QT prolongation
Monitor blood urea
Monitor fluid and electrolyte status
Monitor haematological parameters regularly throughout treatment
Monitor serum potassium regularly
Excess consumption of liquorice may increase the risk of hypokalaemia
Increased risk of hyperkalaemia with K+ suppl. and K+ sparing diuretic
May precipitate diabetes mellitus
May precipitate gout
Discontinue treatment before glucose tolerance test
Discontinue if evidence of significant bone marrow depression
Withdraw drug if skin rash or pruritus occur
Advise patient not to take NSAIDs unless advised by clinician
Hypotensive effects may be potentiated by alcohol
Advise on problems of salt substitutes/high intake of potassium-rich food

Pregnancy and Lactation

Pregnancy

Co-amilofruse is contraindicated in pregnancy.

Furosemide should be used with caution during pregnancy as animal studies in rats and rabbits have reported teratogenicity. Furosemide crosses the placenta, and can stimulate foetal urine production for a short time. Briggs (2011) states that furosemide does not significantly increase amniotic fluid volume. Furosemide inhibits physiological closure of the ductus arteriosus in premature babies. Briggs (2011) and Schaefer(2007) suggest that furosemide can be used when treatment of heart or renal failure requires a diuretic. However, if treatment is continued throughout pregnancy, there is a risk of neonatal hypoglycaemia.

No reports of amiloride passing to the foetus in humans have been found. However, due to it's low molecular weight and the fact that it crosses the placenta in mice and rabbits, amiloride is expected to pass through the placenta in humans. There is a lack of human data for amiloride use during pregnancy. However, in one study where 28 newborns had been exposed to amiloride in the first trimester two major birth defects where seen (one expected), one of these was a hypospadias. No anomalies where seen in the other five categories (cardiovascular, oral clefts, spina bifida, polydactyly and limb reduction defects) for which specific data were available. Briggs (2011) states that there is limited human data, but due to animal data there is a low risk to the foetus. Schaefer (2007) concludes that amiloride should not be used during pregnancy. However, use with any of the diuretics is not an indication for termination of the pregnancy.

Diuretics are no longer used as part of the standard therapy for hypertension and oedema during pregnancy, due to the maternal, hypovolaemic character of the disease. Many sources contraindicate the use of diuretics during pregnancy, except for patients with heart disease, mainly because they do not prevent or alter the course of toxaemia and they may decrease placental perfusion. If long term treatment is necessary the mother's electrolytes and haematocrit should be measured and the development of oligohydramnios should be ruled out. Hypoglycaemia in the newborn should also be monitored.

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

Co-amilofruse is contraindicated in breastfeeding.

Furosemide has been found in breast milk. It is frequently used in paediatric units (Hale, 2014) and because of the extremely poor bioavailability exhibited by furosemide in newborns very high doses are required. The amounts transferred into human milk would be very unlikely to produce any effects in infants, although theoretical suppression of lactation could occur. Schaefer (2007) state that if furosemide is indicated then it may be prescribed.

It is not known whether amiloride is excreted in human milk. Due to its low molecular weight and the fact that amiloride is excreted in the milk of lactating rats at concentrations higher than that measured in blood, passage into human milk is expected. There is a lack of human data with amiloride during breastfeeding and the effects on the nursing infant are unknown. Schaefer (2007) concludes that due to insufficient information amiloride should not be used during breastfeeding. However, single doses do not require limitation of breastfeeding, but therapy should be changed.

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 generalised exanthematous pustulosis
Agranulocytosis
Allergic reaction
Alopecia
Altered liver function tests
Anaphylactoid reaction
Anaphylaxis
Angina
Anorexia
Aplastic anaemia
Arthralgia
Bone marrow depression
Bullous pemphigoid
Cardiac arrhythmias
Cholestatic jaundice
Confusion
Constipation
Deafness
Decreased glucose tolerance
Dehydration
Delayed reactions
Diarrhoea
Dizziness
Drowsiness
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dry mouth
Eosinophilia
Erythema multiforme
Exacerbation of systemic lupus erythematosus
Exfoliative dermatitis
Fever
Fluid and electrolyte disturbances
Gastric upset
Gastro-intestinal symptoms
Glycosuria
Gout
Haemolytic anaemia
Headache
Hepatic encephalopathy
Hyperglycaemia
Hyperkalaemia
Hypersensitivity reactions
Hyperuricaemia
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Hyponatraemia
Hypotension
Hypovolaemia
Impaired concentration
Increase in blood urea nitrogen
Increase in plasma cholesterol
Increase in plasma triglyceride concentration
Increased calcium excretion
Increased intra-ocular pressure
Interstitial nephritis
Leucopenia
Light-headedness
Malaise
Metabolic acidosis
Metabolic alkalosis
Minor psychiatric disturbances
Muscle cramps
Nausea
Nephrocalcinosis
Nephrolithiasis
Orthostatic hypotension
Ototoxicity
Pancreatitis
Paraesthesia
Photosensitivity
Precipitation of diabetes
Pruritus
Purpura
Rash
Sensation of pressure
Serum creatinine increased
Sexual dysfunction
Shock
Skin reactions
Stevens-Johnson syndrome
Systemic lupus erythematosus
Tetany
Thirst
Thrombocytopenia
Tinnitus
Toxic epidermal necrolysis
Urinary retention
Urticaria
Vasculitis
Visual disturbances
Vomiting
Weakness

Presentation

Oral formulations of furosemide and amiloride hydrochloride

Drugs List

Therapeutic Indications

Uses

Ascites and oedema associated with hepatic cirrhosis
Congestive cardiac failure
Diuresis (potassium sparing) in nephrosis
Diuresis (potassium sparing) required due to corticosteroid therapy
Diuresis (potassium sparing) required due to oestrogen therapy
Prompt diuresis especially where potassium conservation is important

Dosage

Adults

Contraindications

Acute renal failure
Addison's disease
Anuria
Breastfeeding
Electrolyte imbalance
Galactosaemia
Hyperkalaemia
Hypovolaemia
Long QT syndrome
Pre-coma associated with hepatic cirrhosis
Pregnancy
Renal damage secondary to nephrotoxic agents
Renal impairment - creatinine clearance below 30ml/minute/1.73m sq
Renal impairment associated with hepatic coma
Renal impairment secondary to hepatotoxic agents
Severe hypokalaemia
Severe hyponatraemia
Torsade de pointes

Precautions and Warnings

Children under 18 years
Elderly
Family history of long QT syndrome
Hypoproteinaemia
Predisposition to hypotension
Predisposition towards electrolyte imbalance
Benign prostatic hyperplasia
Diabetes mellitus
Glucose-galactose malabsorption syndrome
Gout
Hepato-renal syndrome
History of torsade de pointes
Hypotension
Lactose intolerance
Systemic lupus erythematosus
Urinary obstruction

Adjustment of hypoglycaemic therapy may be necessary in diabetes mellitus
Correct electrolyte disorders before treatment
Correct hypotension before initiating treatment
May exacerbate or activate systemic lupus erythematosus
Advise ability to drive/operate machinery may be affected by side effects
Correct hypovolaemia prior to administration
Contains lactose
Consider monitoring ECG in patients at risk of QT prolongation
Monitor blood urea
Monitor fluid and electrolyte status
Monitor haematological parameters regularly throughout treatment
Monitor serum potassium regularly
Excess consumption of liquorice may increase the risk of hypokalaemia
Increased risk of hyperkalaemia with K+ suppl. and K+ sparing diuretic
May precipitate diabetes mellitus
May precipitate gout
Discontinue treatment before glucose tolerance test
Discontinue if evidence of significant bone marrow depression
Withdraw drug if skin rash or pruritus occur
Advise patient not to take NSAIDs unless advised by clinician
Hypotensive effects may be potentiated by alcohol
Advise on problems of salt substitutes/high intake of potassium-rich food

Pregnancy and Lactation

Pregnancy

Co-amilofruse is contraindicated in pregnancy.

Furosemide should be used with caution during pregnancy as animal studies in rats and rabbits have reported teratogenicity. Furosemide crosses the placenta, and can stimulate foetal urine production for a short time. Briggs (2011) states that furosemide does not significantly increase amniotic fluid volume. Furosemide inhibits physiological closure of the ductus arteriosus in premature babies. Briggs (2011) and Schaefer(2007) suggest that furosemide can be used when treatment of heart or renal failure requires a diuretic. However, if treatment is continued throughout pregnancy, there is a risk of neonatal hypoglycaemia.

No reports of amiloride passing to the foetus in humans have been found. However, due to it's low molecular weight and the fact that it crosses the placenta in mice and rabbits, amiloride is expected to pass through the placenta in humans. There is a lack of human data for amiloride use during pregnancy. However, in one study where 28 newborns had been exposed to amiloride in the first trimester two major birth defects where seen (one expected), one of these was a hypospadias. No anomalies where seen in the other five categories (cardiovascular, oral clefts, spina bifida, polydactyly and limb reduction defects) for which specific data were available. Briggs (2011) states that there is limited human data, but due to animal data there is a low risk to the foetus. Schaefer (2007) concludes that amiloride should not be used during pregnancy. However, use with any of the diuretics is not an indication for termination of the pregnancy.

Diuretics are no longer used as part of the standard therapy for hypertension and oedema during pregnancy, due to the maternal, hypovolaemic character of the disease. Many sources contraindicate the use of diuretics during pregnancy, except for patients with heart disease, mainly because they do not prevent or alter the course of toxaemia and they may decrease placental perfusion. If long term treatment is necessary the mother's electrolytes and haematocrit should be measured and the development of oligohydramnios should be ruled out. Hypoglycaemia in the newborn should also be monitored.

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

Co-amilofruse is contraindicated in breastfeeding.

Furosemide has been found in breast milk. It is frequently used in paediatric units (Hale, 2014) and because of the extremely poor bioavailability exhibited by furosemide in newborns very high doses are required. The amounts transferred into human milk would be very unlikely to produce any effects in infants, although theoretical suppression of lactation could occur. Schaefer (2007) state that if furosemide is indicated then it may be prescribed.

It is not known whether amiloride is excreted in human milk. Due to its low molecular weight and the fact that amiloride is excreted in the milk of lactating rats at concentrations higher than that measured in blood, passage into human milk is expected. There is a lack of human data with amiloride during breastfeeding and the effects on the nursing infant are unknown. Schaefer (2007) concludes that due to insufficient information amiloride should not be used during breastfeeding. However, single doses do not require limitation of breastfeeding, but therapy should be changed.

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 generalised exanthematous pustulosis
Agranulocytosis
Allergic reaction
Alopecia
Altered liver function tests
Anaphylactoid reaction
Anaphylaxis
Angina
Anorexia
Aplastic anaemia
Arthralgia
Bone marrow depression
Bullous pemphigoid
Cardiac arrhythmias
Cholestatic jaundice
Confusion
Constipation
Deafness
Decreased glucose tolerance
Dehydration
Delayed reactions
Diarrhoea
Dizziness
Drowsiness
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dry mouth
Eosinophilia
Erythema multiforme
Exacerbation of systemic lupus erythematosus
Exfoliative dermatitis
Fever
Fluid and electrolyte disturbances
Gastric upset
Gastro-intestinal symptoms
Glycosuria
Gout
Haemolytic anaemia
Headache
Hepatic encephalopathy
Hyperglycaemia
Hyperkalaemia
Hypersensitivity reactions
Hyperuricaemia
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Hyponatraemia
Hypotension
Hypovolaemia
Impaired concentration
Increase in blood urea nitrogen
Increase in plasma cholesterol
Increase in plasma triglyceride concentration
Increased calcium excretion
Increased intra-ocular pressure
Interstitial nephritis
Leucopenia
Light-headedness
Malaise
Metabolic acidosis
Metabolic alkalosis
Minor psychiatric disturbances
Muscle cramps
Nausea
Nephrocalcinosis
Nephrolithiasis
Orthostatic hypotension
Ototoxicity
Pancreatitis
Paraesthesia
Photosensitivity
Precipitation of diabetes
Pruritus
Purpura
Rash
Sensation of pressure
Serum creatinine increased
Sexual dysfunction
Shock
Skin reactions
Stevens-Johnson syndrome
Systemic lupus erythematosus
Tetany
Thirst
Thrombocytopenia
Tinnitus
Toxic epidermal necrolysis
Urinary retention
Urticaria
Vasculitis
Visual disturbances
Vomiting
Weakness

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: June 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.

Martindale: The Complete Drug Reference. 39th Edition. London: Brayfield A (ed). Pharmaceutical Press; 2017.

Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.

Summary of Product Characteristics: Co-Amilofruse 20mg/2.5mg Tablets. Aurobino Pharma - Milpharm Ltd. Revised May 2012.
Summary of Product Characteristics: Co-Amilofruse 40mg/5mg Tablets. Aurobino Pharma - Milpharm Ltd. Revised May 2012.
Summary of Product Characteristics: Co-Amilofruse 80mg/10mg Tablets. Aurobino - Milpharm Ltd. Revised May 2012.

Summary of Product Characteristics: Frumil. Sanofi. Revised May 2015.
Summary of Product Characteristics: Frumil LS. Sanofi. Revised May 2015.
Summary of Product Characteristics: Frumil, Frumil LS. Sanofi. Revised September 2010.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 23 June 2017