Fosinopril

Fosinopril Sodium 10 mg Tablets

Each tablet contains 10 mg fosinopril sodium

Tablet.

White to off-white rectangular shaped tablet with “G” scoreline “G” on one side and “FS” scoreline “10” on the other side.

The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses

Hypertension

Fosinopril is indicated in adults for the treatment of hypertension. Fosinopril may be used alone as initial therapy or in combination with other antihypertensive agents. The antihypertensive effects of fosinopril and diuretics used concomitantly are approximately additive.

Heart Failure

Fosinopril is indicated for adults for the treatment of heart failure in combination with a non-potassium sparing diuretic and where appropriate, digitalis. In these patients, fosinopril improves symptoms and exercise tolerance, reduces severity of heart failure and decreases the frequency of hospitalisation for heart failure.

Posology

Hypertensive patients not being treated with diuretics:

The dose range is 10 to 40 mg per day administered in a single dose and without regard to meals. The normal starting dose for patients is 10 mg once a day. Dosage may need to be adjusted after approximately 4 weeks according to blood pressure response. No additional blood pressure lowering is achieved with doses greater than 40 mg daily. If blood pressure is not adequately controlled with fosinopril alone, a diuretic can be added.

Hypertensive patients being treated with concomitant diuretic therapy:

The diuretic should preferably be discontinued for several days prior to beginning therapy with fosinopril to reduce the risk of an excessive hypotensive response. If blood pressure is inadequately controlled after an observation period of approximately 4 weeks, diuretic therapy may be resumed. Alternatively, if diuretic therapy cannot be discontinued, an initial dose of 10 mg of fosinopril should be used with careful medical supervision for several hours, until blood pressure has stabilised. In diuretic treated hypertensive patients, mean cerebral blood flow is maintained between 4 and 24 hours after fosinopril, despite significant reduction in blood pressure.

Heart Failure:

The recommended initial dose is 10 mg once daily, initiated under close medical supervision. If the initial dose is well tolerated patients should then be titrated to a dose of up to 40 mg once daily. The appearance of hypotension after the initial dose should not preclude careful dose titration of fosinopril, following effective management of the hypotension. Fosinopril is used in addition to diuretics and digitalis.

Heart failure - High Risk Patients:

It is recommended that treatment is initiated in hospital for patients with severe cardiac failure (NYHA IV) and those at particular risk of first dose hypotension, i.e. patients on multiple or high dose diuretics (e.g.> 80 mg furosemide), patients with hypovolaemia, hyponatraemia (serum sodium < 130 mEq/l), pre-existing hypotension (systolic blood pressure <90 mmHg), patients with unstable cardiac failure and those on high-dose vasodilator therapy.

Paediatric population:

Use in this age group is not recommended.

There is limited clinical trial experience of the use of fosinopril in hypertensive children aged 6 years and above. The optimum dosage has not been determined in children of any age. An appropriate dose strength is not available for children weighing less than 50 kg.

Older people:

No dosage reduction is necessary in patients with clinically normal renal and hepatic function as no significant differences in the pharmacokinetic parameters or antihypertensive effect of fosinoprilat (active form of fosinopril) have been found compared with younger subjects.

Impaired hepatic function:

Treatment should be initiated at a dose of 10 mg. The rate of hydrolysis may be slowed in patients with hepatic impairment and patients could develop elevated plasma levels of fosinopril.

Renal Impairment:

Treatment should be initiated at a dose of 10 mg. Depending on the response, the dose should then be titrated to achieve the desired therapeutic effect.

Absorption, bioavailability, protein binding, biotransformation and metabolism are not appreciably altered by reduced renal function. In patients with impaired renal function, the total body clearance of fosinoprilat is approximately 50% slower than that in patients with normal renal function. However, since hepatobiliary elimination compensates at least partially for diminished renal elimination, the body clearance of fosinoprilat is not appreciably different over a wide range of renal insufficiency (creatinine clearances ranging from <10 to 80 ml/min/1.73m2, i.e. including end-stage renal failure).

Fosinopril / fosinoprilat is not well dialysed. In a study on radiolabelled intravenous fosinoprilat (7.5mg) and oral fosinopril (10mg), haemodialysis for four hours cleared only approximately 1.5% of the administered dose.

Clearance of fosinoprilat by haemodialysis and peritoneal dialysis averages 2% and 7%, respectively, of urea clearances.

Method of administration

For oral use.

History of angioneurotic oedema associated with previous ACE inhibitor therapy.

Hereditary / idiopathic angioneurotic oedema.

Second and third trimesters of pregnancy.

Renal artery stenosis.

Cardiogenic shock.

It should be noted that Fosinopril is not licensed for use in acute myocardial infarction.

The concomitant use of Fosinopril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²).

Hypersensitivity / angioedema:

Head and Neck Angioedema:

Angioedema has been seen in patients treated with ACE inhibitors, including fosinopril. If angioedema involves the tongue, glottis or larynx airway obstruction may occur and can be fatal. Emergency therapy, should be promptly instituted. Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of fosinopril; some cases required medical therapy.

Intestinal Angioedema:

Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C -1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus):

Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment).

Anaphylactoid- reactions during high-flux dialysis/lipoprotein apheresis membrane exposure:

Clinical observations have shown a high incidence of anaphylactoid-like reactions during haemodialysis with high-flux dialysis membranes (e.g. AN69) in patients receiving ACE inhibitors. Similar reactions during low-density lipoprotein (LDL) apheresis with dextran sulfate absorption have been observed. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication.

Anaphylactoid reactions during desensitisation:

Two patients undergoing desensitising treatment with hymenoptera venom whilst receiving another ACE inhibitor, enalapril, sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore, caution should be used in patients treated with ACE inhibitors undergoing such desensitisation procedures.Hypotension:

Fosinopril has been rarely associated with hypotension in uncomplicated hypertensive patients. As with other ACE inhibitors, symptomatic hypotension is most likely to occur in salt/volume depleted patients such as those treated vigorously with diuretics and/or salt restriction, renovascular hypertension, or those patients undergoing renal dialysis. Volume and/or salt depletion should be corrected before initiating therapy with fosinopril. A transient, hypotensive response is not a contraindication to continuing therapy which may be given without difficulty after replenishment of salt and/or volume.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, fosinopril therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of fosinopril or diuretic is increased. Consideration should be given to reducing the dose of diuretic therapy in patients with normal or low blood pressure who have been treated vigorously with diuretics or who are hyponatraemic.

Hypotension is not per se a reason to discontinue fosinopril. The magnitude of the decrease is greatest early in the course of treatment; this effect stabilises within a week or two, and generally returns to pre-treatment levels without a decrease in therapeutic efficacy.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended. If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Impaired Renal Function:

Hypertensive patients with pre-existing congestive heart failure, renovascular hypertension (especially renal artery stenosis in one or both kidneys), or salt and/or volume depletion of any aetiology are at increased risk of developing findings indicative of renal dysfunction, including: increases in blood urea nitrogen (BUN) and serum creatinine and potassium; proteinuria; changes in urine volume (including oliguria/anuria); and an abnormal urinalysis. These increases are usually reversible upon discontinuation of therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease develop increases in BUN and serum creatinine, usually minor or transient, when fosinopril is given concomitantly with a diuretic. This effect is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of diuretic and/or fosinopril may be required.

In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with an ACE inhibitor may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.

Dialysis:

The dialysis clearance of fosinopril is not clinically significant; hence, supplemental dosing following dialysis should not be necessary.

Hepatic Failure:

Rarely, ACE inhibitors have been associated with a potentially fatal syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients who develop jaundice or marked elevations of hepatic enzymes should discontinue ACE inhibitor treatment and receive appropriate medical follow-up.

Prior to starting treatment with fosinopril, renal and hepatic function should be assessed.

Impaired Hepatic Function:

Patients with impaired liver function could develop elevated plasma levels of fosinopril. In a study in patients with alcoholic or biliary cirrhosis, the apparent total body clearance of fosinoprilat was decreased and the plasma AUC approximately doubled.

Hyperkalaemia:

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including fosinopril. Patients at risk of developing hyperkalaemia include those with renal insufficiency, diabetes mellitus, and those using concomitant potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, or other drugs associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole).

Neutropenia/Agranulocytosis:

ACE inhibitors have been reported rarely to cause agranulocytosis and bone marrow depression; these occur more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Monitoring of white blood cell counts should be considered in such patients.

Surgery/Anaesthesia:

ACE inhibitors may augment the hypotensive effects of anaesthetics, analgesics, or other agents that produce hypotension. If hypotension occurs in patients undergoing surgery/anaesthesia and concomitantly receiving ACE inhibitors, it can usually be corrected by intravenous administration of fluid.

Aortic stenosis, mitral stenosis / Hypertrophic cardiomyopathy:

ACE inhibitors should be used with caution in patients with an obstruction in the outflow tract of the left ventricle.

Ethnicity:

The antihypertensive effect of ACE inhibitors is generally lower in black patients than in non-black patients.

Cough:

Cough has been reported with the use of ACE inhibitors, including fosinopril. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Pregnancy:

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Foetal/Neonatal Morbidity and Mortality:

When used in pregnancy, ACE inhibitors can cause injury and even death to the developing foetus.

Paediatric population:

There is limited clinical trial experience of the use of fosinopril in hypertensive children aged 6 years and above.

Older people:

Among patients who received fosinopril in clinical studies, overall differences in efficacy or safety were not observed between older patients (65 years or older) and younger patients; however, greater sensitivity of some older individuals cannot be ruled out.

Not recommended combination

Potassium supplements and potassium-sparing diuretics:

Fosinopril can attenuate potassium loss caused by a thiazide diuretic. Potassium-sparing diuretics (e.g. spironolactone, amiloride, triamterene and others) or potassium supplements can increase the risk of hyperkalaemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently.

Take special care

Antacids:

Antacids (e.g. aluminum hydroxide, magnesium hydroxide, and simeticone) may impair absorption of fosinopril sodium. Administration of fosinopril and antacids should be separated by at least 2 hours

Inhibitors of Endogenous Prostaglandin Synthesis:

It has been reported that indometacin may reduce the antihypertensive effect of other ACE inhibitors, especially in cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents (NSAIDs) (including aspirin) may have a similar effect.

Lithium:

Concomitant therapy with lithium may increase the serum lithium concentration and risk of lithium toxicity. Fosinopril and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended.

Other Anti-hypertensive agents:

Combination with other anti-hypertensive agents such as beta blockers, methyldopa and calcium antagonists may increase the anti-hypertensive effect.

Patients on diuretics and especially those in whom diuretic therapy was recently instituted, as well as those on severe dietary salt restrictions or dialysis, may occasionally experience a precipitous reduction of blood pressure usually within the first hour after receiving the initial dose of fosinopril.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.

Immunosuppressants:

Concomitant administration of immunosuppressants with fosinopril may lead to an increased risk of leukopenia.

mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus):

Patients taking concomitant mTOR inhibitors therapy may be at increased risk for angioedema.

Other drugs:

In pharmacokinetic studies with nifedipine, propranolol, cimetidine, metoclopramide and propantheline the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs.

Fosinopril has been used concomitantly with paracetamol, antihistamines, hypoglycaemic agents, insulin, lipid-lowering agents, or oestrogen without evidence of clinically important adverse events.

Co-trimoxazole (trimethoprim/sulfamethoxazole):

Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia.

Interference with serological testing:

Fosinopril may cause a false low measurement of serum digoxin levels with assays using the charcoal absorption method for digoxin. Other kits which use the antibody coated-tube method may be used instead. Therapy with fosinopril should be interrupted for a few days before carrying out tests for parathyroid function.

Pregnancy

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension.

Breastfeeding

Fosinopril is detectable in breast milk. Because only very limited information is available regarding the use of Fosinopril tablets during breastfeeding, Fosinopril tablets are not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

There are no studies on the effect of fosinopril on the ability to drive. However, adverse events such as hypotension, dizziness and fatigue may interfere with driving.

The list of undesirable effects shown below is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories: very common (>1/10), common (>1/100 < 1/10), uncommon (>1/1,000 <1/100), rare (>1/10,000 <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

In placebo controlled studies, there were no significant differences in clinical adverse experiences. Hypotension or syncope was a cause for discontinuation of therapy in 0.3% of patients.

The incidence of side effects did not differ between older people (>65 years old) and younger patients.

A symptom-complex of cough, bronchospasm, and eosinophilia has been observed in two patients treated with fosinopril.

Laboratory test findings showed some modest, usually transient, decreases in haemoglobin and haematocrit values and infrequently, small increases in blood urea.

Paediatric population

Safety data in the paediatric population receiving fosinopril is still limited, as only short-term exposure has been evaluated. In a randomised clinical trial of 253 children and adolescents aged 6 to 16 years, the following adverse events occurred in the 4 week double blind phase: headache (13.9%), hypotension (4.8%), cough (3.6%) and hyperkalaemia (3.6%), elevated serum creatinine levels (9.2%) and elevated serum creatinine kinase (CK) levels (2.9%). Different from adults are the elevated CK reported in this trial (even transient and with no clinical symptoms). The long-term effects of fosinopril on growth, puberty, and general development have not been studied.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Symptoms of overdosage are severe hypotension, shock stupor, bradycardia, electrolyte disturbances and renal failure.

No specific information is available on the treatment of overdosage with fosinopril; therapeutic measures depend on the nature and severity of the symptoms and should be symptomatic and supportive.

Measures to prevent absorption, such as induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate, within 30 minutes after intake, to hasten elimination, should be applied if ingestion is recent. Blood pressure should be monitored and if hypotension occurs, the patient should be placed in the shock position and salt and volume supplementation should be given rapidly. If volume expansion alone does not restore blood pressure, treatment with angiotensin II should be considered. Fosinopril /fosinoprilat is poorly removed from the body by peritoneal dialysis or haemodialysis.

After ingestion of an overdose, therapy with fosinopril should be discontinued and the patients should be kept under close supervision, preferably in an intensive care unit. Serum electrolytes and creatinine should be monitored.

Pharmacotherapeutic group: ACE inhibitors, plain, ATC Code: C09AA09

Fosinopril sodium salt is the ester prodrug of an angiotensin converting enzyme (ACE) inhibitor, fosinoprilat. Angiotensin converting enzyme is a peptidyl dipeptidase enzyme that catalyses a number of peptide conversions. These include the conversion of decapeptide Angiotensin I to the octapeptide, Angiotensin II. Fosinopril also inhibits kininase, the enzyme that degrades bradykinin.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Paediatric population

Reduction of blood pressure with low (0.1mg/kg), medium (0.3mg/kg) and high (0.6mg/kg) target doses of once-daily fosinopril was evaluated in a randomised double-blind study of 253 children and adolescents aged 6 to 16 years with hypertension or high-normal blood pressure. At the end of the four weeks of treatment, the mean reduction from baseline in trough systolic blood pressure was similar for children treated with low, medium and high dose fosinopril. No dosage response relationship was demonstrated between the three doses. The optimum dose has not been determined in children of any age. An appropriate dose strength is not available for children weighing less than 50kg.

The absolute absorption of fosinopril averaged 36% of an oral dose, and was not affected by the presence of food. Rapid and complete hydrolysis to active fosinoprilat occurs in the gastrointestinal mucosa and liver.

The time to reach Cmax is independent of dose, achieved in approximately three hours and consistent with peak inhibition of the angiotensin I pressor response 3 to 6 hours following administration.

In hypertensive patients with normal renal and hepatic function who received repeated doses of fosinopril, the effective T½ for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective T½ was 14 hours. Fosinoprilat is highly protein bound (>95%), has a relatively small volume of distribution and negligible binding to cellular components in blood. The elimination of fosinopril is by both hepatic and renal routes. Unlike other ACE-inhibitors, there is compensatory excretion by the alternative route in patients with renal insufficiency.

Limited pharmacokinetic data in children and adolescents were provided by a single-dose pharmacokinetic study in 19 hypertensive patients aged 6 to 16 years who received 0.3mg/kg of a solution of fosinopril.

Whether AUC and Cmax values of fosinoprilat (active form of fosinopril) in children aged 6 to 16 years were comparable to those seen in adults receiving 20 mg of fosinopril as a solution, has to be demonstrated.

The terminal elimination half-life for fosinoprilat was 11-13 hours and similar at all stages studied.

Maize starch, pregelatinised, cellulose, microcrystalline, sodium starch glycolate, hydroxypropylcellulose, crospovidone, and glycerol dibehenate.

Blisters: 24 months

Bottles: 18 months

Bottles: Do not store above 25°C. Store in the original package in order to protect from moisture. Keep the container tightly closed.

Blisters: Do not store above 25°C. Store in the original package in order to protect from moisture.

PVC/ACLAR/Aluminium blister strips in pack sizes of 10, 14, 20, 28, 30, 50, 60, 84, 90, 100 and 250 tablets*.

High Density Polypropylene (HDPP) tablet containers with polyethylene (PE) caps (with desiccant and optional polyethylene ullage filler) in pack sizes of 30, 60 and 250 tablets*.

*Not all pack sizes may be marketed.

No special handling instructions

Generics [UK] Ltd t/a Mylan, Station Close, Potters Bar, Herts. EN6 1TL.

PL 04569/0610

Date of first authorisation: 30/06/2005

Date of latest renewal: 12/08/2011

03 April 2017

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain