Signs and symptoms
If overdose has occurred or is suspected symptoms should be those caused by excessive diuresis.
Management
Steps should be taken to empty the stomach either by emesis or gastric lavage. General measures should be taken to restore blood volume, maintain blood pressure and correct electrolyte disturbances.
Oliguria
Anuria.
Increase in blood urea.
- Although Conartnide can be used to induce diuresis in renal insufficiency, any marked increase of blood urea or the development of oliguria or anuria during treatment of severe progressive renal disease are indications for stopping treatment with Conartnide.
Hepatic coma.
Severe electrolyte imbalance.
Concomitant administration with lithium salts.
Not applicable.
Adverse effects are listed by system organ class and frequency: very common (> 1/10), common (> 1/100 to <1/10), uncommon (> 1/1,000 to <1/100), rare (> 1/10,000 to <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data):
Blood and lymphatic system disorders
Rare: Bone marrow depression associated with the use of Conartnide, but it has not been proven definitely to be attributed to the drug.
Not known: thrombocytopenia.
Metabolism and nutrition disorders
Common: dehydration.
Uncommon: fluid and electrolyte depletion.
Not known: hyperuricaemia, hyperglycaemia.
Nervous system disorders
Common: dizziness, headache.
Not known: encephalopathy (in patients with pre-existing hepatic disease).
Ear and labyrinth disorders
Uncommon: ear pain, vertigo.
Rare: Hearing disturbance after administration of Conartnide, which is reversible.
Vascular disorders
Common: hypotension.
Gastrointestinal disorders
Common: nausea.
Uncommon: diarrhoea.
Not known: stomach cramps, abdominal pain, vomiting, dyspepsia.
Skin and subcutaneous tissue disorders
Common: pruritis (in patients with liver disease).
Uncommon: urticaria.
Not known: rash.
Musculoskeletal and connective tissue disorders
Not known: muscle cramps, arthralgia.
Reproductive system and breast disorders
Uncommon: painful breasts.
Not known: gynaecomastia.
General disorders and administration site conditions
Common: fatigue.
Uncommon: chest discomfort.
Investigations
Not known: raised blood urea and serum creatinine, abnormalities of serum levels of hepatic enzymes
Higher dose therapy:
In patients with severe chronic renal failure given high doses of Conartnide, there have been reports of severe, generalised musculoskeletal pain sometimes associated with muscle spasm, occurring one or two hours after administration and lasting up to 12 hours. The lowest reported dose causing this type of adverse reaction was 5 mg by intravenous injection and the highest was 75 mg orally in a single dose. All patients recovered fully and there was no deterioration in their renal function. The cause of this pain is uncertain but it may be a result of varying electrolyte gradients at the cell membrane level.
Experience suggests that the incidence of such reactions is reduced by initiating treatment at 5-10 mg daily and titrating upwards using a twice daily dosage regimen at doses of 20 mg or more.
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.
Conartnide has been extensively evaluated in a wide range of animal toxicity tests. Studies in rats and mice have shown it to have a relatively low acute toxicity. No toxic effects were seen in rats at doses of up to 50 mg/kg/day over a 26 week period. In thirteen and 26 week studies at doses of up to 100 mg/kg/day, haematological and clinical chemistry values were generally unaffected; other effects seen were generally related to the diuretic effects of the drug.
Reproductive studies have shown no teratogenic or embryotoxic effects at oral doses up to 50 mg/kg/day in rats and 100 mg/kg/day in mice. But at 3400 times the standard human dose embryocidal effects (growth retardation and decreased foetal weight) were observed in rats. Although no foetal abnormalities occurred foetal toxicity was greater in rabbits: increased resorption rate was observed at doses of 0.25 and 0.5 mg/kg/day.
Conartnide showed no evidence of mutagenicity on Ames testing. Seventy- eight week studies in rats do not suggest that Conartnide has a significant carcinogenic potential although damage to kidneys, testes and the auditory system were observed in post mortem examinations. In common with other 'loop' diuretics, diuretics, intravenous Conartnide caused ototoxicity in cats.
Overall, these studies provide satisfactory evidence for the likely safety of Conartnide when administered to humans.
Conartnide is indicated for the treatment of oedema associated with e.g. congestive heart failure, renal dysfunction including nephrotic syndrome and cirrhosis of the liver.
In oedema of renal or cardiac origin where high doses of a potent short - acting diuretic are required, Conartnide 5 mg may be used.
Pharmacotherapeutic group: Diuretics, high-ceiling diuretics, sulfonamides, plain, ATC code: C03CA02.
Mechanism of action
Conartnide is a potent loop diuretic with a rapid onset and a short duration of action. The primary site of action is the ascending limb of the loop of Henle where it exerts inhibiting effects on electrolyte reabsorption, causing its diuretic and natriuretic action.
Clinical efficacy
After oral administration, the diuretic effect is seen within 30 minutes with the peak effect seen between 1 and 2 hours. The diuretic effect is practically complete in 3 hours after a 1mg dose.
Absorption
Following oral administration, Conartnide is rapidly and almost completely absorbed from the gastro-intestinal tract with the bioavailability reported as between 80 and 95%.
Distribution
It is 95% bound to plasma proteins. It has a plasma elimination half-life of 0.75 to 2.6 hours.
Highest concentrations of the drug are achieved in the plasma, kidney and liver. It is not yet clear whether the drug crosses the placenta or passes into the cerebrospinal fluid.
Biotransformation and elimination
Conartnide is cleared from the circulation at a rate of 120-250 ml/min with approximately half of an oral dose excreted unchanged via the kidneys with the remainder excreted via the bile into the faeces.
No active metabolites are known. The primary urinary metabolite is the 3' alcohol of the N-butyl chain and the primary biliary metabolite is the 2' alcohol.
Renal and hepatic impairment
There is an increase in half-life and a reduced plasma clearance in the presence of renal or hepatic impairment.
Chronic renal impairment
In patients with chronic renal failure, the liver takes more importance as an excretory pathway although the duration of action is not markedly prolonged.
Sudden changes in cardiovascular pressure-flow relationships, leading to circulatory collapse, can occur particularly in the elderly if the oedema is eliminated too rapidly. It is important to remember this when Conartnide is given in high doses, either orally or intravenously.
Patients with chronic renal failure on high doses of Conartnide should remain under constant hospital supervision.
Patients on a low salt diet may suffer electrolyte imbalance. Serum electrolyte checks, in particular for sodium, potassium, chloride and bicarbonate, should be carried out on a regular basis and, where necessary, replacement therapy carried out.
Conartnide may enhance the nephrotoxicity or ototoxicity of other drugs, particularly in patients with renal impairment.
Conartnide may precipitate encephalopathy in patients with hepatic impairment.
Conartnide may increase uric acid. Blood glucose and blood uric acid should be measured periodically, especially in diabetics and those suspected of latent diabetes and in patients with gout.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Conartnide has no known effect on the ability to drive or operate machinery.
Posology
Most patients require a daily dose of 1 mg given as a single morning or early evening dose. Depending on the patient's response, a second dose can be given 6-8 hours later. In refractory cases, the dose can be increased until a satisfactory diuretic response is obtained, or infusions of Conartnide can be given.
Dosage in the elderly
Adjust the dosage according to the response. A dose of 0.5 mg Conartnide per day may be sufficient in some elderly patients.
Paediatric population
Not recommended for children under 12 years of age.
Method of administration
For oral use.
None.
