SIBNAYAL 24 MEQ 24mEq(847mg+1582mg) prolonged-release granules medication leaflet

Sibnayal 8 mEq prolonged-release granules

Sibnayal 24 mEq prolonged-release granules

Sibnayal 8 mEq prolonged-release granules

One sachet contains 282 mg of potassium citrate and 527 mg of potassium hydrogen carbonate.

This corresponds to 7.9 mEq of alkali (i.e. 2.6 mEq of citrate and 5.3 mEq of hydrogen carbonate) andto 7.9 mEq of potassium (i.e. 308 mg of potassium).

Sibnayal 24 mEq prolonged-release granules

One sachet contains 847 mg of potassium citrate and 1,582 mg of potassium hydrogen carbonate.

This corresponds to 23.6 mEq of alkali (i.e. 7.8 mEq of citrate and 15.8 mEq of hydrogen carbonate)and to 23.6 mEq of potassium (i.e. 924 mg of potassium).

For the full list of excipients, see section 6.1.

Prolonged-release granule

Green (potassium citrate) and white (potassium hydrogen carbonate), biconvex, 2 mm diameter.

Sibnayal is indicated for the treatment of distal renal tubular acidosis (dRTA) in adults, adolescentsand children aged one year and older.

Dosing is based on age and weight.

When initiating alkalising therapy, the target starting daily dose indicated below for each age groupshould be used and incrementally titrated to obtain the optimal dose that provides adequate metabolicacidosis control based on plasma bicarbonate levels.

- Adults: initiation at 1 mEq/kg/day, with a maximal incremental increase/decrease of0.5 mEq/kg/day to optimal dose

- Adolescents from 12 years: initiation at 1 mEq/kg/day, with a maximal incrementalincrease/decrease of 1.0 mEq/kg/day to optimal dose

- Children from 4 to 11 year inclusive: initiation at 2 mEq/kg/day, with a maximal incrementalincrease/decrease of 1.5 mEq/kg/day to optimal dose

- Children from 1 to 3 years inclusive: initiation at 4 mEq/kg/day, with a maximal incrementalincrease/decrease of 1.5 mEq/kg/day to optimal dose

When switching from another alkalising therapy to Sibnayal, treatment should be initiated at the targetdose used with the previous therapy (in mEq/kg/day) and titrated where necessary as described above.

The maximum dose, regardless of the age group, is either 10 mEq/kg/day or a total daily dose of336 mEq, whichever is lower.

The total daily dose should be administered in two intakes. For each individual patient, the nearestdose to the target dose should be fixed by combining whole sachets of the two available strengths.

In case of vomiting within two hours after intake, the patient should take another dose.

The use of this medicine requires medical supervision.

No dose adjustment is required.

Sibnayal should only be used in individuals with glomerular filtration rate(GFR) > 44 mL/min/1.73m². For individuals with GFR between 45 and 59 mL/min/1.73m² Sibnayalshould only be used if the potential benefits are considered to outweigh the potential risks (see

Table 1).

Table 1: Dosing recommendations in individuals with renal impairment

GFRmL/min/1.73m² Treatment of dRTA

* Plasma potassium levels in the normal ranges:

A regular monitoring of renal function parameters and blood potassiumlevels is necessary at starting dose and after new dose increase or if any45-59 decrease of GFR. Then frequency is according to physicians´s criteria, butat least twice a year (see section 4.4).

* Elevated plasma potassium:

Contraindicated≤ 44 Contraindicated

There is no need for specific target starting daily dose adjustment in patients with hepatic impairment.

The safety and efficacy of Sibnayal in children below one year of age have not been established. Nodata are available.

For oral use.

The total daily dose is administered twice daily, typically twelve hours apart.

Sibnayal must be taken orally, swallowed with a large glass of water.

The full dose of granules per intake can be swallowed in several smaller portions if necessary, but thecontent of each sachet must be entirely taken.

Doses should be taken preferably during meals.

For patients who are unable to swallow granules as described above, the granules may be mixed(without crushing) with small amounts of soft food (e.g., fruit puree, yoghurt). The Sibnayal soft foodmixture must be used immediately and cannot be stored. The mixture should be swallowed withoutchewing. Care should be taken to ensure that Sibnayal is not retained in the mouth.

In no instance granules must be mixed with hot food, hot liquid or alcohol or chewed or crushed as thiscan disrupt their prolonged release properties and may lead to large sudden release of alkalising agentthat could affect product efficacy and safety (see section 5.2).

Sibnayal granules are not suitable for administration via feeding tubes due to high risk of obstructingthe tubes.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Renal impairment with GFR ≤ 44 mL/min/1.73m².

Hyperkalaemia and cardiotoxicity

Sibnayal should be used with caution in patients who have conditions pre-disposing them tohyperkalaemia, such as renal impairment, or crush syndrome, as a further rise in plasma potassiummay lead to cardiac arrest. Close monitoring of plasma potassium in patients at risk is required atstarting dose and after new dose increase or in case of worsening of pre-existing disease. Thenfrequency is according to physicians´s criteria, but at least twice a year.

Sibnayal should be used with caution in case of combination with other products increasing plasmapotassium or predisposing to cardiac dysrhythmia (see section 4.5).

Sibnayal should be used with caution in patients having gastro-intestinal disorders as they could affectefficacy and safety, such as malabsorption, delayed gastric emptying, diarrhoea, nausea, vomiting.

In such cases the blood bicarbonate levels should be regularly monitored and dose adjusted to maintainwithin normal ranges.

The matrix of the granules can be found in the stools, which does not affect the efficacy or safety of

Sibnayal.

Sibnayal should only be used in individuals with glomerular filtration rate(GFR) > 44 mL/min/1.73m². For individuals with GFR between 45 and 59 mL/min/1.73m² Sibnayalshould only be used if the potential benefits are considered to outweigh the potential risks. For thesepatients doses should be adjusted by regular monitoring of plasma bicarbonate and potassium (seesection 4.2). Special care should be taken in elderly people in whom renal function can be decreased.

Potassium contents

Sibnayal 8 mEq contains 308 mg of potassium per sachet. This is to be taken into consideration if thepatient has a reduced kidney function or if the patient is on a controlled potassium diet.

Sibnayal 24 mEq contains 924 mg of potassium per sachet. This is to be taken into consideration if thepatient has a reduced kidney function or if the patient is on a controlled potassium diet.

No interaction studies have been performed.

Medicinal products that may increase plasma potassium or induce hyperkalaemia

Concomitant use of Sibnayal with medicinal products that may increase potassium levels or inducehyperkalaemia (e.g. ACE inhibitors, potassium-sparing diuretics, potassium supplements, saltsubstitutes containing potassium, ciclosporin or other medicinal products such as heparin sodium ornonsteroidal anti-inflammatory medicinal products) necessitates monitoring of potassium plasmalevels (see section 4.4).

Medicinal products affected by plasma potassium disturbances

Periodic monitoring of plasma potassium and ECG is recommended when Sibnayal is administeredwith medicinal products affected by plasma potassium disturbances due to the potential risk for a pro-arrhythmic effect (e.g. digitalis glycosides, corticosteroids, anti-arrhythmics such as quinidine,amiodarone, chlorpromazine, cisapride or sparfloxacine).

Medicinal products affected by increased urine pH

Patients with dRTA have alkaline urine due to their proton secretion defect. This may impact theexcretion of the medicinal product into the urine (such as an increase of the elimination of salicylates,tetracyclines, and barbiturates and a decrease in the elimination of quinidine) or reduce theeffectiveness of methenamine. As Sibnayal may further increase urine pH to a small extent, theinteraction of alkaline urine with these medications may be enhanced.

There are no data from the use of Sibnayal in pregnant women. Animal studies do not indicate director indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition orpostnatal development (see section 5.3).

Sibnayal should only be used during pregnancy if the expected benefits outweigh the potential risks.

Although during pregnancy and more so during labour, there is more risk associated to a potentiallysevere acidosis and hypokalaemia in dRTA patients than to alkali treatment, in women with problempregnancies there might be an increased risk to develop hyperkalemia when potassium intake is high.

Potassium is excreted in human milk, but at therapeutic doses of Sibnayal no effects on the breastfednewborns/infants are anticipated.

Sibnayal can be used during breast-feeding.

Potassium citrate and potassium hydrogen carbonate are not known to affect fertility.

Sibnayal has no or negligible influence on the ability to drive and use machines.

The most frequently reported adverse reactions are abdominal pain (14%, very common), upperabdominal pain (8%, common) and gastro-intestinal pain (2%, common).

Nausea (2%, common) can be experienced at initiation of therapy.

The list of adverse reactions is based on the experience in clinical trials.

The frequency of adverse reactions is defined using the following convention: very common (≥1/10) ;common (≥1/100 to <1/10) ; uncommon (≥1/1000 to <1/100) ; rare (≥1/10000 to <1/1000) and veryrare (<1/10000).

- abdominal pain as very common

- abdominal pain upper, diarrhoea, dyspepsia, gastrointestinal disorder, gastrointestinal pain,nausea and vomiting as common.

Gastro-intestinal pain, abdominal pain and upper abdominal pain were generally of mild or moderateintensity and resolved within 24 hours without the need to modify or stop the treatment. All other gastro-intestinal adverse reactions (dyspepsia, vomiting, diarrhoea) were also of mild or moderate intensity,and resolved within 1 to 3 days, without modification or interruption of treatment.

In clinical trials, although numbers were small, the safety profile was comparable in treated patientsfor adults (N= 16 healthy subjects and 7 dRTA patients) and paediatric population (N=27, including10 adolescents (12-17 years old inclusive), 14 children (4-11 years old inclusive) and 3 infants(6 months - 3 years inclusive)).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Reports of a laxative effect after excessive oral doses of individual alkalising salts have occurred.

An acute massive intake of potassium can cause hyperkalaemia resulting in nausea, vomiting, anddiarrhoea and in severe cases paraesthesia, muscular weakness, mental confusion, electrocardiographicabnormalities (large and symmetric T waves), arrhythmia, atrioventricular block and heart failure.

Hyperkalaemia is a particular concern in patients with underlying renal insufficiency.

In case of severe hyperkalaemia, patients should be monitored (mostly plasma potassium level and

ECG) and the appropriate symptomatic and supportive therapy instituted in specialised care units,where emergency treatments leading to rapid elimination of potassium such as ion exchange resin,combination of insulin-dextrose or β2 mimetics (salbutamol) or haemodialysis will be implemented.

Pharmacotherapeutic group: mineral supplements, potassium, ATC code: A12BA30.

Sibnayal is a fixed-dose combination of potassium citrate and potassium hydrogen carbonate (alsoknown as potassium bicarbonate) as prolonged release granules.

The pharmacological properties are directly linked to the capacity of potassium citrate and potassiumhydrogen carbonate to maintain electrolyte balance. Both act as alkalising agents and buffer themetabolic acidosis. Sibnayal provides a source of potassium to correct hypokalaemia. In addition,citrate acts also as a calcium chelating agent.

In a randomised, double blind, placebo-controlled, two-period, incomplete crossover study in healthyadults, Sibnayal at doses ranging from 1.0 to 2.9 mEq/kg/day during 5 days was shown to increaseurine pH (marker of alkalinising effect in healthy subjects) with a dose-proportional effect ascompared to placebo. The effect was maintained over 12 hours at all the doses evaluated.

The efficacy and safety of Sibnayal for the treatment of dRTA was evaluated in a multi-centre, open-label, sequential study that included 37 patients with an established diagnosis of dRTA (7 adults,10 adolescents (12-17 years), 15 children (4-11 years), 5 infants (1-4 years)) who were being treatedwith their standard-of-care (SoC) short-acting alkalising agents in repeated daily intakes . Patientscontinued on their SoC for 5 days (n=35) and then received Sibnayal twice daily, initially during atitration period to establish the optimal dose (up to 30 days duration) and then for 5 days at thisoptimal dose (n=32).

With Sibnayal, the primary endpoint showed that the mean (SD) plasma bicarbonate pre-dose levelduring 3 days of treatment at steady state was 23.1 (1.62) mmol/L with 90% (26/29) of the patientsachieving 3-day mean normal bicarbonate levels. This effect was generally maintained during 24months of therapy, although some variability was observed with a responder rate of 56-92%. Meanachieved plasma potassium level was 4.0 (0.44) mmol/L with 83% (24/29) of the patients at normallevels.

With SoC, the mean (SD) plasma bicarbonate pre-dose level during 3 days of treatment at steady statewas 21.7 (3.06) mmol/L with 45% (13/29) of the patients at normal levels. The mean achieved plasmapotassium level was 3.8 (0.44) mmol/L with 82% at normal levels.

Sibnayal is a prolonged-release granules formulation to cover a 12-hour treatment period afteradministration.

Pharmacokinetic features of citrate, bicarbonate and potassium are based on the literature.

Oral citrate is absorbed at a pH between 4.8 and 6.4 along the upper portion of the small intestine(duodenum, early part of jejunum). Under these conditions, the intestinal absorption of citrate is rapidand almost complete.

Oral bicarbonate is absorbed throughout the gastrointestinal tract. Bicarbonate neutralises gastric acidwith the production of CO2 eliminated by the respiratory route. Bicarbonate not involved in thatreaction is rapidly absorbed by the intestinal mucosa.

The potassium ions are fully absorbed, irrespective of the amount consumed. The majority ofpotassium absorption occurs in the small intestine, mainly through passive diffusion.

Distribution and biotransformation

Most of the citrate in the blood circulates unbound and the remaining quota is complexed to calcium,potassium or sodium. The citrate ion from oral alkali citrates undergoes oxidative metabolicbreakdown to carbon dioxide (CO2) or bicarbonate. Consequently, a basifying effect is associated withits metabolism. Ingestion of 36 mmol of citrate (i.e. 108 mEq) is equivalent to less than 2% of thedaily turnover of citrate involved in energy metabolism within the body.

The absorbed bicarbonate is distributed like the endogenous bicarbonate in the intracellular andextracellular compartments of the organism. Bicarbonate is not really metabolised. However,bicarbonate is in equilibrium with hydrogen ions and carbon dioxide and, through its concentration,regulates the acid-base balance.

Potassium is carried from extracellular fluids to the intracellular fluids, and its distribution betweencells is tightly controlled, with only 1.5-2.5% of total body potassium found in the extracellular fluid.

A large proportion of the body burden of potassium (98%) is found in muscle and the skeleton, and itis also present in high concentrations in the blood, central nervous system, intestine, liver, lung andskin. An active ion transport system maintains the gradient across the plasma membrane.

Citrate is mainly eliminated by the renal route. In its trivalent form, it is filtered freely through therenal glomerulus. Dietary alkali absorption increases citrate excretion by inhibiting its reabsorption atthe mitochondrial level and by increasing its secretion by the nephron.

Bicarbonate provides an alkali load and therefore stimulates an increase in urinary excretion of citrate.

Increased excretion of bicarbonate in the urine also occurs. Bicarbonate can also be partiallyeliminated by the respiratory route (in the form of CO2). The major excretory route of potassium is viathe kidneys (90%). The rest is eliminated in the faeces and small amounts may also be excreted insweat.

Special population

Pharmacokinetics of potassium can be modified in patients with renal impairment for whomglomerular filtration of potassium is less active, in cardiac patients who present a susceptibility tohyperkalaemia and in adrenocortical patients for whom the risk of hyperkalaemia is accentuated.

Pharmacokinetics of citrate, bicarbonate and/or potassium can be modified in patients with gastro-intestinal issues (e.g. malabsorption, delayed gastric emptying, oesophageal compression, intestinalobstruction or other chronic gastro-intestinal disease) that could modify absorption.

Pharmacokinetics should not be modified in patients with hepatic impairment, or in patients withoverweight or obesity.

Interaction with alcohol

When Sibnayal is mixed with alcohol in vitro, the rate of dissolution of the granules increases and canoccur rapidly leading to a loss of the prolonged-effect (see section 4.2).

Non-clinical data reveals no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

Core granules

Hypromellose (E464)

Microcrystalline cellulose (E460(i))

Glycerol dibehenate

Magnesium stearate (E470b)

Silica colloidal anhydrous

Magnesium oxide, heavy (E530)

Ethylcellulose (E462)

Chlorophyllin (E140 (ii))

Technological agent (on coated granules)

Talc

Not applicable.

5 years.

Do not store above 25 °C.

Three-layered foil (polyethylene terephthalate polyester/aluminium/low density polyethylene) sealedsachet for single use.

Sibnayal 8 mEq prolonged-release granules

Packs of 60 sachets.

Multipacks containing 120 (2 packs of 60) sachets.

Multipacks containing 180 (3 packs of 60) sachets.

Multipacks containing 240 (4 packs of 60) sachets.

Multipacks containing 300 (5 packs of 60) sachets.

Multipacks containing 360 (6 packs of 60) sachets.

Sibnayal 24 mEq prolonged-release granules

Packs of 60 sachets.

Multipacks containing 120 (2 packs of 60) sachets.

Multipacks containing 180 (3 packs of 60) sachets.

Multipacks containing 240 (4 packs of 60) sachets.

Multipacks containing 300 (5 packs of 60) sachets.

Multipacks containing 360 (6 packs of 60) sachets.

Not all pack sizes may be marketed.

After opening the sachet, discard any unused content.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

ADVICENNE262 rue du Faubourg Saint Honoré75008 Paris

France

Sibnayal 8 mEq prolonged-release granules

EU/1/20/1517/001

EU/1/20/1517/002

EU/1/20/1517/003

EU/1/20/1517/004

EU/1/20/1517/005

EU/1/20/1517/006

Sibnayal 24 mEq prolonged-release granules

EU/1/20/1517/007

EU/1/20/1517/008

EU/1/20/1517/009

EU/1/20/1517/010

EU/1/20/1517/011

EU/1/20/1517/012

Date of first authorisation: 30 April 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.