Added            Deleted

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4.4 Special Warnings and special precautions for Use

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Redoxon Double Action This medicinal product contains 194 mg sodium per tablet, equivalent to 9.7% of the WHO recommended maximum daily dietary intake of 2 g sodium for an adult. This should be taken into consideration by patients on a controlled sodium diet.

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4.6 Fertility, pregnancy and lactation

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Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

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10 Date of Revision of the Text

December 2014 January 2019

2.                QUALITATIVE AND QUANTITATIVE COMPOSITION

…

Excipients:

Aspartame 15 mg

Sorbitol     655 mg

Sodium      8.4mmol194 mg

3.                PHARMACEUTICAL FORM

Effervescent Tablet.

Light orange round tablet with bevelled edges and flat faces. with a smell of orange.

4.                CLINICAL PARTICULARS

4.2              Posology and method of administration

Adults and children over 12 years: 1 effervescent tablet a day dissolved in a glass of water (200 ml).

4.3              Contra-indications

Redoxon Double Action must not be taken by persons known to be hypersensitive to any of its ingrHypersensitivity to any of the active substances or to any of the excipients listed in section 6.1.

Patients suffering from or having a history of Nephrolitiasis must not take this product.

Patients suffering from oxalate urolithiasis or oxaluria must not take this product.

Patients suffering from severe renal insufficiency or renal failure must not take the product. This includes patients on dialysis. For patients who take large amounts of vitamin C, the lack of the normal renal clearance mechanism may result in very high plasma levels which could result in the development of crystals and or/stones or may lead to renal failure.

Patients suffering from Hemochromatosis must not take this product.

4.4              Special warnings and special precautions for use

Patients suffering from renal insufficiency should consult a physician or healthcare professional prior to intake of large doses of ascorbic acid (see section 4.9).

Do not exceed the recommended doses. Acute or chronic overdose (> 2 g / day) increases risk of adverse effects including formation of calcium oxalate deposits, acute tubular necrosis, and/or renal failure, especially in patients with renal disorders (see section 4.9).

Patients with a predisposition for calcium-oxalate nephrolithiasis and recurrent nephrolithiasis on an oxalate restricted diet should use caution with use of high dose vitamin C formulations

Patients suffering from glucose-6-phosphatase deficiency should must not take higher than the recommended dose. Overdose of vitamin C in this patient population (> 3 g in children and > 15 g in adults) has been associated with hemolytic anemia (see section 4.9).

Patients receiving other single vitamins or multivitamin preparations, any other medication or those under medical care must consult a health care professional before taking this product (see sections 4.5 and 4.9).

Separate the intake of the product from other medication by 4 hours unless otherwise specified (see section 4.5).

High doses of vVitamin C may interfere with laboratory tests  diagnostic measures resulting in false readings. Inform your physician when taking this product and diagnostic measures are planned or done.

Vitamin C may interfere with test kits and meters measuring glucose levels resulting in false results. Please check the package insert of the test kit or meter for guidance (see section 4.5).

Redoxon Double Action contains a source of phenylalanine. and, therefore, may Therefore, may be harmful to people with phenylketonuria.

Redoxon Double Action contains 196mg 194mg sodium per tablet. This should be taken into consideration by patients on a controlled sodium diet.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5                                     Interactions with other medicinal products and other forms of interaction

Drug interactions:

Ascorbic Acid:

Desferrioxamine: Vitamin C may enhance tissue iron toxicity, especially in the heart, causing cardiac decompensation.

Cyclosporine: Vitamin C may reduce cyclosporine blood levels.

Warfarin: High doses of vitamin C may interfere with the effectiveness of warfarin

Zinc:

Zinc forms complexes with certain substances (including tetracycline antibiotics, quinonolone antibiotics, penicillamine) resulting in decreased absorption of both substances. As these interactions occur in the gastro-intestinal tract, the potential for interaction should be reduced by taking the product separately from other drugs. It is usually sufficient to separate the intake by at least 2 hours before or 4-6 hours after ingestion of the other drug, unless otherwise specified.

Food interactions:

Copper:

Zinc may reduce copper absorption.

Lab interactions:

As vitamin C is a strong reducing agent, it can cause chemical interference in laboratory tests that involve oxidation-reduction reactions, such as the analyses of glucose, creatinine, carbamazepine, uric acid, and inorganic phosphates in urine, serum and of occult blood in feces. Refer to the manufacturer’s information to determine if vitamin C interferes with the test.

At high doses (more than 2 g/day) vitamin C may interfere with the following biological tests: plasmatic and urinary dosages of creatinine and glucose (control with glucose-oxydase device) as well as with tests for occult bleeding in stool.

4.6              Pregnancy ,lactation and fertilityFertility, pregnancy and lactation

Pregnancy and lactationLactation

Vitamin C or Vitamin C and Zinc citrate areThe product is generally considered safe during pregnancy and lactation when the recommended dose is takenused as labelled. However, since there are no sufficient controlled human studies assessing the risk of the product ascorbic acid treatment during pregnancy or lactation, the product should be administered in pregnancy or lactation only when clinically indicated and recommended considered essential by the physician.

The labelled dose should not be exceeded as chronic overdose might be harmful to the foetus and neonate.

Vitamin C and Zinc are secreted into breast milk. This must be taken into consideration if the infant is receiving any other supplements.

Fertility

To date, there is no evidence suggestive that vitamin C and/or zinc causes adverse reproductive effects in humans.

 4.7             Effects on ability to drive and use machines

None.The product has no or negligible influence on the ability to drive and use machines.

4.8              Undesirable effects

The listed adverse drug reactions have been identified during the post-approval use of the product. As these reactions are reported voluntarily, a reliable estimation of their frequency is not possible.

are based on spontaneous reports, thus an organization according to CIOMS III categories of frequency is not  possible.

Gastrointestinal disorders

Diarrhoea. , nausea, vomiting, gastrointestinal and abdominal pain., stomach discomfort

Immune System Disorders

Allergic reaction, anaphylactic reaction, anaphylactic shock.

Rare hypersensitivity Hypersensitivity reactions with respective laboratory and clinical manifestations include allergic asthma syndrome, mild to moderate reactions potentially affecting skin, respiratory tract, gastrointestinal tract, and cardiovascular system, including symptoms such as rash, urticaria, allergic oedema and angioedema, pruritus, cardio-respiratory distress, and very rarely, severe reactions, including anaphylactic shock have been reported.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9              Overdose

There is no evidence that this product can lead to an overdose when used as recommended.

Allowance should be made for intake of vitamin C and zinc from all other sources.

Most, if not all reports concerning overdoses are associated with concomitant intake of high dosed single and/or multi- vitamin preparations.

Single cases of acute and chronic overdoses are reported in the literature. Ascorbic acid overdose may result in oxidative hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, disseminated intravascular coagulation, and significantly elevated levels of serum and urinary oxalate levels. Increased levels of oxalate concentration have been shown to lead to calcium oxalate deposits in dialysis patients. Additionally, there are several reports which showed that large doses of vitamin C both orally and intravenously can provoke calcium oxalate deposits, calcium oxalate crystalluria in patients who have a predisposition for increased crystal aggregation, tubulointerstitial nephropathy, and acute renal failure as a result of calcium oxalate crystals.Clinical signs and symptoms, laboratory findings, and consequences of overdose are highly diverse, dependent on an individual’s susceptibility and surrounding circumstances.

General manifestations of overdose with vitamin C and/or zinc may include increase of gastrointestinal disturbances including diarrhea, nausea, and vomiting.

If such symptoms occur, the product should be stopped and a healthcare professional consulted.

Specific clinical manifestations may include the following:

Vitamin C:

Acute or chronic overdose of vitamin C may significantly elevate serum and urinary oxalate levels. In some instances, this may lead to hyperoxaluria, calcium oxalate crystalluria, calcium oxalate deposition, kidney stone formation, tubulointerstitial nephropathy, and acute renal failure. Individuals with mild to moderate renal insufficiency may be susceptible to these effects of vitamin C toxicity at lower doses and should consult a health care professional before use of the product.

Overdose of vitamin C may result in oxidative hemolysis or disseminated intravascular coagulation in patients with glucose-6-phosphate dehydrogenase deficiency.

Zinc:

Zinc overdose can cause irritation and corrosion of the gastrointestinal (GI) tract, acute renal tubular necrosis, interstitial nephritis, copper deficiency, sideroblastic anemia, and myeloneuropathies.

If overdose with the product is suspected, intake should be stopped and a health care professional consulted for treatment of clinical manifestations. Vitamin C is removed by hemodialysis.

5.                PHARMACOLOGICAL PROPERTIES

5.2              Pharmacokinetic properties

…

Distribution: The physiological body pool of vitamin C is about 1500 mg. Plasma protein binding of ascorbic acid is approximately 24%. Serum concentrations are normally 10 mg/l (60 mol/l). Concentrations below 6 mg/l (35 mol/l) indicate that the intake of vitamin C is not always adequate, and concentrations below 4 mg/l (20 mol/l) indicate that the intake is actually inadequate. In clinically manifest scurvy, serum concentrations are below 2 mg/l (10 mol/l).

…

5.3              Preclinical safety data

Not applicable.No specific study with this product was done, but the preclinical safety of the individual components has been extensively documented.

6.                PHARMACEUTICAL PARTICULARS

6.4              Special precautions for storage

…

Aluminium tube and polyethylenepolypropylene tube:

Keep the tube tightly closed, in order to protect from moisture.

10.              DATE OF (PARTIAL) REVISION OF THE TEXT

December 2014       March 2012

In Section 4.1. ascorbic acid was changed to vitamin C.

In Section 4.3 the text was revised to read:
Redoxon Double Action must not be taken by persons known to be hypersensitive to any of its ingredients.
Patients suffering from oxalate urolithiasis or oxaluria must not take this product.
Patients suffering from severe renal insufficiency or renal failure must not take the product. For patients who take large amounts of vitamin C, the lack of the normal renal clearance mechanism may result in very high plasma levels which could result in the development of crystals and or/stones or may lead to renal failure.

The following  text was deleted:
In nephrolithiasis accompanied by oxaluria with aciduria or normal urinary pH, vitamin C should not be given if the dose of vitamin C is > 1g/day.

In Section 4.4, the text was revised to read:
Patients suffering from renal insufficiency should consult a physician prior to intake of large doses of ascorbic acid.
Do not exceed the recommended doses. Acute or chronic overdose (> 2 g / day) increases risk of adverse effects including formation of calcium oxalate deposits, acute tubular necrosis, and/or renal failure, especially in patients with renal disorders.
Patients with a predisposition for calcium-oxalate nephrolithiasis and recurrent nephrolithiasis on an oxalate restricted diet should use caution with use of high dose vitamin C formulations.  
Patients suffering from glucose-6-phosphatase deficiency must not take higher than the recommended dose. Overdose of vitamin C in this patient population (> 3 g in children and > 15 g in adults) has been associated with hemolytic anemia.
Patients receiving other single vitamins or multivitamin preparations, any other medication or those under medical care must consult a health care professional before taking this product.
High doses of vitamin C may interfere with diagnostic measures. Inform your physician when taking this product and diagnostic measures are planned or done.
Redoxon Double Action contains a source of phenylalanine and, therefore, may be harmful to people with phenylketonuria.
Redoxon Double Action contains 196mg sodium per tablet and should be taken into consideration by patients on a controlled sodium diet.

In Section 4.6, the text was revised to read:
Pregnancy and lactation
Vitamin C or Vitamin C and Zinc citrate are generally considered safe during pregnancy and lactation when the recommended dose is taken. However, since there are no sufficient controlled human studies assessing the risk of ascorbic acid treatment during pregnancy or lactation the product should be administered in pregnancy or lactation only when clinically indicated and recommended by the physician.
Vitamin C and Zinc are secreted into breast milk. This must be taken into consideration if the infant is receiving any other supplements.
Fertility
To date, there is no evidence suggestive that vitamin C and/or zinc causes adverse reproductive effects in humans.

 The following text was deleted:
No teratogenicity study in animals is available.
Clinical observations of a great number of exposed pregnant women have not shown any malformative or toxic effect of REDOXON Double Action on the fœtus. However, only epidemiological studies could check the absence of any risk.
Consequently, REDOXON Double Action should only be used during pregnancy if necessary.
The vitamin and mineral of REDOXON Double Action effervescent tablets are excreted in the milk, but harmful effect on the child are unlikely at the therapeutic doses.

 In Section 4.8, the text was revised to read:
The listed adverse drug reactions are based on spontaneous reports, thus an organization according to CIOMS III categories of frequency is not  possible.
Gastrointestinal disorders
Diarrhea. nausea, vomiting, abdominal pain, stomach discomfort
Immune System Disorders
Allergic reaction, anaphylactic reaction, anaphylactic shock.
Rare hypersensitivity reactions with respective laboratory and clinical manifestations include allergic asthma syndrome, mild to moderate reactions potentially affecting skin, respiratory tract, gastrointestinal tract, and cardiovascular system, including symptoms such as rash, urticaria, allergic oedema and angioedema, pruritus, cardio-respiratory distress, and very rarely, severe reactions, including anaphylactic shock have been reported

The following text was deleted:
The most commonly found adverse reactions are mild transient multivitamin/mineral gastrointestinal disturbances (>=1/100 - <1/10).
Allergic reactions are very rare (<1/10,000). Urticaria, throat swelling and rash have been reported in isolate cases.
Ascorbic acid may cause haemolytic anaemia in certain individuals with a deficiency of glucose-6-phosphate dehydrogenase.

In Section 4.9, the text was revised to read:
There is no evidence that this product can lead to an overdose when used as recommended.
Most, if not all reports concerning overdoses are associated with concomitant intake of high dosed single and/or multi- vitamin preparations.
Single cases of acute and chronic overdoses are reported in the literature. Ascorbic acid overdose may result in oxidative hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, disseminated intravascular coagulation, and significantly elevated levels of serum and urinary oxalate levels. Increased levels of oxalate concentration have been shown to lead to calcium oxalate deposits in dialysis patients. Additionally, there are several reports which showed that large doses of vitamin C both orally and intravenously can provoke calcium oxalate deposits, calcium oxalate crystalluria in patients who have a predisposition for increased crystal aggregation, tubulointerstitial nephropathy, and acute renal failure as a result of calcium oxalate crystals.

The following text was deleted:
No cases of overdose are known.

In Section 5.2, the following text was revised to read:

 Absorption: Ascorbic acid is absorbed primarily in the upper part of the small intestine via sodium-dependent active transport. When ascorbic acid is present in high concentrations, uptake occurs by means of passive diffusion. After oral administration of doses of 112 g, the proportion of ascorbic acid absorbed falls from approximately 50% to about 15%, though the absolute quantity of substance taken up continues to increase.
Zinc is absorbed all along the small intestine. The absorption of zinc (ionic) administered in solution on an empty stomach ranges from 41-79%, while the zinc present in foods or that given as a supplement with meals is absorbed in the range of 10–40%.
Distribution: Plasma protein binding of ascorbic acid is approximately 24%. Serum concentrations are normally 10 mg/l (60 mol/l). Concentrations below 6 mg/l (35 mol/l) indicate that the intake of vitamin C is not always adequate, and concentrations below 4 mg/l (20 mol/l) indicate that the intake is actually inadequate. In clinically manifest scurvy, serum concentrations are below 2 mg/l (10 mol/l).
Total body zinc content is controlled in part by regulating the efficiency of intestinal absorption and the excretion from endogenous zinc pools to maintain zinc homeostasis. The adult total body zinc content ranges from about 2.3 mmol (1.5 g) in women to 3.8 mmol (2.5 g) in men. Zinc is present in all organs, tissues, fluids, and secretions of the body. Zinc is primarily an intracellular ion, with well over 95% of the total-body zinc found within cells. Zinc is associated with all organelles of the cell, but about 60 to 80% of the cellular zinc is found in the cytosol.Metabolism: Ascorbic acid is metabolised partly via dehydroascorbic acid to oxalic acid and other products. When ingested in excessive quantities, however, ascorbic acid is largely excreted in unchanged form in the urine and faeces. Ascorbic-acid-2-sulphate also appears as a metabolite in the urine.
The total amount of zinc present in the major tissues is much larger than the total in plasma. Thus, relatively small variations in zinc content of tissues, such as the liver, can have dramatic effects on the plasma zinc. All absorbed zinc passes through the plasma to the tissues, and the flux of zinc through the plasma is said to be replaced approximately 130 times per day. There is no specific zinc “store”. Human experimental studies with low-zinc diets 2.6-3.6 mg/day /40-55 mmol/day) have shown that circulating zinc levels and activities of zinc-containing enzymes can be maintained within normal range over several months highlighting the efficiency of the zinc homeostasis mechanism.
Elimination: The physiological body pool of ascorbic acid is about 1500 mg. The elimination half-life of ascorbic acid depends on the route of administration, the quantity administered and the rate of absorption. Following an oral dose of 1 g the half-life is about 13 hours. When 13 g vitamin C /day is taken, the main route of excretion is renal. With doses exceeding 3 g, increasing quantities are excreted unchanged in the faeces.
The major route for endogenous zinc excretion is into the gastrointestinal tract with ultimate loss in the faeces. When tracer doses of zinc are given either orally or intravenously, only about 2 to 10% is recovered in the urine; the remainder is lost in the faeces. In humans, endogenous faecal losses may range from <15 mmol/day (1 mg/day) with extremely low intakes to over 80 mmol/day (5 mg/day) with extremely high intakes. Normally, about 6 to 9 mmol (400 to 600 mg) of zinc is excreted daily in the urine.

Note: The text in bold indicates the newly added text.

1 effervescent tablet contains:

                   Ascorbic acid (vitamin C)                                1000 mg

Zinc (in form of 32 mg zinc citrate trihydrate)       10 mg

Excipients:

                   Aspartame       15mg

                   Sorbitol            655mg

                   Sodium            8.4mmol

                   For a full list of excipients, see section 6.1

 Section 4.4: The following text has been added:

Patients suffering from renal insufficiency should consult a physician prior to intake of large doses of ascorbic acid.

Section 6.1:
E420 has been added after sorbitol.
E951 has been added after aspartame.

Section 6.5: 'Not all pack sizes may be marketed' has been added.