Calcevita is indicated for preventive treatment and treatment of Vitamin B6, Vitamin C and Vitamin D deficiency, and hypocalcaemia, the latter especially in old people and for pregnancy and lactation.

Dosing 1 effervescent tablet daily dissolved in at least 200 ml of water.

Hypersensitivity to the active substances or to any of the excipients. - Hypercalcaemia and/or condition leading to hyperalcaemia like sarcoidosis, malignancy and primary hyperthyroidism - Severe hypercalcuria - Reduced renal function - Hypervitaminosis D - Nephrolithiasis - Hyperoxaluria and/or conditions leading to hyperoxaluria - Haemochromatosis

The recommended dose must not be exceeded (see 4.6 and 4.9).

Take into consideration the dose of vitamin D (300 IU) concomitant with other prescription of vitamin D. Additional administration of vitamin D or calcium should be done under medical monitoring. In these cases frequent check-ups of serum calcium levels and calcium excretion in the urine are needed. - Calcevita contains aspartame that is metabolised to phenylalanine, which is important to people with phenylketonuria. - The effervescent tablet contains 430 mg of sucrose corresponding to 30 kJ. Patients with any of the following rare, hereditary conditions should not use this medication: intolerance to fructose, glucose galactose malabsorption or sucrase isomaltase deficiency. - The effervescent tablet contains 228 mg of sodium and therefore may be unsuitable for patients who have been recommended a diet with a low sodium content. - In case of long-term treatment the calcium levels in serum and urine should be monitored, and the renal function should be checked by measurement of serum creatinine. Continuous check-ups are particularly important in older patients with concomitant treatment with heart glycosides or diuretics (see 4.5) and in patients in whom there is a strong tendency to create stones. In case of hypercalcaemia or signs of reduced renal function the dose should be decreased or the treatment discontinued. - Calcevita should be given with care to immobilised patients with osteoporosis due to an increased risk of hypercalcaemia. - It has been described that an overdosing of vitamin C has caused haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. - Laboratory Interactions - Vitamin C - - Vitamin C may cause chemical interference in laboratory tests involving non-specific colour creation through redox reactions, like analyses of glucose, creatinine, uric acid and inorganic phosphates in urine and faecal occult blood. - - Vitamin C can affect tests for urine glucose. It is therefore recommended that diabetics discontinue their intake of vitamin C for a couple of days prior to measuring their glucosuria. Vitamin C can also interfere with certain blood glucose tests

Vitamin C Deferoxamine: Concomitant treatment with high doses of ascorbic acid (> 500 mg daily) can increase the iron toxicity in tissues, especially the heart, which may cause cardiac failure. Vitamin C should not be started until treatment with deferoxamine has been given for 4 weeks. - Ciklosporin: Limited data hint that ciklosporin and simultaneous supplement with antioxidants with ascorbic acid (500-1,000 mg/day) can decrease the blood concentration of ciklosporin. Concomitant use should therefore be avoided.

Iron: Vitamin C may increase iron absorption. Calcium - Divalent cations like calcium create complexes with certain substances resulting in decreased absorption of both substances. As these interactions occur in the gastrointestinal tract the risk of interaction could be minimised if calcium is taken separately from other medications. Usually it is sufficient to separate the intake of these medications by at least 2 hours before or 4-6 hours after calcium supplement, if nothing else is stated. Substances creating complexes include: - Antibiotics like tetracyclines and quinolones. - Levothyroxine. The patients should take levothyroxine at least 4 hours before or 4 hours after calcium supplement. - Phosphates, biphosphonates and fluorides. Patients should take biphosphonates at least 1 hour before calcium, but preferably at a different time of day. - Eltrombopag. Calcium carbonate can interact with many substances by changing pH in the ventricle and during intestinal passage. As these interactions occur in the gastrointestinal tract the risk of interactions could be minimised if calcium carbonate is taken separately from other medications. Substances that can be affected by changes in the gastrointestinal pH by calcium carbonate (e.g. protease inhibitors) should be given at least 2 hours before or 1 hour after calcium carbonate. Iron: Calcium can decrease the absorption of iron supplements because of competitive binding. Calcium and iron supplements should therefore be taken at least 2 hours apart. Calcium and/or vitamin D: - Thiazide diuretics: Thiazide diuretics decrease the excretion of calcium in urine. Because of an increased risk of hypercalcaemia the serum concentrations of calcium should be monitored regularly with concomitant use of thiazide diuretics. - Heart glycosides: Hypercalcaemia increases the risk of fatal heart arrhythmias with heart glycosides like digoxin. It is recommended that calcium levels be monitored in people taking calcium and/or vitamin D and these medications simultaneously. Systemic treatment with corticosteroids decreases the absorption of calcium. With concomitant treatment it may be necessary to increase the dose of Calcevita. Vitamin D: - Certain medications can decrease the gastrointestinal absorption of vitamin D. Intake of these medications and vitamin D should be occur at least 2 hours before or 4-6 hours after vitamin D, which should minimise this interaction. These medications include: - Ion exchangers (e.g. cholestyramine) - Laxatives (e.g. mineral oil, stimulating laxatives like senna) - Orlistat - Carbamazepine, phenytoin or barbiturates: Carbamazepine, phenytoin or barbiturates increase the metabolism of vitamin D into its inactive metabolite, which decreases the efficacy of vitamin D3

Vitamin B6: - Levodopa: Vitamin B6 increases the metabolism of levodopa, which counteracts the effect of levodopa. B6 interaction is minimised when levodopa is combined with a peripheral decarboxylase inhibitor, e.g. benserazide, carbidopa. Diet / Supplement Interactions Calcium: - Oxalic acid, phytic acid: Oxalic acid (found in spinach and rhubarb) and phytic acid (found in wholemeal flakes) can inhibit the absorption of calcium. It is recommended not to take calcium products within 2 hours after eating foods with a high content of oxalic acid and phytic acid. - Zinc, magnesium: Calcium supplements can decrease the absorption of zinc and magnesium in the food. This can be important for people with a high risk of deficiency in these minerals. Patients with a risk of zinc or magnesium deficiency should take calcium supplements at bedtime instead of with meals. This should be done in order to inhibit mineral absorption from food.

Pregnancy: Calcevita is not expected to carry any risk for the foetus with the recommended dose. During pregnancy and breast-feeding the daily intake should not exceed 1,500 mg of calcium and 600 IU of vitamin D. In animal tests overdosing of vitamin D during pregnancy has caused teratogenic effects. Pregnant women should avoid overdosing of calcium and vitamin D as permanent hypercalcaemia has been associated with negative effects on the development of the foetus. There are no signs that vitamin D should be teratogenic for humans in therapeutic doses. Calcevita can be used during pregnancy in cases of calcium and vitamin D deficiency. Breast-feeding: No expected effects on the nursed child with therapeutic doses. During pregnancy and breast-feeding the daily intake should not exceed 1,500 mg of calcium and 600 IU of vitamin D3. The included substances pass into the breast milk. This should be taken into consideration when giving vitamin D supplement to the child. Fertility: Normal endogenous levels of calcium, vitamin D, vitamin C and vitamin B6 are not expected to have any negative effects on fertility

Calcevita has no effect on the capacity to drive a vehicle and use machinery.

The incidence of listed adverse effects is not known (cannot be calculated from available data).

Gastrointestinal tract Gastrointestinal and stomach pain, constipation, diarrhoea, flatulence, nausea and vomiting may occur. Immune system Allergic reaction Hypersensitivity reactions with laboratory and clinical manifestations respectively include asthma syndrome, mild to moderate reactions affecting either the skin and/or the airways, the gastrointestinal tract and/or the cardiovascular system. The symptoms include skin rash, urticaria, oedema, itching, heart and lung problems, and very rarely severe reactions like anaphylactic shock have been reported. To report any side effect(s) National Pharmacovigilance and Drug Safety Center (NPC). Fax: + 966 - 11 - 205 - 7662. Call NPC at +966 - 11 - 2038222, Ext.: 2317 - 2356 - 2353 - 2354 - 2334 - 2340. Toll - free: 8002490000. E - mail: npc.drug@sfda.gov.sa. Website: www.sfda.gov.sa/npc

For substances included in Calcevita the following is valid: Vitamin C: Overdosing of vitamin C (>2 g/day) can considerably increase the levels of oxalate in serum and urine. Increased levels of the oxalate concentrations have been found to lead to calcium oxalate deposition in dialysis patients. There are also several reports showing that large doses of vitamin C both orally and intravenously can provoke calcium oxalate deposits and calcium oxalate crystalluria in patients with a predisposition for aggregation of crystals. This may result in creation of stones and/or tubulointerstitial nephropathy and acute renal failure as a result of calcium oxalate crystals. Overdosing of vitamin C (>3 g/day in children and >15 g/day in adults) may lead to oxidative haemolysis in patients with glucose-6-phosphatase dehydrogenase deficit or disseminated intravascular coagulation. Chronic overdosing of high doses of vitamin C (>500 mg/day) may lead to excess iron and to tissue destruction in patients with haemochromatosis. Vitamin D and calcium: Acute or long-term overdosing of calcium and Vitamin D, especially in sensitive patients may lead to hypervitaminosis D, hypercalcaemia, hypercalcuria and hyperphosphateaemia. The consequences include renal insufficiency, “milk-alkali syndrome”, vascular and connective tissue calcification including calcinosis leading to nephrolithiasis. Uncharacteristic initial symptoms like sudden onset headache, confusion and gastrointestinal problems like constipation, diarrhoea, nausea and vomiting may be signs of an acute overdose. If those symptoms occur the treatment must be discontinued and medical staff consulted. Laboratory and clinical manifestations of toxicity and hypercalcaemia vary greatly and are dependant on the patient’s sensitivity and surrounding conditions. The symptoms may include anorexia, weight loss, thirst, polyuria and interference with the uptake of other minerals. Changes in laboratory values may include an increase of the blood concentration of aspartate aminotransferase and alanine aminotransferase. Chronic overdosing may lead to calcification of vessels and organs secondary to hypercalcaemia. Extreme hypercalcaemia may result in coma and death. Treatment of hypercalcaemia: Treatment with calcium and vitamin D must be discontinued. Treatment with tiazide diuretics and heart glycosides must also be discontinued. Emptying of the ventricle in patients with decreased consciousness level. Rehydration and, depending on the severity, single or combined treatment with loop diuretics, bisphosphonates, calcitonin and corticosteroids. Serum electrolytes, renal function and diuresis must be monitored. In severe cases ECG and CVP should be monitored. Vitamin B6: The main effect of overdosing of vitamin B6 is sensory axonal neuropathy. Central effects have also been described. Neuropathy has mostly been reported after chronic intake of >100 mg/day. Neuropathy is gradually improved after the discontinuation of vitamin B6

Pharmacotherapeutic group: Vitamins and mineral substances ATC code: A11JB Vitamin C (L-ascorbic acid) is easily oxidised leading to the release of hydrogen, but the oxidated product is equally easily reduced back to ascorbic acid. This makes the vitamin an hydrogen ion carrier in a redox system, which is of great importance for the intermediary metabolism and cellular respiration. Vitamin C promotes creation of intercellular substances (collagen, ossein and dentin). Calcium is a building substance in skeleton and teeth, but it also has several other essential, yet incomplete functions. Thus the bivalent calcium ion is included in several important physiological processes and enzyme systems, e.g. blood coagulation. Above all calcium is indicated for disturbances of the calcium metabolism leading to symptoms of deficiency and for some allergies. Vitamin D Vitamin D increases the interstitial absorption of calcium. Administration of calcium and vitamin D3 counteracts the increase of parathyroid hormone (PTH) caused by calcium deficit, which causes increased bone resorption. Vitamin D regulates an insufficient intake of vitamin D. It increases the intestinal absorption of calcium. The optimal dose of vitamin D to elderly people is 500-1,000 IU/day

The calcium intake compensates lack of calcium in the food. The recommended intake for elderly people is 1,500 mg/day. Vitamin D and calcium correct secondary senile hyperparathyroidism. Vitamin B6 is of central importance for the protein metabolism, as many of the enzymes that participate in the metabolism of amino acids need pyridoxine in phosphorylated form as a co-enzyme. For example, pyridoxine controls the transfer of the amino group between different amino acids and the transfer of these acids to biogenic amines (e.g. serotonin)

No specific study with Calcevita effervescent tablets exists but the pharmacokinetic characteristics for the individual active substances are well documented. Vitamin C is absorbed in the upper part of the gastrointestinal tract. For doses up to 180 mg 70-90% is absorbed, for doses of 1-12 g the fraction that is absorbed decreases from around 50% to 15%. Vitamin C can be found in all tissues. Humans excrete ascorbic acid in the urine, both unchanged and as metabolites. Intake of vitamin C of up to 1 g/day is mostly eliminated via renal excretion. The three different forms of vitamin B6 are absorbed in the small intestine and mainly enter circulation in non-phosphorylated form, before being finally transformed into the active form, pyridoxal phosphate, in the liver. There is considerable muscular deposition of vitamin B6. Pyridoxal phosphate is mostly metabolised in the liver and its metabolite pyridoxal acid is then excreted via the urine. Vitamin D is absorbed in the small intestine and bound to specific α-globulins, it is then transported to the liver where it is metabolised into 25-hydroxykolecalciferol. The metabolite is then hydroxylated a second time in the kidneys to create 1,25-dihydroxikolecalciferol, which represents the vitamin’s ability to increase the absorption of calcium. The non-metabolised fraction of vitamin D is deposited in fat and muscular tissue. Vitamin D is eliminated via faeces and urine. Calcium: In the ventricle calcium ions are released from calcium carbonate because of the surrounding pH. Calcium is administered as calcium carbonate, 20-30% is absorbed and the absorption is done mostly in the duodenum, via vitamin D-dependent, active transport that can be saturated. Calcium is eliminated via urine, faeces and sweat. Excretion of calcium in the urine occurs via glomerular filtration and tubular resorption of calcium.

There are no particular preclinical studies with this product, but the individual components are well documented.

Sucrose 430 mg, aspartame 40 mg, water-free citric acid, sodium hydrogen carbonate, sodium chloride, povidon K30, sucrose esters of fatty acids, orange flavour, tangerine flavour, colouring beta carotene 1% CWS (E160) and beetroot-red (E162a), all-rac-alfa-tokopherol, sodium ascorbate, medium long chain triglycerides, water-free, colloidal silicon dioxide, sodium starch octenylsuccinate (E 1450)

After dissolving Calcevita should not be mixed with other oral or liquid preparations.

2 years

Do not store above 25°C. To be stored in the original package. Close the tube carefully.

10 x 10 effervescent tablets in a plastic tube.

No special instructions.