Prevention and treatment of vitamin D deficiency.

Dibasa can be administered o n a daily, weekly, monthly or annual basis (see section 5.2). In the case of oral therapy, it is recommended to take Dibasa with meals (see section 5.2). Intramuscular therapy is indicated only in case of malabsorption syndromes.

Prevention of vitamin D deficiency: preventive administration of Dibasa is advised in all conditions characterised by  greater risk of deficiency or  increased need. It is generally acknowledged  that prevention of vitamin D deficiency should be carried out:

−   in a systematic manner in newborns (particularly in preterm babies), in breastfed infants, in pregnant women (final trimester) and in breastfeeding women in late winter and spring, in  the elderly and possibly in children and adolescents in the event of insufficient exposure to sunlight;

−    in the following conditions:

▪      minimal sun exposure or intense skin pigmentation, unbalanced diet (low in calcium, vegetarian, etc.), extensive dermatological disorders or granulomatous diseases (tuberculosis, leprosy, etc.);

▪      patients treated with anticonvulsants (barbiturates, phenytoin, primidone);

▪      patients receiving long-term corticosteroid therapy;

▪      digestive disorders (intestinal malabsorption, mucoviscidosis or cystic fibrosis);

▪      liver insufficiency.

Treatment of vitamin D deficiency: Vitamin D deficiency must be identified clinically and/or by laboratory tests (<25 nmol/l). The treatment is designed to replenish vitamin D  reserves  and  will  be  followed  by  maintenance  therapy  if  the  risk  of  deficiency persists (1400-2000 I.U./day). Follow-up 25(OH)D measurements should be made approximately three to four months after initiating maintenance therapy to confirm that the target level has been achieved). In the majority  of  cases,  during  the treatment phase, it is recommended not to exceed a cumulative dose of 600,000 I.U. per year, unless otherwise advised by a doctor.

As  an  indication,  the  following  dosage  scheme  is  provided,  to  be  adapted  as established by the  doctor  on  the  basis  of  nature  and  severity  of  the  deficiency status (see also section 4.4).

Dibasa 10,000 I.U./mL oral drops, solution

The daily doses listed below can be taken even on a weekly  basis  by multiplying the indicated daily dose by seven.

Newborns, Children and Adolescents (< 18 years of age)

Prevention: 2-4 drops per day (equivalent to 500-1,000 I.U. of vitamin D3)

Treatment: 8-16 drops per day (equivalent to 2,000-4,000 I.U. of vitamin D3) for 4-5 months.

Pregnant women

2-3 drops per day (equivalent to 500-750 I.U. of vitamin D3) in the final trimester.

Adults and the Elderly

Prevention: 3-4 drops per day (equivalent to 750-1,000 I.U. of vitamin D3). In patients at a high risk of deficiency, it may be necessary to increase the dose to up to 8 drops per day (equivalent to 2,000 I.U. of vitamin D3).

Treatment:    20-30 drops per day (equivalent to 5,000-7,500 I.U. of vitamin D3) for 2 months, followed by the maintenance therapy (see above “Treatment of vitamin D

deficiency”).

Instructions for use

The package contains 1 bottle and a dropper. The bottle is equipped with a child proof cap. The dropper has its own case. To use, follow the instructions below:

a.  open the bottle by removing the cap as follows: press and unscrew at the same time (see Figure 1);

b.  unscrew the plastic case containing the tip of the dropper (see Figure 2);

c.  insert the dropper into the bottle to extract the contents. Measure out the drops in a tablespoon and administer (see “Posology and method of administration”);

d. close the bottle (see Figure 3). Screw the cap on the tip of the dropper;

e. replace the bottle and the dropper in the package.

Dibasa 25,000 I.U. /2.5 mL oral solution

Newborns, Children and Adolescents (< 18 years of age)

Prevention:  1 single-dose container (equivalent to 25,000 I.U. of vitamin D3) every

1-2 months.

Treatment: 1 single dose container (equivalent to 25,000 I.U. of vitamin D3) once a week for 8-12 weeks, followed by the maintenance therapy (see above “Treatment of vitamin D deficiency”).

Adults and the Elderly

Prevention: 1 single dose container (equivalent to 25,000 I.U. of vitamin D3) once a month. In patients at a high risk of deficiency, it may be necessary to increase the dose  to 2 single dose containers (equivalent  to 50,000 I.U. of vitamin D3) once a month.

Treatment: 2 single dose containers (equivalent to 50,000 I.U. of vitamin D3) once a week for 6-8- weeks, followed by the maintenance therapy (see above “Treatment of

vitamin D deficiency”).

Dibasa 50,000 I.U. /2.5 mL oral solution

Newborns, Children and Adolescents (< 18 years of age)

Prevention: 1 single-dose container (equivalent to 50,000 I.U. of vitamin D3) every

2-4 months.

Treatment: 1 single-dose container (equivalent to 50,000 I.U. of vitamin D3) once a week for 4-6 weeks, followed by the maintenance therapy (see above “Treatment of vitamin D deficiency”).

Adults and the Elderly

Prevention: 1 single-dose container (equivalent to 50,000 I.U. of vitamin D3) every 2 months. In patients at a high risk of deficiency, it may be necessary to increase the dose to 1 single-dose container (equivalent to 50,000 I.U. of vitamin D3) once a

month.

Treatment: 1 single-dose container (equivalent to 50,000 I.U. of vitamin D3) once a week for 6-8 weeks, followed by the maintenance therapy (see above “Treatment of vitamin D deficiency”).

In the event of prolonged administrations at high doses, it is recommended to monitor the serum level of 25-hydroxy-cholecalciferol. Stop taking Dibasa when the serum level of 25-hydroxy-cholecalciferol exceeds 100 ng/mL (equal to 250 nmol/L).

In elderly patients already undergoing treatment with cardiac glycosides or diuretics, it is important to monitor calcaemia and calciuria. In the event of hypercalcaemia or renal insufficiency, reduce the dose or discontinue treatment.

To avoid overdose, take into account the total dose of vitamin D in the event of

association with treatments already containing vitamin D, foods enriched with vitamin

D, or if using milk enriched with vitamin D.

In the following cases, it may be necessary to increase the indicated doses:

•    Patients undergoing treatment with anticonvulsants or barbiturates (see section

4.5);

•    Patients undergoing treatment with corticosteroid therapy (see section 4.5);

•     Patients undergoing treatment with lipid-lowering agents such as colestipol, cholestyramine and orlistat (see section 4.5);

•    Patients undergoing treatment with antacids containing aluminium (see section

4.5);

•    Obese patients (see section 5.2);

•    Digestive disorders (intestinal malabsorption, mucoviscidosis or cystic fibrosis);

•    Liver insufficiency.

The product should be prescribed with caution to patients with sarcoidosis, due to a possible increase in the metabolism of vitamin D in its active form. It is necessary to monitor serum and urine calcium levels in these patients.

Patients with renal insufficiency have an altered metabolism of vitamin D, therefore, if they have to be treated with cholecalciferol, the effects on calcium and phosphate homeostasis should be monitored.

Concomitant use of anticonvulsants or barbiturates may reduce the effect of vitamin

D3 by metabolic inactivation.

In the case of treatment with thiazide diuretics, which decrease urinary elimination of calcium, monitoring of serum calcium levels is recommended.

Concomitant use of glucocorticosteroids may reduce the effect of vitamin D3.

In the event of treatment with drugs containing digitalis, oral administration of calcium combined with  vitamin D  increases the  risk  of digitalis toxicity (arrhythmia).   Strict medical supervision is therefore required and, if necessary ECG monitoring and monitoring of serum calcium levels.

Concomitant  use of aluminium-containing antacids may interfere with the efficacy of the  medicinal  product,  reducing  the  absorption  of  vitamin  D,  while  preparations containing magnesium may lead to a risk of hypermagnesaemia.

Studies on animals have suggested possible strengthening of the action of warfarin when administered with calciferol. Although there is no similar evidence with the use of  cholecalciferol, it  is  best  to  exercise caution when  both  medicinal products are used concomitantly.

Cholestyramine, colestipol and orlistat reduce the absorption of vitamin D, while chronic alcoholism decreases Vitamin D reserves in the liver.

Pregnancy

In the first 6 months of pregnancy, vitamin D should be taken with caution due to the risk of teratogenic effects (see section 4.9).

Lactation

If necessary Vitamin D can be prescribed while a patient  is breastfeeding. This supplementation does not replace the administration of vitamin D in the newborn.

There is no data  available on the effects of this product on the ability to drive. However, an effect on this ability is unlikely.

When the posology complies with actual individual requirements, Dibasa is well tolerated, also thanks to the body’s ability to store cholecalciferol in adipose and muscular tissues (see section 5.2).

The undesirable effects reported with the use of vitamin D are as follows: Immune system disorders:                                                 hypersensitivity reactions Metabolism and nutrition disorders:                                        weakness, anorexia, thirst Psychiatric disorders:                                                              drowsiness, confused state Nervous system disorders:                                                 headaches

Gastrointestinal disorders:                                   constipation, flatulence, abdominal pain, nausea, vomiting, diarrhoea, metallic taste, dry mouth

Skin and subcutaneous tissue disorders:           rash, pruritus

Renal and urinary disorders:                               nephrocalcinosis, polyuria, polydipsia, renal insufficiency

Investigations:                                                      hypercalciuria, hypercalcaemia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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.

To report any side effect(s):

• Saudi Arabia:

•    The National Pharmacovigilance Center (NPC)

-     Fax: + (966-11) 2057662

-     Call NPC at: + (966-11) 2038222, Exts: 2317-2356-2340.

-     SFDA Call Center: 19999

-     E-mail: npc.drug@sfda.gov.sa

-     Website:  https://ade.sfda.gov.sa/

Other GCC States:

Please contact the relevant competent authority.

Discontinue Dibasa when calcaemia exceeds 10.6 mg/dL (2.65 mmol/L) or if calciuria exceeds 300 mg/24 hours in adults or 4-6 mg/kg/day in children.  An overdose  is revealed  as  hypercalciuria  and  hypercalcaemia,  the  symptoms  of  which  are  as follows: nausea, vomiting, thirst, polydipsia, polyuria, constipation and dehydration. Chronic overdoses may lead to vascular and organ calcification as a result of hypercalcaemia. An overdose during the first 6 months of pregnancy may have toxic effects on the foetus: there is a correlation between excess intake or extreme maternal sensitivity to vitamin D during pregnancy and the delayed mental and physical development of the child, supravalvular aortic stenosis and retinopathy. Maternal hypercalcaemia can also lead to the suppression of parathyroid function in infants resulting in hypocalcaemia, tetany and convulsions.

Treatment in the event of overdose

Discontinue the administration of Dibasa and proceed with rehydration.

Pharmacotherapeutic group: Vitamin D and analogues, cholecalciferol. ATC code: A11CC05

Vitamin D corrects vitamin D deficiency and increases the intestinal absorption of

calcium.

As  with  other  lipid-soluble  vitamins,  cholecalciferol  absorption  in  the  intestine  is assisted by a concomitant intake of foods containing fats.

Cholecalciferol is present in the bloodstream in association with specific α-globulins which transport it to the liver, where it is hydroxylated into 25-hydroxycholecalciferol. A second hydroxylation occurs in the kidneys, where 25-hydroxycholecalciferol is transformed into 1,25-dihydroxy-cholecalciferol which is the active metabolite of vitamin D responsible for the effects on phosphocalcium metabolism.

Non-metabolised  cholecalciferol accumulates in adipose and muscular tissues to be

made available according to the body’s needs: for this reason Dibasa can also be administered on a weekly, monthly or annual basis. In obese patients, the bioavailability of vitamin D is reduced due to the excess adipose tissue.

Vitamin D is eliminated through the faeces and urine.

Preclinical  studies  carried  out  on  various  animal  species  have  demonstrated  that toxic effects occur in  animals at doses much higher than those required for therapeutic use in humans.

In repeat-dose toxicity studies, the effects most commonly found were: increased calciuria, decreased phosphaturia and proteinuria

Hypercalcaemia  was  reported  at  high  doses.  In  a  state  of  prolonged hypercalcaemia the  most  frequent histological alterations (calcification) have  involved

the kidneys, heart, aorta, testicles, thymus and intestinal mucosa.

Reproductive toxicity studies have shown that cholecalciferol does not have negative effects on fertility and reproduction.

At  doses     equivalent  to  the  therapeutic  doses,  cholecalciferol  has  no  teratogenic activity.

Cholecalciferol has no potential mutagenic and carcinogenic activity.

Dibasa 10,000 I.U./mL oral drops, solution: refined olive oil. Dibasa 25,000 I.U./2.5 mL oral solution: refined olive oil. Dibasa 50,000 I.U./2,5 mL oral solution refined olive oil.

There are no known incompatibilities with other medicinal products.

Do not store above 30° C. Do not freeze.

Store in the original package in order to protect from light.

Dibasa 10,000 I.U./mL oral drops, solution

Amber glass bottle containing 10 mL, closed with a polypropylene child-proof cap. The package contains 1 bottle and 1 dropper.

Dibasa 25,000 I.U. /2.5 mL oral solution

Amber glass container containing 2.5 mL, closed with a polypropylene cap. Packs of 1,

2 or 4 single-dose containers.

Dibasa 50,000 I.U. /2.5 mL oral solution

Amber glass container containing 2.5 mL, closed with a polypropylene cap. Packs of 1,

2 or 4 single-dose containers.

Not all pack sizes may be marketed.

No special requirements.