As a supplement for the prevention of vitamin A & D deficiency

§ Infants and children under 5 years: 1 mL daily

§ Infants fed on vitamin D-fortified milk and children over 5 years: ½ mL daily.

When prescribing Vit A+D drops, as with all multi-vitamin preparations, allowance should be made for vitamins obtained from other sources to prevent hypervitaminosis occurring.

None stated.

None indicated.

None known

Vit A+D does not usually cause any side effects at normal recommended doses and taken as directed.

To report any side effect(s):

The National Pharmacovigilance and Drug Safety Centre (NPC)

Fax: +966-11-205-7662

Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

Toll free phone: 8002490000

E-mail: npc.drug@sfda.gov.sa

Website: www.sfda.gov.sa/npc

Symptoms and signs

-    Vitamin A palmitate

Acute administration of high doses of vitamin A can cause headache, nausea, vomiting and irritability. In infants acute toxicity can lead to transient hydrocephalus. All these effects disappear within 24 hours of taking retinol.

-      Vitamin D

Excessive doses of vitamin D, 60 000 units per day, can result in hypercalcaemia and hypercalciuria. Adverse effects of hypercalcaemia may include muscle weakness, apathy, headache, anorexia, nausea and vomiting, hypertension and cardiac arrhythmias.

Treatment

Treatment should be supportive and symptomatic.

Vitamin A

1.      Vitamin A is required for growth and bone development and vision, and for differentiation and maintenance of epithelial tissue. Retinol is also required as a cofactor in the glycosylation of glycoproteins. Vitamin A may enhance the function of the immune system, and some evidence indicates that it affords some protection against cancer. Some evidence suggests that vitamin A also affects membrane systems such as the mitochondria and lysosomes; however further research is necessary to confirm this finding.

2.      Retinol is the parent compound of vitamin A, and the form which is transported within the body. Retinol is released from the liver and is bound to a serum retinol binding protein (RBP), which facilitates absorption, transport and mediation of the biological activity. Retinal is the active form required for formation of the visual pigment rhodopsin in the rods and cones of the retina.

3.      Retinoic acid may be the active form for processes involving growth and differentiation. Although its exact mechanism of action is unknown, retinoic acid may act directly at the level of genetic transcription via a nuclear receptor to promote the synthesis of some proteins and inhibit the synthesis of others.

4.      Symptoms of vitamin A deficiency generally become apparent when serum levels are less than 30mcg/mL, which occurs when hepatic stores are depleted. In well-nourished subjects, greater than 6 months was required to exhaust vitamin A stores during depletion studies where vitamin A use was withheld.

5.      The biologically active forms of vitamin A are retinol, retinal, and retinoic acid. Retinyl esters or fatty acid esters of retinol are the storage form of vitamin A in the body. Beta-carotene is a precursor to vitamin A.

6.      Vitamin A is involved in vision after conversion in the body to 11 cis-retinal. The latter interacts with opsin, a protein, to form rhodopsin, which is the light-sensitive pigment in the rods and cones of the retina. The exact mechanism of action of retinoids is not understood at the molecular level, except for their role in vision.

Vitamin D

Vitamin D is essential for promoting absorption and utilization of calcium and phosphate and for normal calcification of bone. Along with parathyroid hormone and calcitonin, it regulates serum calcium concentrations by increasing serum calcium and phosphate concentrations as needed. Vitamin D stimulates calcium and phosphate absorption from the small intestine and mobilizes calcium from bone.

Exposure of the skin to ultraviolet rays in sunlight results in formation of cholecalciferol (vitamin D3). Ergocalciferol (calciferol, vitamin D2) is found in commercial vitamin preparations and is used as food additive; cholecalciferol is found in vitamin D-fortified milk.

Cholecalciferol and ergocalciferol are transferred to the liver where they are converted to calcifediol (25-hydroxycholecalciferol), which is then transferred to the kidneys and converted to calcitriol (1,25-dihydroxycholeclciferol, thought to be the most active form) and 24,25-dihydroxycholeclciferol (physiologic role not determined).

Dihydrotachysterol is a synthetic reduction product of ergocalciferol; it has only weak antirachitic activity; it is metabolically activated 25-hydroxylation in the lover. Alfacalcidol is rapidly converted to 1,25-dihydroxycholecalciferol in the liver.

Calcitriol appears to act by binding to a specific receptor in the cytoplasm of the intestinal mucosa and subsequently being incorporated into the nucleus, probably leading to formation of the calcium-binding protein that result in increased absorption of calcium form the intestine. Also, calcitriol may regulate the transfer of calcium iron from bone and stimulate reabsoprption of calcium in the distal renal tubule, thereby effecting calcium homeostasis in the extracellular fluid.

Vitamin A

Drug concentration levels

Therapeutic drug concentration:

Normal serum concentrations, 30 to 80 mcg/dL.

Normal levels of serum vitamin A and retinol binding protein range from 30 to 80mcg/dL and 30 to 70mg/L, respectively. The retinol binding protein level is generally a good indication of the retinol concentration and plasma and does not require a fasting state. However, for most purposes the serum vitamin A level is probably the ideal parameter to monitor for identifying vitamin A abnormalities.

Absorption

Bioavailability (f):

1.   Prior to absorption, vitamin A (except retinoic acid) must be converted to retinol. Retinyl esters are hydrolyzed to retinol by pancreatic and mucosal hydrolases and preformed retinal is reduced to retinol. Retinol is then absorbed into mucosal cells where it is re-esterified. The retinyl esters bind to chylomicrons and enter the systemic circulation via the lymphatics. The bound esters are subsequently cleared from circulation hepatically, where they are stored.

2.   Uptake of retinol occurs in the small intestine. The uptake is by a carrier-mediated process and is facilitated by a specific binding protein in the cytosol called CRBP II. Some retinol is directly absorbed into the circulation and is carried by the retinol-binding protein (RBP) in plasma.

3.   Retinoic acid is absorbed unchanged through the portal vein and is transported into systemic circulation via albumin. Specific mechanisms for absorption of retinoic acid do not exist because it normally does not occur in dietary sources.

Distribution

Distribution sites

Liver: Approximately 90% of vitamin A stored in the body is found in the liver.

Metabolism

Metabolites

-      11-cis-retinal.

-      It is converted to 11-cis-retinal in the retina and to retinoic acid in other tissues.

-      Retinaldehyde.

-      Tretinoin (all-trans-retinoic acid).

-      Isotretinoin (13-cis-retinoic acid).

-      4-oxo-tretinoin.

-      4-oxo-isotretinoin.

Half-life

Parent compound

Data for the elimination half-life of retinol in rats fit a three-compartment model.

Vitamin D

Vitamin D substances are well absorbed from the gastrointestinal tract. The presence of bile is essential for adequate intestinal absorption; absorption may be decreased in patients with decreased fat absorption.

Vitamin D and its metabolites circulate in the blood bound to a specific alpha-globulin. Vitamin D can be stored in adipose and muscle tissue for long periods of time. It is slowly released from such storage sites and from the skin where it is formed in the presence of sunlight or ultraviolet light. Ergocalciferol and cholecalciferol have a slow onset and a long duration of action; calcitriol and its analogue alfacalcidol, however, have a more rapid action and shorter half-lives.

Cholecalciferol and ergocalciferol are hydroxylated in the liver by the enzyme vitamin D 25-hydroxylase to form 25-hydroxycholecalciferol (calcifediol) and 25-hydroxyergocalciferol respectively. These compounds undergo further hydroxylation in the kidneys by the enzyme vitamin D 1-hydroxylase to form the active metabolites 1,25-dihydroxycholecalciferol (calcitriol) and 1,25-dihydroxyergocalciferol respectively. Further metabolism also occurs in the kidneys, including the formation of the 1,24,25-trihydroxy derivatives. Of the synthetic analogues, alfacalcidol is converted rapidly in the liver to calcitriol, and dihydrotachysterol is hydroxylated, also in the liver, to its active form 25-hydroxydihydrotachysterol.

Vitamin D compounds and their metabolites are excreted mainly in the bile and faeces with only small amounts appearing in urine; there is some enterohepatic recycling but it is considered to have a negligible contribution to vitamin D status. Certain vitamin D substances may be distributed into breast milk.

Not applicable.

None known

Store below 30°C, protect from light.

§ 15mL in glass bottle with dropper packed in a printed carton along with a leaflet.

§ 25mL in glass bottle with dropper packed in a printed carton along with a leaflet.

Not applicable.