SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

InVita D3 25,000 IU oral solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution (1 ampoule) contains 0.625 mg cholecalciferol, equivalent to 25,000 IU vitamin D.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Oral solution

Clear, slightly yellow, oily liquid with an orange odour

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The prevention and treatment of vitamin D deficiency.

As an adjunct to s pecific th erapy for os teoporosis in pa tients w ith v itamin D deficiency or at risk of vitamin D insufficiency.

4.2    Posology and method of administration

Posology

Paediatric posology:

-    Prevention of deficiency 0-1 years 25000 IU (1 ampoule) every 8 weeks

-    Prevention of deficiency 1-18 years 25000 IU (1 ampoule) every 6 weeks

-    Treatment of deficiency 0-18 years 25000 IU (1 ampoule) once every 2 weeks for 6 weeks (followed

by maintenance therapy of 400-1000 IU/day)

Pregnancy and breastfeeding:

- The high strength formulation is not recommended

Adults:

-    Prevention of vitamin D deficiency 25000 IU/month (1 ampoule), higher doses may be required in

certain situations, see below

-    As an adjunct to specific therapy for osteoporosis: 25000 IU/month (1 ampoule)

-    Treatment of vitamin D deficiency (<25 ng/ml) 50000 IU/week (2 ampoules) for 6-8 weeks, followed

by maintenance therapy (1400-2000 IU/day may be required; 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)

Certain populations are at high risk of vitamin D deficiency, and may require higher doses and monitoring of serum 25(OH)D:

-    Institutionalised or hospitalised individuals

-    Dark skinned individuals

-    Individuals with limited effective sun exposure due to protective clothing or consistent use of sun

screens

-    Obese individuals

-    Patients being evaluated for osteoporosis

-    Use of certain concomitant medications (e.g., anticonvulsant medications, glucocorticoids)

-    Patients with malabsorption, including inflammatory bowel disease and coeliac disease

-    Those recently treated for vitamin D deficiency, and requiring maintenance therapy.

Special populations Renal impairment

InVita D3 should not be used in combination with calcium in patients with severe renal impairment.

Hepatic impairment

No posology adjustment is required in patients with hepatic impairment.

Method of administration

Patients should be advised to take InVita D3 preferably with meal (see section 5.2 Pharmacokinetic properties - “Absorption”).

Administration to adults:

The full contents of the ampoule should be either emptied into the mouth and swallowed orally, or emptied onto a spoon and taken orally. InVita D3 can also be taken by mixing with a small amount of cold or lukewarm food immediately prior to use.

Adm    inistration to children:

In children, InVita D3 can be mixed with a small amount of children’s foods, yogurt, milk, cheese or other dairy products. The parents should be warned not to mix InVita D3 into a bottle of milk or container of soft foods in case the child does not consume the whole portion, and does not receive the full dose. The parents should ensure that their child takes the entire dose. For children who are not breast-feeding, the prescribed dose should be administered with a meal

See also section 6.6, Special precautions for handling and disposal.

4.3 Contraindications

•    Hypersensitivity to the active substance(s) or to any of the excipients.

• Hy    percalcaemia and/or hypercalciuria.

•    Nephrolithiasis and/or nephrocalcinosis

•    Serio us renal impairment

• Hy    pervitaminosis D

•    Pseudohypoparathyroidism as the vitamin D requirement may be reduced due to phases of normal

vitamin D sen sitivity, involving the risk of prolonged overdose. Better-regulatable vitamin D derivatives

are available for this.

4.4 Special warnings and precautions for use

Vitamin D should be used with caution in patients with impairment of renal function and the effect on calcium and phosphate levels should be monitored. The risk of soft tissue calcification should be taken into account.

Caution i s re quired in p atients r eceiving tre atment f or ca rdiovascular d isease (see section 4.5 Interaction with other medicinal products and other forms of interaction -cardiac glycosides including digitalis).

InVita D 3 should b e prescribed with caution in patients with sarcoidosis, due to a possible increase in the metabolism of vitamin D in its active form. In these patients the serum and urinary calcium levels should be monitored.

Allowances should be made for the total dose of vitamin D in cases asso ciated with treatments already containing vitamin D, foods enri ched with vitamin D, cases u sing milk enriched with vitamin D, and the patient’s level of sun exposure.

There is no c lear ev idence for cau sation between v itamin D sup plementation and renal stones, but the risk is plausible, especially in the context of concomitant calcium supplementation. The ne ed fo r ad ditional ca lcium supplem entation s hould b e considered for individual patients. Calcium supplements should be given under close medical supervision.

Oral administration of high-dose vitamin D (500,000 IU by single annual bolus) was reported to result in an increased risk of fractures in elderly subjects, with the greatest increase occurring during the first 3 months after dosing.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use of anticonvulsants (such as phenytoin) or barbiturates (and possibly other d rugs that induce h epatic e nzymes) m ay reduc e th e e ffect of v itamin D3 by metabolic inactivation.

In cases o f treatment with thiazide diuretics, which decrease urinary elimination of calcium, monitoring of serum calcium concentration is recommended.

Concomitant use of glucocorticoids can decrease the effect of vitamin D.

In cases of treatment with drugs containing digitalis and other cardiac glycosides, the administration of vitamin D may increases the risk of digitalis toxicity (arrhythmia). Strict medical supervision is needed, together with serum calcium concentration and electrocardiographic monitoring if necessary.

Simultaneous treatment with ion exchange resin such as cholestyramine, colestipol hydrochloride, orlistat or laxative such as paraffin oil may reduce the gastrointestinal absorption of vitamin D.

The cy totoxic ag ent a ctinomycin and im idazole antifungal agents in terfere with vitamin D activ ity by inhibi ting the conv ersion of 25-hydroxyvitamin D to 1 ,25-dihydroxyvitamin D by the kidney enzyme, 25-hydroxyvitamin D-1-hydroxylase.

4.6    Pregnancy and lactation

In pregnancy and lact ation the h igh strength formulation is not recommended and a low strength formulation should be used.

Pregnancy

There are no or l imited amount of data f rom the use of chol ecalciferol in pr egnant women. Studie s in an imals have shown re productive t oxicity (se e se ction 5.3 Preclinical safety data). The recommended daily intake for p regnant women is 400 IU, however, in women who are considered to be vitamin D deficient a higher dose

may be required (up to 2000 IU/day).

During preg nancy wom en shoul d fo llow the advice of th eir m edical practitioner as their requirements m ay v ary depend ing on the sev erity of their di sease and their response to treatment vitamin D and its metabolites are excreted in breast milk.

Breast-feeding

Vitamin D c an be prescribed while the patient is breast-feeding if necessary. This supplementation does not replace the administration of vitamin D in the neonate.

4.7    Effects on ability to    drive and use machines

Not relevant.

4.8    Undesirable effects

Adverse reactions are listed below, by system organ class and frequency. Frequencies are defined as: uncommon (>1/1,000, <1/100) or rare (>1/10,000, <1/1,000).

Metabolism and nutrition disorders Uncommon: Hypercalcaemia and hypercalciuria

Skin and subcutaneous disorders:

Rare: pruritus, rash, and urticaria.

4.9    Overdose

Symptoms of overdose

Ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) have a re latively low therapeutic index. The threshold for vitamin D in toxication is between 40,000 and 100,000 IU daily for 1 to 2 months in adults with normal parathyroid function. Infants and small children may react sensitively to far lower concentrations. Therefore, it is warned against intake of vitamin D without medical supervision.

Overdose l eads to increased se rum and ur inary phospho rus levels, as we ll as hypercalcaemic syndrome and consequently calcium deposits in the tissues and above all in the kidneys (nephrolithiasis, nephrocalcinosis) and the vessels.

Discontinue InVita D 3 when calcaemia exceeds 10.6 mg/dl (2.65 mmol/l) or if the calciuria exceeds 300 mg/24 hours in adults or 4-6 mg/kg/day in children.

Chronic ov erdosage m ay lead to v ascular and o rgan ca lcification, as a result o f hypercalcaemia.

The sy mptoms of intoxic ation are l ittle cha racteristic and m anifest as nau sea, vomiting, ini tially als o di arrhoea, later con stipation, los s of app etite, w eariness, headache, muscle pain, joint pain, muscle weakness, persistent sleepiness, azotaemia, polydipsia and p olyuria a nd, in th e f inal stage, d ehydration. Typical b iochemical findings in clude hy percalcaemia, hy percalciuria, as w ell as increased serum 2 5 hydroxycholecalciferol concentrations.

Treatment of overdose

Symptoms of chron ic vitamin D o verdosage may require forced diuresis as well as administration of glucocorticoids or calcitonin.

Overdosage re quires m easures fo r treating th e - ofte n pe rsisting and under c ertain circumstances life-threatening - hypercalcaemia.

The first measure is to discontinue the vitamin D preparation; it takes several weeks to normalise hypercalcaemia caused by vitamin D intoxication.

Depending on the deg ree of hypercalcaemia, measures include a d iet that is low in calcium or f ree of calcium, abundant liquid intake, increase of urinary excretion by means of the drug furosemide, as well as the administration of g lucocorticoids and calcitonin.

If kidney function is adequate, calcium levels can be reliably lowered by infusions of isotonic sodium chloride solution (3-6 liters in 24 hours) with addition of furosemide and, in s ome circum stances, a lso 15 m g/kg bod y weig ht/hour sod ium edeta te accompanied by continuous calcium and ECG monitoring. In oligoanuria, in contrast, haemodialysis (calcium-free dialysate) is necessary.

No special antidote exists.

It is recommended to point out the symptoms of potential overdose to patients under chronic th erapy w ith hig her d oses of v itamin D (nausea, v omiting, in itially also diarrhoea, later constipation, anorexia, weariness, headache, muscle pain, joint pain, muscle weakness, persistent sleepiness, azotaemia, polydipsia and polyuria).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vitamin D, cholecalciferol

ATC Code: A11CC05

In its b iologically active form Vitamin D stimulates intestinal calcium absorption , incorporation of calcium into the osteoid, and release of calcium from bone tissue. In the small intestine it promotes rapid and delayed calcium uptake. The passive and active transport of phosphate is also stimulated. In the kidney, it inhibits the excretion of ca lcium and phosp hate by prom oting tubu lar resorption. The p roduction o f parathyroid horm one (P TH) in the parathyroids is inhibited d irectly by th e biologically active form of vitamin D3. PTH secretion is inhibited additionally by the increased calcium uptake in the small intestine under the influence of biologically

active vitamin D.

5.2 Pharmacokinetic properties

The pharmacokinetics of vitamin D is well known.

Absorption

Vitamin D is well absorbed from the gastro-intestinal tract in the presence of bile, so the adm inistration w ith th e m ajor m eal of the day might there fore facilitate the absorption of Vitamin D.

Distribution and biotransformation

It is hydroxylated in the liver to form 25-hydroxy-cholecalciferol and then undergoes further hy droxylation in the k idney t o form t he a ctive m etabolite 1, 25-dihydroxycholecalciferol (calcitriol).

Elimination

The metabolites circulate in the blood bound to a specific a - globin, vitamin D and its metabolites are excreted mainly in the bile and faeces.

Characteristics in Specific Groups of Subjects or Patients

A 57% lower metabolic clearance rate is reported in subjects with renal impairment as compared with that of healthy volunteers.

Decreased absorption and increased elimination of vitamin D occurs in subjects with malabsorption.

Obese subjects are less able to maintain vitamin D levels with sun exposure, and are likely to require larger oral doses of vitamin D to replace deficits.

5.3 Preclinical safety data

Pre-clinical studies conducted in various animal species have demonstrated that toxic effects occur in animals

at doses much higher than those required for therapeutic use in humans.

In toxicity studies at re peated dos es, the e ffects most com monly reported were increased calciuria and decreased phosphaturia and proteinuria.

Hypercalcaemia has bee n reported in high dos es. In a state of pr olonged hypercalcaemia, histological alterations (calcification) were more frequently borne by the kidneys, heart, aorta, testes, thymus and intestinal mucosa.

Colecalciferol has been shown to be teratogenic at high doses in animals.

At doses equivalent to those used therapeutically, cholecalciferol has no teratogenic activity.

Cholecalciferol has no potential mutagenic or carcinogenic activity.

6    PHARMACEUTICAL    PARTICULARS

6.1    List of excipients

Tocopherol acetate,

Polyglyceryl oleate (E475),

Olive oil,refined,

Sweet orange peel oil.

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

36 months.

6.4    Special precautions for    storage

Do not store above 30°C.

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

6.5    Nature and contents of container

Transparent PVC/PVDC/PE ampoules.

Original Pack with 1, 2, 3 or 4 ampoules.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements

Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Consilient Health Limited,

5th Floor, Beaux Lane House,

Mercer Street Lower,

Dublin 2,

Ireland

8    MARKETING AUTHORISATION NUMBER(S)

PL 24837/0039

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/04/2014

10 DATE OF REVISION OF THE TEXT

24/04/2014