Detremin

Document: Detremin oral drops, solution ENG SmPC change

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Detremin 20,000 I.U./ml oral drops, solution.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution (40 drops) contains 0.5 mg cholecalciferol, equivalent to 20,000 I.U. vitamin D₃.

1 drop contains 12.5 microgram cholecalciferol, equivalent to 500 I.U. vitamin D₃.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Oral drops, solution.

Clear, weakly yellowish, viscous solution.

4. Clinical particulars

4.1 Therapeutic indications

Treatment of vitamin D deficiency or insufficiency (for definition, see section 4.2)
Prophylaxis and treatment of Vitamin D deficiency in malabsorption
Treatment of rickets in infants and children
Treatment of osteomalacia caused by vitamin D deficiency
Supportive treatment in osteoporosis, in combination with calcium and, when indicated, with a specific antiosteoporotic agent
Prophylaxis in patients at increased risk of osteoporotic fractures, e.g. elderly patients and patients in glucocorticoid treatment, in combination with calcium
Treatment of secondary hyperparathyroidism

4.2 Posology and method of administration

Recommended dose is dependent on the patient’s indication in accordance with the table below:

Indication	Number of drops/day	Equivalent to I.U. vitamin D₃/day	Equivalent to µg cholecalciferol/day	Weekly dosage: I.U. vitamin D₃	Comment
Treatment of vitamin D deficiency or insufficiency	1-8 drops daily	500-4,000 I.U.	12.5-100 µg	3,500-28,000 I.U. (7 drops to 1.4 ml) weekly	Deficiency: Serum 25-hydroxycalciferol (25OHD) <25 nmol/l. Insufficiency: 25OHD 25–50 nmol/l. Patient’s 25OHD level, age, symptoms, and vitamin D supplement by other sources, including skin, should be taken into consideration*
Prophylaxis of Vitamin D deficiency in malabsorption	1-4 drops daily	500-2,000 I.U.	12.5-50 µg	3,500-14,000 IU (7‑28 drops) weekly	Children and infants: 500 I.U. daily. Dose >1,500 I.U. daily only for patients with special needs.
Treatment of Vitamin D deficiency in malabsorption	1-20 drops daily	500-10,000 I.U.	12.5-250 µg	3,500-70,000 I.U. (7 drops to 3.5 ml) weekly	Malabsorption is common e.g. after bariatric surgery.
Treatment of rickets in infants and children	Age <1 year: 6 drops daily Age >1 year: 12 drops daily Maintenance dose: 1 drop daily	<1 year: 3,000 I.U. >1 year: 6,000 I.U. Maintenance 500 I.U.	<1 year: 75 µg >1 year: 150 µg Maintenance 12.5 µg	<1 year: 21,000 I.U. (1.1 ml) weekly >1 year: 42,000 I.U. (2.1 ml) weekly Maintenance3,500 I.U. (7 drops) weekly	Calcium supplementation is advisable during the first weeks of therapy in the growing child.
Treatment of osteomalacia caused by vitamin D deficiency	20 drops daily Maintenance dose: 2-4 drops daily	10,000 I.U. Maintenance 1,000-2,000 I.U.	250 µg Maintenance 25-50 µg	70,000 I.U. (3.5 ml) weekly Maintenance 7,000-14,000 I.U. (14‑28 drops) weekly	Treatment should be continued for 8-12 weeks, thereafter maintenance dose. An adequate calcium supply is recommended.
Supportive treatment in osteoporosis, in combination with calcium and, when indicated, with a specific anti-osteoporotic agent	1 drop daily	500 I.U.	12.5 µg	2,500-5,500 I.U. (5‑11 drops) weekly	Doses above 800 I.U. of vitamin D₃ daily have not been systematically investigated in randomised clinical studies and should therefore not be recommended. Weekly dosage corresponds to 357-786 I.U. daily.
Prophylaxis in patients at increased risk of osteoporotic fractures, e.g. elderly patients and patients in glucocorticoid treatment, in combination with calcium	1 drop daily	500 I.U.	12.5 µg	2,500-5,500 I.U. (5-11 drops) weekly	Doses above 800 I.U. of vitamin D₃ daily have not been systematically investigated in randomised clinical studies and should therefore not be recommended. Weekly dosage corresponds to 357-786 I.U. daily.
Treatment of secondary hyperparathyroidism	2-6 drops daily	1,000-3,000 I.U.	25-75 µg	7,000-21,000 I.U. (14 drops to 1.1 ml) weekly

* For treatment of vitamin D deficiency or insufficiency:
A regular daily dose of 100 I.U. raises serum 25-hydroxycalciferol in average by approx. 2.5 nmol/l within 4-5 months in adults.

Level of serum 25-hydroxycalciferol <25 nmol/l: 4-8 drops (2,000-4,000 I.U.) vitamin D₃ daily or 28 drops-1.4 ml ( 14,000-28,000 I.U.) vitamin D₃ weekly for 3-6 months

Level of serum 25-hydroxycalciferol 25-50 nmol/l or maintenance treatment following deficiency:
1-4 drops (500-2,000 I.U.) vitamin D₃ daily or 7-28 drops (3,500‑14,000 I.U.) vitamin D₃ weekly

Patients with higher BMI may need higher doses to raise serum 25-hydroxycalciferol to the desired level.

It is recommended that serum levels of 25-hydroxycalciferol and calcium are measured three months after initiation of treatment. The necessity of further monitoring can be individualised, guided by the diagnosis causing the therapy, by the dose administered and by the individual patient’s needs.

In treatment of secondary hyperparathyroidism, measurements of PTH levels are recommended, that can be complemented by measurements of serum levels of 25-hydroxycalciferol and calcium.

Vitamin D₃ should preferably be taken together with the major meal of the day (see section 5.2). The bottle should be held still and straight upside down. It may take approximately 10 seconds to the first drop. The following drops will come slightly faster. The drops are preferably taken with a spoon. Care should be taken that the entire dose is ingested.

Dosage in renal impairment

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

4.3 Contraindications

Detremin must not be used in:

hypersensitivity to the active substance or to any of the excipients
hypercalcaemia.
hypervitaminosis D

Detremin must not be used in combination with calcium in patients with severe renal impairment.

4.4 Special warnings and precautions for use

If Detremin is given together with other vitamin D containing products, the total dose of vitamin D should be considered. Vitamin D is fat soluble and may accumulate in the body. This may cause toxic effects in case of overdose and long term treatment with excessive doses. Recommended treatment should therefore not be exceeded.

At high doses of vitamin D3, the serum calcium levels may be monitored and particular caution is recommended in patients with a history of renal calculi.

Vitamin D₃ 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. In patients with severe renal insufficiency, vitamin D in the form of cholecalciferol is not metabolized normally and another form of vitamin D may therefore be needed.

The active metabolite of vitamin D₃ (1,25-dihydroxycholecalciferol) may affect the phosphate balance. Therefore, in conditions with increased phosphate levels, treatment with a phosphate binder may be considered.

Vitamin D₃ should be prescribed with caution to patients suffering from sarcoidosis or other granulomatous disorders, due to the risk of increased metabolism of vitamin D into its active form. These patients should be monitored with regard to the calcium content in serum and urine.

4.5 Interaction with other medicinal products and other forms of interaction

Phenytoin and barbiturates may diminish the effect of vitamin D₃ due to hepatic enzyme induction.
Rifampicin may also reduce the effectiveness of vitamin D₃ due to hepatic enzyme induction.
Isoniazid may reduce the effectiveness of vitamin D₃ due to inhibition of the metabolic activation of vitamin D.
Patients treated with cardiac glycosides may be susceptible to high calcium levels and should have ECG parameters and calcium levels monitored.
Simultaneous administration of benzothiadiazine derivatives (thiazide diuretics) increases the risk of hypercalcaemia because they decrease the calcium loss in the urine.
Vitamin D₃ might increase the intestinal absorption of aluminium.
If Vitamin D₃ is combined with metabolites or analogues of vitamin D careful monitoring of serum calcium levels is recommended.
Drugs leading to fat malabsorption, e.g. orlistat and colestyramin, may impair the absorption of vitamin D.

4.6 Fertility, pregnancy and lactation

Pregnancy

Detremin can be used during pregnancy, in case of a vitamin D deficiency.

Studies in animals have shown reproductive toxicity of high doses of vitamin D (see section 5.3). There are no indications that vitamin D at therapeutic doses is teratogenic in humans.

Breast-feeding

Detremin can be used during breast-feeding. Vitamin D and its metabolites are excreted in human milk. This should be considered when giving additional vitamin D to the child.

Overdose in infants induced by nursing has not been observed.

Fertility

There are no data on the effect of Detremin on fertility. However, normal endogenous levels of vitamin D are not expected to have any adverse effects on fertility.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Detremin has no known side effects which are likely to affect the ability to drive and use machines.

Undesirable effects

Frequencies of adverse reactions are not known, as no larger clinical trials have been conducted, which would allow estimation of frequencies. The following reactions have been reported:

Metabolism and nutrition disorders:

Frequency unknown: hypercalcaemia, hypercalciuria

Gastrointestinal disorders:

Frequency unknown: constipation, flatulence, nausea, abdominal pain, diarrhoea.

Skin and subcutaneous tissue disorders:

Frequency unknown: hypersensitivity reactions such as pruritus, rash, urticaria.

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 the national reporting system listed in Appendix V.

4.9 Overdose

Symptoms:

Acute or chronic overdose of vitamin D can cause hypercalcaemia. Symptoms of hypercalcemia are tiredness, psychiatric symptoms (e.g., euphoria, dazedness, disturbed consciousness), nausea, vomiting, lack of appetite, weight loss, thirst, polyuria, formation of renal calculi, nephrocalcinosis, extraosseous calcification and kidney failure, changes in ECG, arrhythmias, and pancreatitis. In isolated cases their course has been described as fatal.

Treatment:

If a massive dose has been ingested ventricular emptying may be considered, together with administration of carbon. Sun light and further administration of vitamin D or calcium should be avoided. Rehydration and treatment with diuretics, e.g. furosemide to ensure adequate diuresis. In hypercalcemia biphosphonates or calcitonin and corticosteroids may be given. The treatment is directed to symptoms.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

In its biologically active form vitamin D₃stimulates 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 calcium and phosphate by promoting tubular resorption. The production of parathyroid hormone (PTH) in the parathyroids is inhibited directly by the 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 D₃.

5.2 Pharmacokinetic properties

At alimentary doses vitamin D₃ is almost completely absorbed. Vitamin D₃ is absorbed together with fat and administration with the major meal of the day might therefore facilitate absorption. Vitamin D₃ is stored in the fatty tissue and its biological half-life is approx. 50 days. After a single dose of vitamin D₃ maximum serum concentrations of the active metabolite 25-hydroxycholecalciferol are reached after about a week. 25-Hydroxycholecalciferol is then slowly eliminated with an apparent half-life in serum of about 50 days, due to the slow elimination of the parent compound. 25-Hydroxycholecalciferol is metabolised to the active metabolite 1,25-dihydroxycholecalciferol. After high vitamin D₃ doses serum 25-hydroxycholecalciferol concentrations can be increased for a month or two. Hypercalcaemia resulting from overdose can persist for several weeks.

5.3 Preclinical safety data

At doses far higher than the human therapeutic range teratogenicity has been observed in animal studies. There is no further information of relevance to the safety assessment in addition to what is stated in other parts of the SPC.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Medium chain triglycerides (received from coconut oil and palm kernel oil).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

Shelf life after first opening of container: 6 months.

6.4 Special precautions for storage

Keep the bottle in the outer carton in order to protect from light.

Nature and contents of container

Dropper container with 10 ml solution.

Container: 10 ml molded glass bottles, brown, glass type III.

Dropper: Dropper made of polyethylene, colourless or white.

Closure: Screw cap made of polypropylene, white.

6.6 Special precautions for disposal <and other handling>

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Renapharma AB

Kungsängsvägen 21B

SE-753 23 Uppsala, Sweden

Tel: +46 18 7001140

e-mail: info@renapharma.se

8. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

2011-03-16/2016-03-16

10. DATE OF REVISION OF THE TEXT

2016-08-11