1.

NAME OF THE MEDICINAL PRODUCT

Betnesol tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 effervescent tablet contains 0.5 mg betamethason (as sodium

phosphate) Excipient with known effect: 0.5 mg sodium-saccharose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Effervescent tablet

Appearance: Pink, round, on both sides oblated tablet with beveled edges, with a breakline on one side
and embossed with "BETNESOL" on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Diseases responsive to oral glucocorticosteroid therapy.

4.2 Posology and method of administration

Glucocorticoids should only be administered at lowest therapeutic required doses and as long
as it is absolutely necessary to achieve and maintain the desired therapeutic effect.
The dosage must be adjusted to the specific situation of the patient, considering severity of disease
of the occurred effect and glucocorticoid tolerance.

Posology

Adults and adolescents as of 12 years

The daily dose is administered usually in the morning and at once as this will less affect the
rhythm of adrenal cortex-secretion.

Short-term treatment
Acute asthma attacks, Pillinosis or other allergic diseases of the respiratory tract, generalised
eczema, urticaria, dermatitis medicamentosa, and various inflammatory skin diseases.

6 tablets in the morning for 2 days, followed by

1 tablet in the morning for 2 days, followed by
½ tablet in the morning for 2 days.

Arthritis rheumatica:
1 -4 tablets (0,5 mg to 2 mg) daily in the morning for 1 – 2 weeks, then a gradual withdrawal of the
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treatment, starting with one tablet less a day, later half a tablet less, by keeping each dosage for one
week. Thus it is possible to evaluate the minimum effective dose.

Other diseases:
Betnesol effervescent tablets is indicated particularly for patients with nephrosis since it shows
nearly no sodium chloride and water retention effect. In this disease the usual dose is 1–8 tablets
(0,5 mg to 4 mg) daily in the morning for 1 to 3 weeks, maybe also longer.

Then the medication is withdrawn step by step. To reach the therapeutic effect in pemphigus,
erythematodes or collagenoses of the skin often higher doses are required.

Dosage in children as of 6 years:

The effects of glucocorticoids on the pathophysiology and history of the disease are considered
similar in adults and children.

In children in general lower doses than indicated above are sufficient, but the dosage should be
adjusted more to the severity of the disease than to age, body weight, or body size. After sufficient
response Betnesol should be withdrawn step by step as quickly as possible. Long-term treatment is
not recommended. Exact dosages have been not been established in clinical trials. From clinical
experience following guidelines for short-time treatment were shown:

Recommended initial dose:

7 to 12 years: up to 8 tablets/day (= 4 mg).

Elderly
Caution is advised on higher frequency of adverse events in older patients during administration of
betamethasone particularly in long-term therapy including osteoporosis, worsening of diabetes,
hypertension, susceptibility to infections and thinning of the skin.

Patients with impaired liver function and thyroid disease

Betamethasone is basically metabolized in the liver. In patients with hepatic insufficiency or
hypothyroidism relatively low doses may be sufficient or dose reduction may be required.

Method of administration

Betnesol tablets should be solved in water and then the solution should be drunk, or the tablets could
be swallowed whole with some water.
Only for short-term treatment

The dosage to continue therapy has to be adjusted to the disease and the response of the patient. The
patient must therefore be monitored and the dosage be checked frequently or adjusted, respectively.
Maintenance doses of more than 7.5 mg prednisolone equivalent/day (= Cushing threshold dose;
corresponding approximately to 1 mg Bethametason) have to be avoided, because they suppress
the endogenous cortisol production by hypothalamic inhibition without reaching the intended
pharmacologic effects.

To lower the undesired effects the following therapy instructions have to be followed:
lowest therapeutic required dose and shortest duration of therapy have to be aimed for.

Although the short-term high-dosage glucocorticoid administration (up to 10 days) is not critical, an
initial high dose should be lowered to a maintenance dose below twice the Cushing threshold dose
within short time.

The entire dose should be administered in the morning before 8 o’clock, since the rhythm of the
adrenal secretion is less affected.
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In children and adolescents up to 14 years a 4 days-therapy-free interval (intermittent therapy) should
be kept following 3-days therapy because of the risk of growth retardation.

Withdrawal has to be done solely with treatment pauses.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Contraindications for administration beyond emergency therapy:

Systemic mycosis
Ulcus ventriculi
Ulcus duodeni
Severe osteoporosis
Myopathies (excluding Myasthenia gravis)
Virus diseases (e.g. varicella, herpes simplex, herpes zoster – viremic phase))
Poliomyelitis with the exception of bulbar encephalitic form)
Lymphomas following BCG – immunization
Approximately 8 weeks before and 2 weeks after immunization or 1 year after a BCG
vaccination
Narrow-angle glaucoma and open-angle glaucoma
Manifest or latent tuberculosis
Amoebic infections
Anamnestic psychoses
Herpes keratitis
Children below 6 years

4.4 Special warnings and precautions

for use

Betnesol therapy should be performed only on strict indication including additional targeted anti-
infective therapy where appropriate for:

- HBsAg positive chronic active hepatitis

- Hardening of the lymph nodes (up to one year after a BCG vaccination is to exclude a
specific histiocytosis before starting therapy)
- Acute and chronic bacterial infections
- Tuberculosis in history (cave: reactivation); Administration only under protection of
tuberculostatics

In addition Betnesol therapy should be performed only on strict indication including additional
targeted anti- infective therapy where appropriate for:

- Difficulty adjustable hypertension

- Difficulty adjustable Diabetes mellitus
- Corneal ulcers and –injuries
- Epilepsy
- Thrombophilia/thromboembolic processes
- Hart failure
- Renal failure

Because of the risk of intestinal perforation with peritonitis Betnesol may be used on mandatory
indication only and under appropriate observation for:
- Severe ulcerative colitis with impending perforation, abscess or purulent inflammation
- Diverticulitis
- Enteroanastomosis (immediately after surgery).
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Administration of glucocorticoids for severe infections may only occur in combination with a
casual therapy.

Before starting a glucocorticoid therapy detailed investigation has to be performed; particularly

gastric and intestinal ulcer have to be excluded.

For prevention of ulcer in the gastrointestinal tract the administration of acid inhibitors and
careful monitoring (including X-ray control/gastroscopy) is indicated in sensitive patients.

The signs of peritoneal irritation after gastrointestinal perforation may be missing in patients
receiving high doses of glucocorticoid.

Under systemic administration with glucocorticoid a degradation of carbohydrate metabolism can

occur which can lead to the manifestation of latent diabetes or worsening of manifest diabetes. In
diabetics the metabolic status must therefore be checked and if necessary antidiabetic treatment
must be adjusted.

During treatment with Betnesol a regular blood pressure monitoring is required in patients with
hypertension.

In treatment of myasthenia gravis deterioration of symptom may occur initially, therefore adjustment on
glucocorticoids should occur in hospital. Especially in severe facio-pharyngeal symptoms and reduction
of respiratory volume, therapy with Betnesol should be started step by step.

Treatment with Betnesol can mask the symptoms of existing or developing infection and thus
complicate the diagnosis.

Treatment with glucocorticoids can lead to an increased risk of infection due to

immunosuppression in particular also by opportunistic germs.

Vaccinations with inactivated vaccines are basically possible. It should be noted that the immune
response and hence the success of vaccination may be affected by higher corticosteroid doses.

At high doses, it is important to ensure an adequate intake of potassium and sodium restriction. The
serum potassium levels has to be monitored and to be adapted if necessary. This especially applies to
simultaneous administration of medicines, of which it is known that they can lead to QT interval
prologation.

Certain viral diseases (Varicella, Measles, Herpes zoster) can be more severe in patients who are
treated with glucocorticoids. Immunocompromised children and persons who have not been previously
infected with Varicella or –Measles are at risk. If these patients come in contact to infected persons
during treatment with Betnesol preventive therapy should be initiated if necessary.

In children indication should be strictly adjusted due to the growth-inhibiting effect of

glucocorticoids and the length growth should be regularly monitored during long- term treatment.

If particularly physical stress situations (e.g. accident, surgery, birth) occur during therapy
with glucocorticoids a temporary dose increase may be necessary. Because of possible danger
in stressful situations, a corticosteroid identity card should be issued for patients with
prolonged therapy.

Depending on duration and dose of the treatment a negative effect on the calcium metabolism must be
taken into account, an osteoporosis prophylaxis is recommended if necessary. Prevention consists in
adequate calcium and vitamin D intake and physical activity. For existing osteoporosis medical
treatment should be additionally considered.

In hypothyroidism or liver cirrhosis relatively low doses may be sufficient - or dose reduction
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may be required.

Betnesol is primarily intended for short-term use. When applied over a longer period also warnings
described for glucocorticoid-containing drugs for long term use have to be considered.

At termination or required discontinuation of a long-term systemic therapy with glucocorticoids

caution is advised on occurrence of acute adrenal insufficiency (especially under stress, such as
infections, accidents, increased physical stress, and fever), withdrawal syndrome or a relapse of the
disease.

Too rapid dose reduction after prolonged treatment may lead to symptoms such as muscle and

joint pain. Patients should be advised to inform subsequent physicians of the prior administration

of corticosteroids.
(e.g. surgeries, travel, vaccinations).

In long-term glucocorticoid therapy monitoring in reasonable intervals regarding possible undesirable

events may be necessary independent from checks due to disease and depending on the dosage and the
individual condition of the patient.

Athletes
Administration of Betnesol tablets can lead to a positive doping test result.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablets Betnesol, i.e. it is almost
"sodium-free".

4.5 Interaction with other medicinal products and other forms of interaction

Heart glycosides Increased glycoside action by hypokalemia

Medicinal products leading to QT prolongation Hypokalaemia has to be corrected if appropriate
and clinical condition has to be monitored
Antidiabetics The blood glucose-lowering effect of insulin and
oral antidiabetics can be reduced.
Cumarin-Derivates Action of anticoagulants is decreased
Anticoagulants Possible increased or decreased anti-coagulant effect
Barbiturates, Hydantoine, Rifampicin Action of corticoids is decreased
Nonsteroidal antiphlogistics, antirheumatics Increased incidence of stomach ulcers and
stomach bleeding
Estrogenes Corticoid action may be increased, therefore a dose
adjustment may be necessary if estrogens are used or
discontinued.
Vaccines Live vaccines may be more toxic because of the
immune compromising effect of corticosteroids
Disseminated viral infections can occur. For
inactivated or toxoid vaccines the immune
response can fail or can be reduced (see 4.3
Contraindications)
Aluminium salts - complex-forming acids The aluminum concentration in the plasma can
increase while taking in combination with
complex- forming acids such as citric acid in drinks
or medicinal products (for the treatment of acidosis
or urinary alkalinisation) or Ascorbic acid for
several weeks.
Bupropion Increased risk of seizures.
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Chinindin The action of quinidine may be increased.
Non-depolarizing muscle relaxants Muscle relaxation can last longer.
Atropine, other anticholinergics Possible additional increase of intraocular pressure
Praziquantel Possible decrease of Praziquantel
blood concentration
Chloroquine, Hydrochloroquin, Mefloquine Increased risk for myopathy and cardiomyopathy.
Somatropin Effect of somatropin can be reduced
Protirelin Increase of TSH can be reduced
Ciclosporin Possible increase of cyclosporine blood
levels. Increased risk of cerebral seizures.
ACE-Inhibitors Increased risk for blood count changes.
Diuretics Increased loss of potassium - increased risk
of hypokalaemia.
Azole Antimykotiks (such as ketoconazole or Increased action of glucocorticoids
itraconazole)
Enzyme inductors (CYP 3A4) Decreased action of glucocorticoids
Copper (intrauterine devices) Decreased action of intrauterine devices
Lithium salts Possible decreased action of lithium
Influence on analytical methods Skin reactions to allergy tests (Prick - test) can
be suppressed.

4.6 Fertility, pregnancy and lactation

Fertility
No data avaialble.

Pregnancy
There are no controlled studies on the administration of betamethasone during pregnancy and
lactation available.
In animal studies the use of glucocorticoids lead to fetal malformations (see section 5.3). An
increased risk of cleft palate in human fetus by administering of glucocorticoids during the first
trimester is
discussed. If gucocorticoids are administered at the end of pregnancy, there is a risk for the fetus for
atrophy of the adrenal cortex, which may require a compenastive substitution treatment of the
newborn. Furthermore they have to be tested for rare occurrence of congenital cataracts.
For this reason, Betnesol should only be adminiserted during pregnancy if the expected benefit
outweighs the potential risk for the fetus.
Basically no cortisone-containing medicinal products should be administered in the first 3
months of pregnancy.

Breastfeeding
Since glucocorticoids penetrate breast milk in small quantities, it has to be weaned during a
glucocorticoid therapy.

4.7 Effects on ability to drive and use machines

No studies on the effects of the ability to drive and to use machines have been performed.
Due to the known pharmacodynamics and pharmacokinetic of the active ingredient it however can
be assumed, that Betnesol has no direct influence on the ability to drive and the ability to operate
machines. Some adverse events during cortisone therapy (eye disorders, nervous system disorders
or myopathy) may reduce the ability to drive.

4.8 Undesirable effects

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The frequencies of undesirable effects are ranked according to the

following: Very common (≥1/10)

Common (≥1/100,
<1/10) Uncommon
(≥1/1.000, <1/100)
Rare (≥1/10.000,
<1/1.000) Very rare
(<1/10.000)
Not known (frequency cannot be estimated from the

available data) Table 1: Undesirable effects, appeared with

systemic Bethametason

System organ classes Undesirable effects

and frequencies
Endocrine disorders
Not known Cushing-Syndrome, adrenal inactivation or atrophia,

Gastrointestinal disorders
Not known Abdominal discomfort, Ulcus ventriculi or duodeni (risk of perforation),
ulcerative oesophagitis , bleeding, pancreatitis; risk of perforation with
preexisting Colitis ulcerosa
Infections and infestations
Not known Increased risk of susceptibility to infections; masking of infections;
exazerbation of latent infections (mycosis, virus infections, bacterial
infections, Protozoa infection, candidosis, tuberkulosis, etc.);
Blood and lymphatic system disorders
Not known Leukocytosis.
Immune system disorders
Not known Decreased immune response; allergic reaction, anaphylactic reactions
including shock.
Eye disorders
Not known Cataract, glaucoma, exophthalmos.
Cardiac disorders
Not known Myocardial rupture after recent infarct
Metabolism and nutritional disorders
Not known decreased carbohydrate tolerance, diabetes mellitus, oedema,
osteoporosis, sodium retention with formation of oedema, increased
potassium excretion, catabolic effect on protein metabolism (negative
nitrogen balance),
Musculoskeletal and connective tissue disorders
Not known amyotrophy and amoysthenia, myopathy, growth retardation in children
osteoporosis, osteonecrosis (Femur- and Capitulum humeri), tendon
rupture
Psychiatric disorders
Not known Mental disorders, psychosis, personality changes, confusion.
Nervous system disorders
Not known Insomnia, vertigo, headache Pseudotumor cerebri (particularly in
children), manifestation of latent epilepsy und increase of seizures in
manifest epilepsy, increased nervousness and anxiety.

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 Reproductive system and breast disorders
Not known disturbance of sexual hormone secretion (menstrual disorder, impotence)
Skin and subcutaneous tissue disorders
Not known striae rubrae, atrophy, telangiectasia, petechiae, ecchymosis, hirsutismus,
steroid acne, impaired wound healing, rosacea-like (periorale) dermatitis,
change in pigmentation of the skin, hypersensitivities (e.g. drug
eruption).

Vascular disorders
Not known hypertension, thrombosis, vasculitis

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. Any suspected
adverse events should be reported to the Ministry of Health according to the National Regulation by
using an online form
https://forms.gov.il/forms/Resources/DowloadSetup/AGFormsDownloadToolbar.htm?formid=Advers
EffectMedic@moh.gov.il

4.9 Overdose

In acute overdose with glucocorticoids including betamethasone a life-threatening situation is not to be

expected. Also at extremely high doses, an excessive doses of glucocorticoid over some days will not
lead to any risk for the patient, if special contraindications such as diabetes, glaucoma, gastrointestinal
ulcera, as
well as concomitant treatment with potassium sparing diuretics, Digitalis, anticoagulants (coumarin
type) can be excluded.
Possibly occurring undesirable events due to glucocorticoids must be treated symptomatic
accordingly. For ulcer prophylaxis, H2 receptor antagonist or antacid should be administered. In
diabetics blood glucose levels must be monitored and antidiabetic drugs dose hast to be increased if
necessary. At increased risk of infection an antibiotic therapy may be necessary.

Treatment: Symptomatic; Adequate hydration. Check of electrolytes in serum and urine, in

particular the balance of sodium and potassium. Electrolyte imbalance is to compensate.

An antidote for betamethasone is not known.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Glucocorticoid for systemic administration, betamethasone

ATC Code: H02AB01

Betamethasone is a mono-fluorinated glucocorticoid, which has about 25-fold more potent anti-
inflammatory effect than the natural adrenal hormone cortisol. The mineralocorticoid effect-component
is however almost completely missing.
Glucocorticoids such as betamethasone develop their biological effect by activating the transcription
of corticosteroid-sensitive genes. The anti-inflammatory, immunosuppressive and antiproliferative
effects are caused for example by reduced formation, release and activity of inflammatory mediators
and by inhibition of specific functions and migration of inflammatory cells. In addition
corticosteroids may prevent the effect of sensitised T-lymphocytes and macrophages on target cells.

Glucocorticoids such as betamethasone promote the surfactant synthesis in the fetal lung.

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Possible induction of temporary adrenal insufficiency must be taken into account with necessary
long-term corticosteroid medication. Suppression of the hypothalamus-pituitary-adrenal axis also
depends on individual factors.

The Cushing threshold dose is specified with 1.5 mg / day.

Betamethasone is a glucocorticoid which is 8 to 10 times more active than prednisolone (based on

weight;
750µg betamethasone corresponding to approximately 5mg prednisolone). Betamethasone sodium
phosphate is well soluble in water and is therefore quickly absorbed. Betamethasone usually only causes
poor retention of sodium chloride or water. Due to lack of mineralocorticoid properties betamethasone
is suitable especially for the treatment of diseases where water retention is affected adversely.

5.2 Pharmacokinetic properties

Betamethasone sodium phosphate is hydrolysed in the body to the biologically active form
betamethasone, reaches the highest blood levels within 60 minutes and is excreted almost entirely after
the first day.

Corticosteroids are in general broadly absorbed in the gastrointestinal tract, in different ways
bound to plasma proteins, primarily metabolized in the liver and excreted by the kidneys.
Corticosteroids are rapidly distributed in all body tissues. They cross the placenta in different extent
and small quantities may be distributed into breast milk. The (serum) elimination half-life of
betamethasone in adults is approximately 5-7 hours.
Betamethasone binds with 62.5% to proteins (compared to hydrocortisone 89%).
While the plasma half-life of betamethasone is ≥300 minutes, the biological half-life was identified
with 36-
54 hours. Due to the long duration of effects betamethasone hence may lead, with a daily
continuous administration, to continuous accumulation and overdose. In patients with liver disease
the degradation is slower.
In infiltrating administration of betamethasone sodium phosphate in healthy subjects a negative
feedback mechanism on the hypothalamic-pituitary system leads to a suppression of the cortisol
plasma level within approximately 8-10 hours. This was normalized within a few days.

5.3 Preclinical safety data

Based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and
carcinogenic potential suggest no special hazard for humans, except the known for the corticosteroids.

Reproductive toxicity
Following parenteral administration Betamethasone showed teratogenic effects in rats and
The most common malformations were cleft palates. Higher doses showed embryonic lethality.
Animal studies showed evidence of malformations and other embryo-toxic effects. During long-
term therapy intrauterine growth retardation cannot be excluded. Following administration at the
end of pregnancy the fetus is at risk for atrophy of the adrenal cortex (see 4.6).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Saccharin-
Sodium
Sodium
carbonate
Sodium
9
 Citrate
Povidone
30
Erythrosine
(E127)
Sodium
benzoate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

The expiry date of the product is indicated on the packaging materials

Do not use more than 1 month after opening.

6.4 Special precautions for storage

Store below 25 °C.

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

6.5 Nature and contents of container

LDPE/Alu Blister package

Betnesol tablets are available with 10 and 30 packs. Not all pack

sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements

7. MANUFACTURER

Alfasigma S.p.A., Viale Sarca, n.223 - 20126, Milano (MI),Italy

8. LICENSE HOLDER

Devries & Co.

32 Habarzel st.
Tel-Aviv

9. MARKETING AUTHORISATION NUMBER

135 65 22066 00

10. DATE OF REVISION OF THE TEXT

04.2015

This leaflet format has been determined by the Ministry of Health and the content has been checked and
approved in April 2015
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