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TRETINOIN 10MG SOFT CAPSULES

Active substance(s): TRETINOIN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Vesanoid 10 mg soft capsules
Tretinoin 10mg soft capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Active substance:
1 capsule contains 10 mg of tretinoin
Excipients with known effect:
1 capsule contains 107.92 mg of soya-bean oil.

The capsule-shell contains between 1.93 – 2.94 mg of sorbitol.
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Capsule, soft
Bi-coloured orange-yellow / reddish-brown capsules.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Vesanoid/Tretinoin is indicated for induction of remission in acute
promyelocytic leukaemia (APL; FAB classification AML-M3).
This treatment is intended for previously untreated patients as well as patients
who relapse after a standard chemotherapy (anthracycline and cytosine
arabinoside or equivalent therapies) or patients who are refractory to
chemotherapy.

4.2

The association of tretinoin with chemotherapy increases the duration of
survival and reduces the risk of relapse compared to chemotherapy alone.
Posology and method of administration

Posology

A total daily dose of 45 mg/m2 body surface divided in two equal doses is
recommended for oral administration. This is approximately 8 capsules per adult dose.
Paediatric population
There is limited safety and efficacy information on the use of tretinoin in children.
Paediatric patients can be treated with 45 mg/m2 unless severe toxicity becomes
apparent. Dose reduction should be particularly considered for children with
intractable headache.

Patients with hepatic and/or renal impairment
Due to limited information on patients with hepatic and/or renal insufficiency, the
dose will be decreased to 25 mg/m2 as a precautionary measure.
Method of administration
The capsules should be swallowed whole with water. They should not be chewed. It is
recommended to take the capsules with a meal or shortly thereafter.
Treatment should be continued until complete remission has been achieved or up to a
maximum of 90 days.
Full-dose anthracycline-based chemotherapy should be added to the tretinoin regimen
as follows (see section 4.4):





When the leukocyte count at start of therapy is greater than 5 x 10 9/L,
chemotherapy should be started together with tretinoin on day one.
When the leukocyte count at start of therapy is less than 5 x 10 9/L but rapidly
increases during tretinoin therapy, chemotherapy should be immediately added
to the tretinoin regimen if the leukocyte count reaches greater than 6 x 10 9/L by
day five, or greater than 10 x 109/L by day ten, or greater than 15 x 109/L by day
28.
All other patients should receive chemotherapy immediately after complete
remission is attained.

If chemotherapy is added to tretinoin because of hyperleukocytosis, it is not necessary
to modify the dose of tretinoin.
After completion of tretinoin therapy and the first chemotherapy course, consolidation
anthracycline-based chemotherapy should be given, for example, a further two
courses at 4 to 6 week intervals.
In some patients the plasma levels of tretinoin may fall significantly in spite of
continued administration.
4.3
Contraindications
Hypersensitivity to tretinoin, retinoids, soya, peanut or to any of the excipients listed
in section 6.1.

Pregnancy (see section 4.6).
Breast-feeding (see section 4.6).
Tetracyclines (see section 4.5).
Vitamin A (see section 4.5).
4.4
Special warnings and precautions for use
Tretinoin should be administered to patients with acute promyelocytic leukaemia only
under the strict supervision of a physician who is experienced in the treatment of
haematological / oncological diseases.
Supportive care appropriate for patients with acute promyelocytic leukaemia, for
example prophylaxis for bleeding and prompt therapy for infection, should be
maintained during therapy with tretinoin. The patient’s haematologic profile,
coagulation profile, liver function test results, and triglyceride and cholesterol levels
should be monitored frequently.
During clinical trials hyperleukocytosis has been frequently observed (in 75% of the
cases), sometimes associated with the “Retinoic Acid Syndrome”. Retinoic acid
syndrome has been reported in many acute promyelocytic leukaemia patients (up to
25% in some centres) treated with tretinoin.
Retinoic acid syndrome is characterized by fever, dyspnoea, acute respiratory distress,
pulmonary infiltrates, pleural and pericardial effusions, hypotension, oedema, weight
gain, hepatic, renal and multi-organ failure.
Retinoic acid syndrome is frequently associated with hyperleukocytosis and may be
fatal.
The incidence of the retinoic acid syndrome is diminished when full dose
chemotherapy is added to the tretinoin regimen based on the white blood cell count.
The current therapeutic treatment recommendations and method of administration are
detailed in section 4.2.
Immediate treatment with dexamethasone (10 mg every 12 hours for up to maximum
3 days or until resolution of the symptoms) should be given, if the patient presents any
symptom(s) or sign(s) of this syndrome.
In cases of moderate and severe retinoic acid syndrome, temporary interruption of
Vesanoid/Tretinoin therapy should be considered.
Vesanoid/Tretinoin may cause pseudotumor cerebri. This condition should be treated
according to standard medical practice. Temporary discontinuation of
Vesanoid/Tretinoin should be considered in patients not responding to treatment.
Cases of Sweet’s syndrome or acute febrile neutrophilic dermatitis responded
dramatically to corticosteroid treatment.
There is a risk of thrombosis (both venous and arterial) which may involve any organ
system, during the first month of treatment (see section 4.8). Therefore, caution
should be exercised when treating patients with the combination of

Vesanoid/Tretinoin and anti-fibrinolytic agents, such as tranexamic acid,
aminocaproic acid or aprotinin (see section 4.5).
Because hypercalcaemia may occur during therapy, serum calcium levels should be
monitored.
Micro-dosed progesterone preparations (“minipill”) are an inadequate method of
contraception during treatment with tretinoin (see section 4.6).
Vesanoid/Tretinoin contains sorbitol, therefore patients with rare hereditary problems
of fructose intolerance should not take Vesanoid/Tretinoin.
4.5
Interaction with other medicinal products and other forms of interaction
Tetracyclines: systemic treatment with retinoids may cause elevation of the
intracranial pressure. As tetracyclines may also cause elevation of the intracranial
pressure, patients must not be treated with tretinoin and tetracyclines at the same time
(see section 4.3).
Vitamin A: As with other retinoids, tretinoin must not be administered in combination
with vitamin A because symptoms of hypervitaminosis A could be aggravated (see
section 4.3).
The effect of food on the bioavailability of tretinoin has not been characterised. Since
the bioavailability of retinoids, as a class, is known to increase in the presence of
food, it is recommended that tretinoin be administered with a meal or shortly
thereafter.
As tretinoin is metabolised by the hepatic P450 system, there is the potential for
alteration of pharmacokinetics parameters in patients administered concomitant
medications that are also inducers or inhibitors of this system. Medications that
generally induce hepatic P450 enzymes include rifampicin, glucocorticoids,
phenobarbital and pentobarbital. Medications that generally inhibit hepatic P450
enzymes include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and
ciclosporin. There are no data to suggest that co-use with these medications increases
or decreases either efficacy or toxicity of tretinoin.
Cases of fatal thrombotic complications have been reported rarely in patients
concomitantly treated with all-trans retinoic acid and anti-fibrinolytic agents such as
tranexamic acid, aminocaproic acid and aprotinin (see section 4.4). Therefore, caution
should be exercised when administering all-trans retinoic acid concomitantly with
these agents.
There are no data on a possible pharmacokinetic interaction between tretinoin and
daunorubicin or AraC.

4.6

Fertility, pregnancy and lactation

All the measures listed below should be considered in relationship to the severity of
the disease and the urgency of the treatment.
Fertility & Pregnancy
Vesanoid/Tretinoin contains a retinoid similar to vitamin A. Therefore
Vesanoid/Tretinoin should not be used by women who are pregnant or likely to
become pregnant. Tretinoin causes serious birth defects when administered during
pregnancy. Its use is contraindicated in pregnant women and women who might
become pregnant during the treatment with tretinoin and within one month after
cessation of treatment, unless the benefit of tretinoin treatment outweighs the risk of
foetal abnormalities due to the severity of the patient’s condition and the urgency of
treatment.
There is a very high risk for any exposed foetus that a deformed infant will result if
pregnancy occurs while taking tretinoin, irrespective of the dose or duration of the
treatment.
Therapy with tretinoin should only be started in female patients of child-bearing age if
each of the following conditions is met:


She is informed by her physician of the hazards of becoming pregnant during
and one month after treatment with tretinoin.



She is willing to comply with the mandatory effective contraception measures:
to use a reliable contraception method without interruption during therapy and
for one month after discontinuation of treatment with tretinoin (see section 4.4).



Pregnancy tests must be performed at monthly intervals during therapy.

In spite of these precautions, should pregnancy occur during treatment with tretinoin
or up to one month after its discontinuation, there is a high risk of severe
malformation of the foetus, particularly when tretinoin is given during the first
trimester of pregnancy.
Breast-feeding
Nursing must be discontinued if therapy with tretinoin is initiated.
4.7
Effects on ability to drive and use machines
Vesanoid/Tretinoin has minor or moderate influence on the ability to drive and use
machines, particularly if patients are experiencing dizziness or severe headache.
4.8
Undesirable effects
In patients treated with the recommended daily doses of tretinoin the most frequent
undesirable effects are consistent with the signs and symptoms of the
hypervitaminosis A syndrome (as for other retinoids).
Retinoic acid syndrome has been reported in many acute promyelocytic leukaemia patients
(up to 25% in some centres) treated with tretinoin. Retinoic acid syndrome is characterized by
fever, dyspnoea, acute respiratory distress, pulmonary infiltrates, pleural and pericardial

effusions, hypotension, oedema, weight gain, hepatic, renal and multi-organ failure. Retinoic
acid syndrome is frequently associated with hyperleukocytosis and may be fatal. For
prevention and treatment of retinoic acid syndrome see section 4.4.

In addition, the following adverse reactions have been reported in clinical studies and
during the post-marketing period.
(“Frequency not known” corresponds to post marketing experience)
Infections and infestations:
Frequency not known: Necrotizing fasciitis.
Blood and lymphatic system disorders:
Frequency not known: Thrombocythaemia, basophilia.
Metabolism and nutrition disorders:
Very common (≥ 1/10): Decreased appetite.
Frequency not known: Hypercalcaemia.
Psychiatric disorders:
Very common (≥ 1/10): Confusional state, anxiety, depression, insomnia.
Nervous system disorders:
Very common (≥ 1/10): Headache, intracranial pressure increased, benign intracranial
hypertension, dizziness, paraesthesia.
Frequency not known: Cerebrovascular accident.
Eye disorders:
Very common (≥ 1/10): Visual disturbances, conjunctival disorders.
Ear and labyrinth disorders:
Very common (≥ 1/10): Hearing impaired.
Cardiac disorders:
Very common (≥ 1/10): Arrhythmia.
Frequency not known: Myocardial infarction.
Vascular disorders:
Very common (≥ 1/10): Flushing.
Frequency not known: Thrombosis, vasculitis.
Respiratory, thoracic and mediastinal disorders:
Very common (≥ 1/10): Respiratory failure, nasal dryness, asthma.
Gastrointestinal disorders:
Very common (≥ 1/10): Dry mouth, nausea, vomiting, abdominal pain, diarrhoea,
constipation, pancreatitis, cheilitis.
Skin and subcutaneous tissue disorders:
Very common (≥ 1/10): Erythema, rash, pruritus, alopecia, hyperhidrosis.
Frequency not known: Erythema nodosum, acute febrile neutrophilic dermatosis.

Musculoskeletal and connective tissue disorders:
Very common (≥ 1/10): Bone pain.
Frequency not known: Myositis.
Renal and urinary disorders:
Frequency not known: Renal infarct.
Reproductive system and breast disorders:
Frequency not known: Genital ulceration.
General disorders and administration site conditions:
Very common (≥ 1/10): Chest pain, chills, malaise.
Investigations:
Very common (≥ 1/10): Blood triglyceride increased, blood creatinine increased,
blood cholesterol increased, transaminases increased.
Frequency not known: Histamine level increased.
The decision to interrupt or continue therapy should be based on an evaluation of the benefit
of the treatment versus the severity of the side-effects.
Teratogenicity: See section 4.6.

There is limited safety information on the use of tretinoin in children. There have been
some reports of increased toxicity in children treated with tretinoin, particularly
increased pseudotumor cerebri.
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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9
Overdose
In case of overdose with all-trans retinoic acid, reversible signs of hypervitaminosis A
(headache, nausea, vomiting, mucocutaneous symptoms) can appear.
The recommended dose in acute promyelocytic leukaemia is one quarter of the
maximum tolerated dose in solid tumor patients and below the maximum tolerated
dose in children.
There is no specific treatment in the case of an overdose, however it is important that
the patient be treated in a special haematological unit.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Cytostatic-differentiating agent, ATC code: L01XX14.
Tretinoin is a natural metabolite of retinol and belongs to the class of retinoids,
comprising natural and synthetic analogs.
In vitro studies with tretinoin have demonstrated induction of differentiation and
inhibition of cell proliferation in transformed hemopoietic cell lines, including human
myeloid leukaemia cell lines.
The mechanism of action in acute promyelocytic leukaemia is not known but it may
be due to a modification in binding of tretinoin to a nuclear retinoic acid receptor
(RAR) given that the α-receptor of retinoic acid is altered by fusion with a protein
called PML.

5.2

Pharmacokinetic properties

Tretinoin is an endogenous metabolite of vitamin A which is normally present in
plasma.
Absorption
After oral administration, tretinoin is absorbed by the digestive tract and maximum
plasma concentrations in healthy volunteers are attained after 3 hours.
There is a large inter-patient and intra-patient variation in plasma levels of tretinoin.
Distribution
Tretinoin is extensively bound to plasma proteins. Following peak levels, plasma
concentrations decline with a mean elimination half life of 0.7 hours. Plasma
concentrations return to endogenous levels after 7 to 12 hours following a single
40 mg dose. No accumulation is seen after multiple doses and tretinoin is not retained
in body tissues.
Biotransformation
During continuous administration a marked decrease in plasma concentration can
occur, possibly due to cytochrome P450 enzyme induction which increases clearance
and decreases bioavailability after oral doses.

Elimination
After an oral dose of radiolabelled tretinoin, about 60% of the radioactivity was
excreted in urine and about 30% in faeces. The metabolites found in urine were
formed by oxidation and glucuronidation.
At present there are no data on a possible interaction between tretinoin and
daunorubicin.

The requirement for dosage adjustment in patients with renal or hepatic insufficiency
has not been investigated. As a precautionary measure, the dose will be decreased (see
section 4.2).
5.3
Preclinical safety data
Oral administration of tretinoin to animals indicated that the compound had very low
acute toxicity in all species investigated.
In animal experimental tests it was shown that in all investigated species the acute
toxicity of tretinoin administered orally is low. After a longer period of administration
rats exhibit a dose- and time-dependent bone matrix dissolution, a decrease in
erythrocyte count and toxic alterations in kidney and testes.
Dogs mainly exhibited disorders concerning spermatogenesis and hyperplasia of the
bone marrow.
The major metabolites of tretinoin (4-oxo-tretinoin, isotretinoin and 4-oxoisotretinoin) are less effective than tretinoin in inducing differentiation of human
leukaemic cells (HL-60).
Subchronic and chronic toxicity studies in rats indicated that the no effect oral dose
was at or below 1 mg/kg/day; in dogs, 30 mg/kg/day was associated with toxic effects
including weight loss, dermatological and testicular changes.
Reproduction studies in animals have demonstrated the teratogenic activity of
tretinoin.
No evidence of mutagenicity has been found.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Capsule contents:
Yellow beeswax
Hydrogenated soya-bean oil
Partially hydrogenated soya-bean oil
Soya-bean oil
Capsule shell:
Gelatin
Glycerol (E 422)
Karion 83: Sorbitol, Mannitol, Starch (maize)
Titanium dioxide (E 171)
Iron oxide yellow (E 172)

Iron oxide red (E 172)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years

6.4

Special precautions for storage
Bottles:
Do not store above 30°C.
Keep the bottle tightly closed in order to protect from moisture.

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

6.5

Nature and contents of container
Amber glass bottles of 100 capsules.

6.6

Special precautions for disposal
Use and handling: No special requirements.
Disposal: Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
CHEPLAPHARM Arzneimittel GmbH
Bahnhofstr. 1a
17498 Mesekenhagen
Germany

8

MARKETING AUTHORISATION NUMBER(S)
PL 27041/0003

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 22 October 1996
Date of latest renewal: 17 August 2006

10

DATE OF REVISION OF THE TEXT
12/02/2015

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Source: Medicines and Healthcare Products Regulatory Agency

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