Summary of medicine characteristics - TESTOSTERONE ENANTATE AMPOULES
1 NAME OF THE MEDICINAL PRODUCT
Testosterone Enantate 250 mg/ ml Solution for Injection
2.
Each 1ml ampoule contains 250mg Testosterone Enantate (the equivalent of about 180 mg testosterone) in oily solution.
Also contains 342 mg benzyl benzoate per ampoule
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for injection.
Clear, yellowish oily solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Testosterone replacement therapy for male hypogonadism, when testosterone deficiency has been confirmed by clinical features and biochemical tests.
4.2 Posology and method of administration
Posology
To stimulate development of underdeveloped androgen-dependent organs and for initial treatment of deficiency symptoms, 250mg Testosterone Enantate intramuscularly every two to three weeks.
For maintenance treatment: 250mg Testosterone Enantate intramuscularly every three to six weeks, according to individual requirement.
Serum testosterone levels should be measured before start of treatment and occasionally during the treatment at the end of an injection interval. Serum levels below normal range would indicate the need for a shorter injection interval. In case of high serum levels an extension of the injection interval may be considered.
Special populations
Paediatric population
Testosterone Enantate is not indicated for use in children and adolescents (see 4.4 Special warnings and precautions for use).
Safety and efficacy have not been adequately determined in children and adolescents.
Elderly patients
Limited data do not suggest the need for a dosage adjustment in elderly patients (see 4.4 Special warnings and precautions for use).
Patients with hepatic impairment
No formal studies have been performed in patients with hepatic impairment. The use of Testosterone Enantate is contraindicated in men with past or present liver tumours (see 4.3 Contraindications).
Patients with renal impairment
No formal studies have been performed in patients with renal impairment.
Method of Administration
Solution for intramuscular injection.
The injection must be administered extremely slowly (see 4.4 Special warnings and precautions for use and 4.8 Undesirable effects). The oily solution is injected immediately after its drawing up into the syringe.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Androgen-dependent carcinoma of the prostate or of the male mammary gland
Hypercalcaemia
Past or present liver tumours
Nephrosis
4.4 Special warnings and precautions for use
Older patients treated with androgens may be at increased risk for the development of prostatic hyperplasia. Although there are no clear indications that androgens actually generate prostatic carcinoma, these can enhance the growth of any existing prostatic carcinoma. Therefore carcinoma of the prostate has to be excluded before starting therapy with testosterone preparations.
There is limited experience on the safety and efficacy of the use of Testosterone Enantate in patients over 65 years of age. Currently, there is no consensus about age specific testosterone reference values. However, it should be taken into account that physiologically testosterone serum levels are lower with increasing age.
As a precaution, regular examinations of the prostate are recommended in men.
In patients receiving long-term androgen therapy, the following laboratory parameters should also be monitored regularly: haemoglobin and haematocrit (to detect cases of polycythaemia), liver function tests and lipid profile.
In patients suffering from severe cardiac, hepatic or renal insufficiency or ischaemic heart disease, treatment with testosterone may cause severe complications characterised by oedema with or without congestive cardiac failure. In such case, treatment must be stopped immediately.
Testosterone may cause a rise in blood pressure and Testosterone Enantate should be used with caution in men with hypertension.
Testosterone Enantate should be used with caution in patients with epilepsy, migraine, diabetes mellitus or skeletal metastases.
Testosterone level should be monitored at baseline and at regular intervals during treatment. Clinicians should adjust the dosage individually to ensure maintenance of eugonadal testosterone levels.
Cases of benign and malignant liver tumours, which may lead to life-threatening intraabdominal haemorrhage, have been observed after the use of Testosterone Enantate. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential-diagnosis and, if necessary, the preparation should be withdrawn.
Caution should be exercised in patients predisposed to oedema, as treatment with androgens may result in increased sodium retention (see 4.8 Undesirable effects).
Clotting disorders
Testosterone should be used with caution in patients with thrombophilia or risk factors for venous thromboembolism (VTE), as there have been post-marketing studies and reports of thrombotic events (e.g. deep-vein thrombosis, pulmonary embolism, ocular thrombosis) in these patients during testosterone therapy. In thrombophilic patients, VTE cases have been reported even under anticoagulation treatment, therefore continuing testosterone treatment after first thrombotic event should be carefully evaluated. In case of treatment continuation, further measures should be taken to minimise the individual VTE risk.
Drug abuse and dependence
Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication(s) and in combination with other anabolic androgenic steroids. Abuse of testosterone and other anabolic androgenic steroids can lead to serious adverse reactions including: cardiovascular (with fatal outcomes in some cases), hepatic and/or psychiatric events. Testosterone abuse may result in dependence and withdrawal symptoms upon significant dose reduction or abrupt discontinuation of use. The abuse of testosterone and other anabolic androgenic steroids carries serious health risks and is to be discouraged.
In children testosterone, besides masculinisation, can cause accelerated growth and bone maturation and premature epiphyseal closure, thereby reducing final height.
Testosterone Enantate should not be used in women since, depending on the individual sensitivity to androgenic impulses, women may develop signs of virilisation, e.g. acne, hirsutism, voice changes.
Pre-existing sleep apnoea may be potentiated.
Androgens should not be used for enhancing muscular development in healthy individuals or for increasing physical ability.
As with all oily solutions, Testosterone Enantate must be injected strictly intramuscularly and very slowly. Pulmonary microembolism of oily solutions can lead to signs and symptoms such as cough, dyspnoea and chest pain. There may be other signs and symptoms including vasovagal reactions such as malaise, hyperhydrosis, dizziness, paraesthesia, or syncope. These reactions may occur during or immediately after the injection and are reversible. Treatment is usually supportive, e.g. by administration of oxygen.
If, in individual cases, frequent or persistent erections occur, the dose should be reduced or the treatment discontinued in order to avoid injury to the penis.
Excipients
Also contains 342 mg benzyl benzoate per ampoule. Benzyl benzoate can be hydrolysed into benzyl alcohol and benzoic acid. Benzyl alcohol may cause allergic reactions. High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation of benzyl alcohol and toxicity (metabolic acidosis).
4.5 Interaction with other medicinal products and other forms of interactionBarbiturates and other enzyme inducers
Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of testosterone
Increased oxyphenbutazone serum levels have been reported.
The clotting status should be monitored particularly closely when
Testosterone Enantate is administered together with coumarin derivatives.
The hypoglycaemic effect of antidiabetics may be enhanced, possibly requiring a reduction in dosage of the hypoglycaemic agent.
4.6 Fertility, pregnancy and lactation
Pregnancy
Testosterone Enantate is intended for use by men only. Testosterone Enantate is not indicated in pregnant women (see 5.3 Preclinical safety data).
Testosterone Enantate is intended for use by men only. Testosterone Enantate is not indicated in breast feeding women (see 5.3 Preclinical safety data).
Testosterone Enantate replacement therapy may reversibly reduce spermatogenesis (see 4.8 Undesirable effects and 5.3 Preclinical safety data).
4.7 Effects on ability to drive and use machines
Testosterone Enantate has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Undesirable effects are listed by MedDRA System Organ Classes.Assessment of undesirable effects is based on the following frequency groupings:
Very common: >1/10
Common: >1/100 to <1/10
Uncommon: >1/1,000 to <1/100
Rare: >1/10,000 to <1/1,000
Very rare: <1/10,000
Not known: cannot be estimated from the available data
| System Organ Class | Undesirable effect | Frequency |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Benign tumour of liver Malignant liver tumour | Not known |
| Blood and lymphatic system disorders | Polycythaemia | Not known |
| Haematocrit increased Red blood cell count increased Haemoglobin increased | Common | |
| Immune system disorders | Hypersensitivity | Not known |
| Metabolism and nutrition disorders | Weight increased | Common |
| Hypercalcaemia Water retention | Not known | |
| Psychiatric disorders | Depression Anxiety | Not known |
| Nervous system disorders | Headache Paraesthesia | Not known |
| Cardiac disorders | Disorder circulatory system | Not known |
| Gastrointestinal disorders | Abdominal disorder Intra-abdominal haemorrhage Nausea | Not known |
| Hepatobiliary disorders | Liver function test abnormal Jaundice Liver enlargement | Not known |
| Skin and subcutaneous tissue disorders | Acne Alopecia Rash Urticaria Pruritus Male pattern baldness | Not known |
| Musculoskeletal and connective tissue disorders | Premature epiphyseal closure* Bone formation increased | Not known |
| General disorders and | Injection site reaction | Not known |
| administration site conditions | Asthenia Oedema | |
| Investigations | Prostatic specific antigen increased | Not known |
| Reproductive system and breast disorders | Libido increased Libido decreased Gynaecomastia Prostatic disorder Erection increased Spermatogenesis abnormal Precocious puberty* | Not known |
*In pre-pubertal males
Injection site pain, Injection site erythema, Injection site induration, Injection site swelling, Injection site inflammation
Description of selected adverse reactions
Injections of oily solutions such as Testosterone Enantate have been associated with systemic reactions: cough, dyspnoea, chest pain. There may be other signs and symptoms including vasovagal reactions such as malaise, hyperhydrosis, dizziness, paraesthesia, or syncope.
High-dosed or long-term administration of testosterone increases the tendency to water retention and oedema.
Spermatogenesis is inhibited by long-term and high-dosed treatment with Testosterone Enantate.
If, in individual cases, frequent or persistent erections occur, the dose should be reduced or the treatment discontinued in order to avoid injury to the penis.
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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseNo special therapeutic measure apart from termination of therapy with the drug or dose reduction is necessary after overdosage.
Acute toxicity data show that Testosterone Enantate can be classified as non-toxic following a single intake. Even in the case of an inadvertent administration of a multiple of the dose required for therapy, no acute toxicity risk is expected.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Androgens, 3-oxoandrosten (4) derivatives
ATC Code: G03BA03
Testosterone Enantate is an ester of the natural male sex hormone testosterone and exhibits all the pharmacological effects of the natural hormone. It differs in that it has a depot effect, due to the fact that Testosterone Enantate is only slowly degraded to testosterone in the body.
5.2 Pharmacokinetic properties
Following intramuscular administration of 200mg of Testosterone Enantate to 6 hypogonadal males:
Peak serum testosterone levels of 1233 ± 484 ng/ml were achieved at 24 hours.
Physiological levels of testosterone (approx. 500 ng/ml) were maintained for 11 days.
Half-life in blood was 2–3 days (healthy male volunteers).
5.3 Preclinical safety data
5.3 Preclinical safety dataStudies in animals showed that the formulation has minimal potential for causing sensitisation or local irritation following intramuscular injection. Long-term systemic studies showed no evidence of testicular toxicity although a temporary inhibition of spermatogenesis may occur. No fertility studies with Testosterone Enantate have been carried out. Testosterone Enantate should not be administered during pregnancy due to the possibility of virilisation of the female foetus. However, investigations into embryotoxic, in particular teratogenic, effects gave no indication that further impairment of organ development may occur.
In vitro investigations of mutagenicity gave negative results.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Benzyl benzoate
Castor oil for injection
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
5 years.
6.4 Special precautions for storage
Protect from light.
6.5 Nature and contents of container
Clear glass ampoules of 1 ml in packs of 3.
6.6 Special precautions for disposal and other handling
6.6 Special precautions for disposal and other handlingNot applicable.
7 MARKETING AUTHORISATION HOLDER
Alliance Pharmaceuticals Limited
Avonbridge House
Bath Road
Chippenham
Wiltshire
SN15 2BB
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 16853/0116
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
19 September 1996