China (Mainland)
PRODUCT INFORMATION
Andriol® Testocaps®
NAME OF THE MEDICINE: Testosterone undecanoate
Testosterone undecanoate, the active ingredient of Andriol Testocaps, is a white to creamy-white
crystalline powder. It is practically insoluble in water, soluble in 2% (w/v) dioxane and in ethanol (96%)
and has a melting point of 60-650C. It is a fatty acid ester of the naturally occurring androgen
testosterone:
Chemical name
3-oxo-androst-4-en-17-yl undecanoate
The structural formula of testosterone undecanoate is:
C* C* C* C* C* C*
O
H H
O O
C
C H
Molecular Formula Molecular Weight
C30H48O3 456.7
CAS Number: 5949-44-0
History and development
Testosterone given orally is known to be mostly deactivated by the liver before reaching the
circulation. Thus it was thought that esterification of testosterone to a lipophilic ester might overcome
the problem. Such a testosterone ester would be absorbed with lipids into the lymphatic system and
pass to the peripheral circulation thus bypassing the liver. Esterification of testosterone with
undecanoic acid was chosen.
DESCRIPTION
Soft oval glossy, transparent orange coloured capsules, containing a clear yellow oil fill. The capsules
are encoded with a white imprint marked DV3 ORG.
Composition
Capsule content: Active ingredient: testosterone undecanoate and the non-active substance, castor
oil- hydrogenated and propylene glycol monolaurate.
The soft capsule shell contains the non active substances: gelatin, glycerol, medium chain
triglycerides, lecithin, sunset yellow FCF CI15985 and printed with Opacode WB monogramming ink
NSP-78-18022 White (ARTG Proprietary Ingredient number 3883).A130501 V4
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PHARMACOLOGY
Pharmacological actions
Testosterone undecanoate (TU) is able to by-pass the liver via the lymphatic system and is therefore
orally bioavailable. TU is intended as a replacement therapy for those who have abnormally low levels
of natural testosterone. TU may induce a fall in LH and FSH levels to just above normal in
hypergonadotrophic hypogonadal patients and may decrease hyper-reactivity to gonadorelin
stimulation. However, there are also reports where there have been no changes or changes in the
opposite direction. It does not change the LH and FSH plasma levels in normal patients. Restoration
of testosterone levels towards normal is associated with a significant improvement in feelings of well
being.
TU has been shown to induce sexual maturation in agonadal boys.
Some increase in plasma oestriol is observed. In patients with a sub-normal prolactin response to
thyrotrophin releasing hormone (TRH), response is normalised during TU therapy. TU does not
change the response of the pituitary to luteinising hormone releasing hormone (LHRH) or to TRH; nor
does it cause any abnormal effects on haematological, blood biochemical or urinary parameters or on
the size and consistency of the prostate gland. Normal prolactin levels are not affected by TU
administration.
Pharmacokinetics
Following oral administration of Andriol Testocaps, an important part of the active substance
testosterone undecanoate is co-absorbed with the lipophilic solvent from the intestine into the
lymphatic system, thus circumventing the first-pass inactivation by the liver. During absorption
testosterone undecanoate is partly reduced to dihydrotestosterone undecanoate. From the lymphatic
system it is released into the plasma. In plasma and tissues both testosterone undecanoate and
dihydrotestosterone undecanoate are hydrolyzed to yield the natural male androgens testosterone and
dihydrotestosterone.
Single administration of 80-160 mg Andriol Testocaps leads to a clinically significant increase of total
plasma testosterone with peak levels of approximately 40nmol/L (Cmax), reached approximately 4-5
hours (tmax) after administration. Plasma testosterone levels remain elevated for at least 8 hours.
Testosterone and dihydrotestosterone are metabolised via the normal pathways. Excretion mainly
takes place via the urine as conjugates of etiocholanolone and androsterone.
Because of the new Andriol Testocaps presentation a new bioequivalence study was conducted. An
open-label, replicate, four period, cross-over trial was performed in 28 healthy postmenopausal
women aged 45-65 years, with a body mass index between 18 and 30 kg/m2
and testosterone levels
0.87 ng/mL. This study was designed to assess bioequivalence between TU administration in the
AndriolTestocaps and Andriolformulation, by comparing the AUC and Cmax of serum testosterone after
administration of both formulations.
The geometric least-squares mean values (CV%) of the pharmacokinetic parameters for testosterone
and baseline-corrected testosterone and the results of average bioequivalence testing are
summarized in Table 1. Based on Cmax and AUCof testosterone and baseline corrected testosterone,
average bioequivalence between TU in Andriol Testocaps and Andriol is concluded.A130501 V4
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Table 1: Bioequivalence testing between Andriol® Testocaps®
and Andriol®
Parameter
(units)
Andriol
Testocaps
Mean* (CV**)
(n=27)
Andriol
Mean* (CV**)
(n=27)
Ratio
AT/A
90%
confidence
interval
Acceptance
Range
Conclusion
Bioequivalence testing based on serum testosterone
Cmax
(ng/mL)
5.67 (27.25) 5.29 (40.50) 1.07 0.97 – 1.18 0.70 - 1.43 Bioequivalent
AUC0-tlast
(ng•h/mL)
26.73 (25.68) 28.00 (30.23) 0.95 0.92 – 1.00 0.80 - 1.25 Bioequivalent
Bioequivalence testing based on baseline corrected serum testosterone
Cmax
(ng/mL)
5.43 (28.25) 5.06 (41.75) 1.07 0.97 – 1.19 0.70 – 1.43 Bioequivalent
AUC0-tlast
(ng•h/mL)
21.42 (28.72) 22.93 (32.26) 0.93 0.89 - 0.98 0.80 – 1.25 Bioequivalent
* geometric least-squares means; ** coefficients of variation derived from SD of log-transformed values; AT:
Andriol Testocaps; A: Andriol; bioequivalent: 90% C.I. contained within the acceptance range.
Food Effect
An open label, single-center, two-way cross-over, food interaction study with Andriol Testocaps was
performed in 16 healthy postmenopausal women aged 45-65 years, with a body mass index between
18 and 30 kg/m2
and testosterone levels 1.0 ng/mL. This study was designed to assess the effect of
food on the bioavailability of testosterone (as measured by Cmax and AUC) after a single administration
of Andriol Testocaps.
Following administration of Andriol Testocaps in the fasted state a poor bioavailability of testosterone
was observed, which was considerably increased when Andriol Testocaps was taken with food (see
Figure 1). Food-effect testing based on Cmax and AUC0-t
last of testosterone as well as baselinecorrected testosterone confirmed the presence of a food effect (see Table 2). This leads to the
conclusion that Andriol Testocaps must be taken with a meal.
Testosterone concentration vs time
0
2
4
6
8
10
12
14
16
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 20 22 24
time (h)
T (ng/mL)
80mg TU Fed
80mg TU Fasted
Figure 1: Mean Testosterone Concentration-Versus-Time Curve .A130501 V4
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Table 2: Summary of food-effect testing
Compound Parameter
(unit)
Mean Fed
(n=16)
Mean Fasted
(n=16)
Ratio
Fed/Fasted
90 % CI Conclusion
T Cmax (ng/mL) 10.32 0.5095 20.26 15.47-26.54 Food-effect
present
AUC0-t
last
(ngh/mL)
53.14 4.227 12.57 9.05-17.46 Food-effect
present
Baselinecorrected T
Cmax (ng/mL) 10.15 0.2876 35.30 24.00-51.91 Food-effect
present
AUC0-t
last
(ngh/mL)
49.00 0.9402 52.11 30.94-87.76 Food-effect
present
Means are geometric least-squares means; T: testosterone
Food-effect present: 90% C.I. outside acceptance range 0.80-1.25
INDICATIONS
Androgen replacement therapy for confirmed testosterone deficiency in males.
CONTRAINDICATIONS
Like any androgen therapy testosterone undecanoate is contraindicated in male patients with known or
suspected carcinoma of the prostate gland or breast. Patients with nephrosis or nephrotic phase of
nephritis. Andriol Testocaps should not be used in case of known hypersensitivity to the active
substance or any of the excipients.
PRECAUTIONS
The following precautions are common to all testosterone containing preparations:
1. Patients with myocardial or renal dysfunction, hypertension, migraine, diabetes mellitus or
epilepsy (or a history of these conditions) should be observed carefully, since androgen therapy
may cause fluid retention.
2. Conditions which may be aggravated by the possible fluid retention or oedema caused by
Andriol Testocaps.
3. Androgen use in prepubertal boys should be cautious and monitored carefully to avoid the
possibility of premature epiphyseal fusion, or precocious sexual development. Skeletal
maturation should be monitored regularly.
4. Patients with psychological disturbances should be cautiously treated since suicide due to
treatment-aggravated depression has been reported.
5. The size and consistency of the prostate should be monitored periodically.
Andriol Testocaps contains Sunset Yellow FCF (E110, FD&C Yellow No. 6) which may cause allergic
reactions.
Medical examination:
Physicians should consider monitoring patients receiving Andriol Testocaps before the start of
treatment, at quarterly intervals for the first 12 months and yearly thereafter for the following
parameters:
Digital rectal examination (DRE) of the prostate and PSA to exclude benign prostate
hyperplasia or a sub-clinical prostate cancer.
Hematocrit and hemoglobin to exclude polycythemia. A130501 V4
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Conditions that need supervision:
Patients, especially the elderly, with the following conditions should be monitored for:
Tumours – Mammary carcinoma, hypernephroma, bronchial carcinoma and skeletal
metastases. In these patients hypercalcemia may develop spontaneously, also during
androgen therapy. The latter can be indicative of a positive tumour response to the
hormonal treatment. Nevertheless, the hypercalcemia should first be treated
appropriately and after restoration of normal calcium levels, hormone therapy can be
resumed.
Pre-existing conditions – In patients with pre-existing cardiac, renal or hepatic
insufficiency/disease androgen treatment may cause complications characterized by
edema with or without congestive heart failure. In such cases treatment must be
stopped immediately.
Patients who experienced myocardial infarction, cardiac-, hepatic- or renal
insufficiency, hypertension, epilepsy, or migraine should be monitored due to the risk
of deterioration of or reoccurrence of disease. In such cases treatment must be
stopped immediately.
Diabetes mellitus – Androgens in general and Andriol Testocaps can improve the
glucose tolerance in diabetic patients.
Anti-coagulant therapy – Androgens in general and Andriol Testocaps can enhance
the anti-coagulant action of coumarin-type agents.
Sleep Apnea –There is insufficient evidence for a recommendation regarding the
safety of treatment with testosterone esters in men with sleep apnea. Good clinical
judgment and caution should be employed in patients with risk factors such as
adiposity or chronic lung diseases.
Adverse events
If androgen-associated adverse reactions occur, treatment with Andriol Testocaps should be
discontinued and, upon resolution of complaints, resumed with a lower dose.
(Mis)use in sports
Patients who participate in competitions governed by the World Anti-Doping Agency (WADA) should
consult the WADA-code before using this product as Andriol Testocaps can interfere with anti-doping
testing. The misuse of androgens to enhance ability in sports carries serious health risks and is to be
discouraged.
Effects on fertility
In men treatment with androgens can lead to fertility disorders by repressing sperm-formation.
Use in Pregnancy (Category D)
This drug is not intended for use in female patients and is contraindicated in pregnancy. Androgenic
substances may have a virilising effect on the female foetus and should be avoided during pregnancy.
Use in Lactation
This drug is not intended for use in female patients.
Paediatric Use:
In pre-pubertal children statural growth and sexual development should be monitored since androgens
in general and Andriol Testocaps in high dosages may accelerate epiphyseal closure and sexual
maturation.A130501 V4
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Carcinogenicity/ Mutagenicity
The potential carcinogenicity of testosterone has been tested by subcutaneous injection and
implantation in mice and rats. In mice, the implant induced cervical uterine tumours, which
metastasized in some cases. There is suggestive evidence that injection of testosterone in some
strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to act
as a tumour promoter and has been shown to increase the number of tumours and decrease the
degree of differentiation of chemically induced carcinomas in the liver of rats. There are rare reports of
hepatocellular carcinoma in patients receiving long term therapy with androgens, particularly the 17-
alpha-alkyl-androgens, in high doses. Withdrawal of the drugs did not lead to regression of the
tumours in all cases. Whether there is a causal relationship or a connection between testosterone
administration and formation of tumours occurring by chance remains unclarified. Chronic and
androgen deficiency, however, is a protective factor for prostatic disease and hypogonadal men
receiving androgen replacement therapy require surveillance for prostate disease similar to that
recommended for eugonadal men of comparable age. Geriatric patients treated with androgens may
be at an increased risk for the development for prostatic hyperplasia and prostatic cancer. However,
there is no clear understanding of the formation and progression of prostatic carcinoma nor of the role
of androgens.
Effect on laboratory tests
Androgens may decrease levels of thyroxine-binding globulin resulting in decreased total T4 serum
levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged,
however, and there is no clinical evidence of thyroid dysfunction.
INTERACTIONS WITH OTHER MEDICINES
Enzyme inducing agents such as barbiturates, may exert decreasing effects on testosterone levels.
Enzyme-inhibiting drugs may increase testosterone levels. Therefore adjustment of the dose of Andriol
may be necessary. Andriol may potentiate the effects of cyclosporin and increase the risk of
nephrotoxicity.
Androgens may improve glucose tolerance and thereby in diabetic patients decrease the need for
insulin or other antidiabetic drugs. Patients with diabetes mellitus should therefore be monitored
especially at the beginning or end of treatment and at periodic intervals during Andriol Testocaps
treatment. High doses of androgens may enhance the anti-coagulant action of coumarin-type agents.
Therefore close monitoring of prothrombin time, and if necessary a dose reduction of the anticoagulant is required during therapy.
The concurrent administration of testosterone with ACTH or corticosteroids may enhance oedema
formation; thus these active substances should be administered cautiously, particularly in patients with
cardiac or hepatic disease or in patients predisposed to oedema.
Andriol may interfere with a number of clinical laboratory tests e.g. those for glucose tolerance and
thyroid function, suppression of clotting factors II, V, VII and X.
ADVERSE EFFECTS
Andriol is generally well tolerated. Very few side effects have been associated with the clinical use of
testosterone undecanoate.
Gastrointestinal complaints Common: (1 to 10%) oily stools. However, these side effects were
attributed to the oily solvent and were not considered serious; Uncommon: (0.1 to 1%) nausea.
Genitourinary Disorders Rare: (< 0.1%) priapism, epididymitis, bladder irritability, gynaecomastia,
impotence, inhibition of testicular function and testicular atrophy. It is possible that prolonged
administration of testosterone undecanoate may induce oligospermia, or decreased ejaculatory
volume, which are reversible upon cessation of the drug.
Blood Disorders Rare: (< 0.1%) leukocytosis, polycythemia and Serum cholesterol concentration
may increase during androgen therapy. It is possible that prolonged administration of testosterone
undecanoate may induce sodium and water retention.A130501 V4
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Neurological Disorders: Rare: (<0.1%) generalised paraesthesia, insomnia, excitation, headache,
anxiety, mental depression (see PRECAUTIONS).
Hypersensitivity and Skin Disorders Uncommon: (0.1 to 1.0%) chills, maculopapular rash, acne,
flushing of skin.
Others Frequency unknown:
Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Prostatic cancer (progression
of a sub-clinical prostatic cancer)
Psychiatric disorders: Nervousness, Mood altered, Libido increased, Libido decreased
Vascular disorders: Hypertension
Hepatobiliary disorders: Hepatic function abnormal
Skin and subcutaneous tissue disorders: Pruritus
Musculoskeletal and connective tissue disorders: Myalgia
Reproductive system and breast disorders: Benign prostatic hyperplasia (prostatic growth to
normogonadal size)
Investigations: Lipids abnormal (decrease in serum LDL-C, HDL-C and triglycerides), PSA increased
The terms used to describe the undesirable effects above are also meant to include synonyms and
related terms.
These symptoms are remedied by a pause in treatment after which therapy should be resumed at a
lower dosage.
In a few patients diarrhoea and abdominal pain / discomfort have been reported during use of Andriol
Testocaps.
Paediatric population:
The following undesirable effects have been reported in pre-pubertal children using androgens (see
Precautions): precocious sexual development, an increased frequency of erections, phallic
enlargement and premature epiphyseal closure.
DOSAGE AND ADMINISTRATION
Adults including elderly
Andriol Testocaps must be taken orally with the morning and evening meal. The capsules should be
taken with some fluid and swallowed whole without chewing. If an uneven number of capsules are to
be taken, the greater dose should be taken in the morning. The dosage of Andriol Testocaps should
be determined by the physician according to the severity of the symptoms. The initial dose is usually
120-160 mg/day for 2-3 weeks. Subsequent dosage (40-120 mg/day) should be based on the clinical
effect obtained in the first weeks of therapy. Responses to dosage should be more closely monitored
in those patients referred to under the heading PRECAUTIONS.
In general the dose should be adjusted according to the response of the individual patient.
Paediatric population
Safety and efficacy have not been adequately determined in children and adolescents. Pre-pubertal
children treated with Andriol Testocaps should be treated with caution.
OVERDOSAGE
The acute oral toxicity of testosterone undecanoate is very low. High dosages of Andriol Testocaps
may cause gastrointestinal complaints due to the oily solvent contained in the capsule. Treatment may
consist of emptying the stomach and supportive measures.
Contact the Poisons Information Centre for advice regarding management of overdose.A130501 V4
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PRESENTATION AND STORAGE CONDITIONS
Andriol Testocaps testosterone undecanoate 40mg = testosterone 25mg (orange, soft gelatin, marked
DV3 ORG): 30’s*, 60’s, 120’s*.
* Some pack sizes may not be currently marketed.
Storage and Shelf Life
Three years, store below 30°C. Do not refrigerate.
Keep the blister in the outer carton to protect from light.
POISONS SCHEDULE OF THE MEDICINE
Schedule 4 – Prescription Medicine
NAME AND ADDRESS OF THE SPONSOR IN AUSTRALIA
Merck Sharp & Dohme (Australia) Pty Limited
54-68 Ferndell Street
South Granville NSW 2142
Australia
NAME AND ADDRESS OF THE SPONSOR IN NEW ZEALAND
Merck Sharp & Dohme (New Zealand) Ltd
P O Box 99 851
Newmarket
Auckland 1149
New Zealand
AUST R 92904
Date of first inclusion in the Australian Register of Therapeutic Goods (the ARTG): 14 July 2003
Date of most recent amendment: 01 May 2013