Each vial contains 1000 mg testosterone undecanoate (corresponding to 631.5 mg testosterone) in a 4-ml solution for injection (250 mg testosterone undecanoate/ml).
Excipients/Inactive Ingredients: Benzyl benzoate, Refined castor oil (for parenteral use).
Pharmacotherapeutic group: Androgens, 3-oxoandrosten (4) derivatives. ATC code: G03B A03.
Pharmacology: Pharmacodynamics: Testosterone undecanoate is an ester of the naturally occurring androgen, testosterone. The active form, testosterone, is formed by cleavage of the side chain.
Pharmacokinetics: Absorption: Nebido is an intramuscularly administered depot preparation of testosterone undecanoate and thus circumvents the first-pass effect. Following intramuscular injection of testosterone undecanoate as an oily solution, the compound is gradually released from the depot and is almost completely cleaved by serum esterases into testosterone and undecanoic acid.
Distribution: In male serum, around 98% of circulating testosterone is bound to sex hormone-binding globulin (SHBG) and albumin. Only the unbound fraction of testosterone is considered biologically active. Following the intravenous infusion of testosterone in elderly men, the elimination half-life was approximately one hour and the apparent volume of distribution about 1.0 L/kg.
Metabolism: Testosterone which is generated by ester cleavage from testosterone undecanoate is metabolized and excreted the same way as endogenous testosterone.
Elimination: Testosterone undergoes extensive hepatic and extrahepatic metabolism. After the administration of radiolabeled testosterone, about 90% of the radioactivity appears in the urine as glucuronic and sulphuric acid conjugates and 6% appears in the feces after undergoing enterohepatic circulation. Urinary products include androsterone and etiocholanolone.
Steady-state conditions: Following repeated i.m. injection of 1000 mg testosterone undecanoate to hypogonadal men using an interval of 10 weeks between two injections, steady-state conditions were achieved between the 3rd and the 5th administration. Mean Cmax and Cmin values of testosterone at steady-state were about 42 and 17 nmol/l, respectively. Post-maximum testosterone levels in the serum decreased with a half-life of about 90 days, which corresponds to the release rate from the depot.
Toxicology: Preclinical safety data: Toxicological studies have not revealed other effects than those which can be explained based on the hormone profile of Nebido.
Testosterone has been found to be non-mutagenic in vitro using the reverse mutation model (Ames test) or hamster ovary cells. A relationship between androgen treatment and certain cancers has been found in studies on laboratory animals. Experimental data in rats have shown increased incidences of prostate cancer after treatment with testosterone.
Sex hormones are known to facilitate the development of certain tumours induced by known carcinogenic agents. The clinical relevance of the latter observation is not known.
Fertility studies in rodents and primates have shown that treatment with testosterone can impair fertility by suppressing spermatogenesis in a dose dependent manner.
Testosterone replacement in primary and secondary male hypogonadism.
Method of administration: Solution for injection.
Dosage regimen: Nebido (1 vial corresponding to 1000 mg testosterone undecanoate) is injected every 10 to 14 weeks. Injections with this frequency are capable of maintaining sufficient testosterone levels and do not lead to accumulation.
The injections must be administered very slowly. Nebido is strictly for intramuscular injection. Special care must be given to avoid intravasal injection. See Instructions for use/handling under Cautions for Usage to avoid injury when opening.
Start of treatment: Serum testosterone levels should be measured before start of treatment. The first injection interval may be reduced to a minimum of 6 weeks. With this loading dose, steady-state levels will be reached quickly.
Individualization of treatment: It is advisable to measure testosterone serum levels occasionally 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. The injection interval should remain within the recommended range of 10 to 14 weeks.
Additional information on special populations: Children and adolescents: Nebido is not indicated for use in children and adolescents and it has not been clinically evaluated in males under 18 years of age (see Precautions).
Geriatric patients: Limited data do not suggest the need for a dosage adjustment in elderly patients (see Precautions).
Patients with hepatic impairment: No formal studies have been performed in patients with hepatic impairment. The use of Nebido is contraindicated in men with past or present liver tumors (see Contraindications).
Patients with renal impairment: No formal studies have been performed in patients with renal impairment.
No special therapeutic measure apart from termination of therapy with the drug or dose reduction is necessary after overdosage.
Androgen-dependent carcinoma of the prostate or of the male mammary gland.
Hypercalcemia accompanying malignant tumors.
Past or present liver tumors.
Hypersensitivity to the active substance or to any of the excipients.
The use of Nebido in women is contraindicated.
Older patients treated with androgens may be at an 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.
As a precaution, regular examinations of the prostate are recommended in men.
Testosterone replacement therapy should only be given to men when deficiency of the hormone has been confirmed by clinical features and biochemical tests. Testosterone levels should then be monitored regularly during treatment. Haemoglobin, haematocrit, liver function and blood lipid profile should also be monitored regularly.
Hemoglobin and haematocrit should be checked periodically in patients on long-term androgen therapy to detect cases of polycythemia (see Adverse Reactions).
As a general rule, the limitations of using intramuscular injections in patients with acquired or inherited bleeding disorders must always be observed. Testosterone and derivatives have been reported to increase the effect of coumarin derived anticoagulants (see also Interactions).
Venous Thromboembolism: There have been post-marketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products such as Nebido. Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with Nebido and initiate appropriate workup and management. Caution is advised when testosterone is used in patients with thrombophilia, as cases of thrombosis have been reported among this patient group during therapy with testosterone in post-marketing studies and reports.
Cases of benign and malignant liver tumors have been reported in users of hormonal substances, such as androgen compounds. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal hemorrhage occur in men using Nebido, a liver tumor should be included in the differential-diagnostic considerations.
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 (see Adverse Reactions). In such a case, treatment must be stopped immediately.
Caution is advised in patients with pre-existing hypertension, since testosterone may cause an increase in blood pressure. Clinical trials with Nebido in children or adolescents under the age of 18 have so far not been conducted.
In children testosterone, besides masculinization, can cause accelerated growth and bone maturation and premature epiphyseal closure, thereby reducing final height. The appearance of common acne has to be expected.
There is limited experience on the safety and efficacy of the use of these medicines in patients over 65 years of age. It should be borne in mind that physiological testosterone levels naturally decrease somewhat with age.
Preexisting sleep apnea may be potentiated.
Androgens are not suitable for enhancing muscular development in healthy individuals or for increasing physical ability.
As with all oily solutions, Nebido must be injected strictly intramuscularly and very slowly. Pulmonary microembolism of oily solutions can in rare cases lead to signs and symptoms such as cough, dyspnea, malaise, hyperhydrosis, chest pain, 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 supplemental oxygen.
Suspected anaphylactic reactions after Nebido injection have been reported.
Pregnancy: Not applicable.
Lactation: Not applicable.
Fertility: Testosterone replacement therapy may reversibly reduce spermatogenesis (see Adverse Reactions and Pharmacology: Toxicology: Preclinical safety data under Actions).
Regarding undesirable effects associated with the use of androgens, please also refer to Precautions.
The most frequently reported undesirable effects during treatment with Nebido are acne and injection site pain.
The table as follows reports adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs)* reported with Nebido. The frequencies are based on clinical trial data and defined as Common (≥1/100 to <1/10) and Uncommon (≥1/1000 to <1/100). The ADRs were recorded in 6 clinical studies (N=422) and considered at least possibly causally related to Nebido.
Tabulated list of adverse reactions:
Click on icon to see table/diagram/image
Description of selected adverse reactions:
Pulmonary microembolism of oily solutions can in rare cases lead to signs and symptoms such as cough, dyspnea, malaise, hyperhydrosis, chest pain, dizziness, paresthesia, or syncope. These reactions may occur during or immediately after the injections and are reversible. Cases suspected by the company or the reporter to represent oily pulmonary microembolism have been reported rarely in clinical trials (in ≥ 1/10,000 and < 1/1,000 injections) as well as from postmarketing experience (see Precautions).
Suspected anaphylactic reactions after Nebido injection have been reported.
In addition to the previously mentioned adverse reactions, nervousness, hostility, sleep apnea, various skin reactions including seborrhoea, increased hair growth, increased frequency of erections and in very rare cases jaundice have been reported under treatment with testosterone containing preparations.
Therapy with high doses of testosterone preparations commonly reversibly interrupts or reduces spermatogenesis, thereby reducing the size of the testicles; testosterone replacement therapy of hypogonadism can in rare cases cause persistent, painful erections (priapism). High-dosed or long-term administration of testosterone occasionally increases the occurrences of water retention and edema.
Drugs that affect testosterone: Barbiturates and other enzyme inducers: Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of testosterone.
Effects of androgens on other drugs: Oxyphenbutazone: Increased oxyphenbutazone serum levels have been reported.
Oral anticoagulants: Testosterone and its derivatives have been reported to increase the activity of oral coumarin-based anticoagulants. Patients receiving oral anti-coagulants required close monitoring, especially at the beginning or end of androgen therapy. Increased monitoring of the prothrombin time, and INR determinations, are recommended.
Hypoglycaemics: Androgens may enhance the blood sugar reducing effects of insulin. Therefore, the dosage of hypoglycaemic agents may need to be lowered.
Instructions for use/handling: Vial: The vial is for single use only.
The content of a vial are to be injected intramuscularly immediately after opening the vial.
The solution for intramuscular injection should be visually inspected prior to use; only clear, particle-free solutions may be used. This medicinal product is intended for single use only. Any remaining unused portions must be disposed of in accordance with local requirements.
G03BA03 - testosterone ; Belongs to the class of 3-oxoandrosten (4) derivative androgens used in androgenic hormone preparations.
Soln for inj (vial) 1000 mg/4 mL (clear, yellowish oily solution) x 1's.