Axelus 200 mg/ml Solution for Injection is indicated for replacement therapy in the male in conditions associated with symptoms of deficiency or absence of endogenous testosterone.

1.  Primary hypogonadism (congenital or acquired)-testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome; or orchidectomy.

2.  Hypogonadotropic hypogonadism (congenital or acquired) - gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation.

Safety and efficacy of testosterone cypionate in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.

Do not use Axelus in the following:

• Known hypersensitivity to the drug (testosterone cypionate) or to any of the excipients listed in section 6.
• Males with carcinoma of the breast.
• Males with known or suspected carcinoma of the prostate gland.
• Women who are pregnant (see “Pregnancy and breast-feeding”).
• Patients with serious cardiac, hepatic or renal disease (see “Warnings and precautions”).

Warnings and precautions

Warnings

Hypercalcemia may occur in immobilized patients. If this occurs, the drug should be discontinued.

Prolonged use of high doses of androgens (principally the 17-α alkyl-androgens) has been associated with development of hepatic adenomas, hepatocellular carcinoma, and peliosis hepatis-all potentially life-threatening complications.

Geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostatic carcinoma although conclusive evidence to support this concept is lacking.

There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as testosterone cypionate. 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 testosterone cypionate and initiate appropriate workup and management.

Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use Axelus (testosterone cypionate).

Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions.

If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.

Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal or hepatic disease.

Gynecomastia may develop and occasionally persists in patients being treated for hypogonadism.

Androgen therapy should be used cautiously in healthy males with delayed puberty. The effect on bone maturation should be monitored by assessing bone age of the wrist and hand every 6 months. In children, androgen treatment may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may result in compromised adult stature. The younger the child the greater the risk of compromising final mature height.

Testosterone cypionate has not been shown to be safe and effective for the enhancement of athletic performance. Because of the potential risk of serious adverse health effects, this drug should not be used for such purpose.

Precautions

General

Patients with benign prostatic hypertrophy may develop acute urethral obstruction. Priapism or excessive sexual stimulation may develop. Oligospermia may occur after prolonged administration or excessive dosage. If any of these effects appear, the androgen should be stopped and if restarted, a lower dosage should be utilized.

Testosterone cypionate should not be used interchangeably with testosterone propionate because of differences in duration of action.

Testosterone cypionate is not for intravenous use.

Information for patients

Patients should be instructed to report any of the following: nausea, vomiting, changes in skin color, ankle swelling, too frequent or persistent erections of the penis.

Laboratory tests

Hemoglobin and hematocrit levels (to detect polycythemia) should be checked periodically in patients receiving long-term androgen administration.

Serum cholesterol may increase during androgen therapy.

Drug/Laboratory test Interferences

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.

Carcinogenesis

• Animal data

Testosterone has been tested by subcutaneous injection and implantation in mice and rats.

The implant induced cervical-uterine tumors in mice, which metastasized in some cases.

• Human Data

There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases.

Geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostatic carcinoma although conclusive evidence to support this concept is lacking.

Pediatric use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

Other medicines and Axelus

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

Androgens may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may require reduction in order to maintain satisfactory therapeutic hypoprothrombinemia.

Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.

In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements.

Pregnancy and breast-feeding

Pregnancy

Teratogenic effects

The use of testosterone in women who are pregnant is contraindicated. Testosterone is teratogenic and may cause fetal harm. Testosterone is known to cause virilization of the female fetus when administrated to pregnant women.

Benzyl alcohol can cross the placenta. See “Axelus contains benzyl alcohol”.

Nursing mothers

Axelus is not recommended for use in nursing mothers.

Axelus contains benzyl alcohol

Axelus contains benzyl alcohol. Axelus 200 mg/ml Solution for Injection contains 9.45 mg benzyl alcohol in each ml:

• Benzyl alcohol may cause allergic reactions. 
• Ask your doctor or pharmacist for advice if you have a liver or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may cause side effects (called “metabolic acidosis”).

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Prior to initiating Axelus (testosterone cypionate), confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range.

Axelus 200 mg/ml Solution for Injection is for intramuscular use only.

It should not be given intravenously. Intramuscular injections should be given deep in the gluteal muscle.

The suggested dosage for Axelus 200 mg/ml Solution for Injection varies depending on the age, sex, and diagnosis of the individual patient. Dosage is adjusted according to the patient’s response and the appearance of adverse reactions.

Various dosage regimens have been used to induce pubertal changes in hypogonadal males; some experts have advocated lower dosages initially, gradually increasing the dose as puberty progresses, with or without a decrease to maintenance levels. Other experts emphasize that higher dosages are needed to induce pubertal changes and lower dosages can be used for maintenance after puberty. The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose.

For replacement in the hypogonadal male, 50-400 mg should be administered every two to four weeks.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Warming and shaking the vial should redissolve any crystals that may have formed during storage at temperatures lower than recommended.

Pediatric use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

If you use more Axelus than you should

There have been no reports of acute overdosage with the androgens.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following adverse reactions in the male have occurred with some androgens:

• Endocrine and urogenital: Gynecomastia and excessive frequency and duration of penile erections. Oligospermia may occur at high dosages.
• Skin and appendages: Hirsutism, male pattern of baldness, seborrhea, and acne.
• Cardiovascular Disorders: myocardial infarction, stroke.
• Fluid and electrolyte disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates.
• Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, rarely hepatocellular neoplasms and peliosis hepatis (see “Warnings and precautions”).
• Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia.
• Nervous system: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia.
• Allergic: Hypersensitivity, including skin manifestations and anaphylactoid reactions.
• Vascular disorders: Venous thromboembolism.
• Special senses: Rare cases of central serous chorioretinopathy (CSCR).
• Miscellaneous: Inflammation and pain at the site of intramuscular injection.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, health care provider or pharmacist.

Keep this medicine out of the sight and reach of children.

Do not store above 30°C.

Protect from light.

Store in the original package.

Do not use this medicine after the expiry date which is stated on the package after “EXP”. The expiry date refers to the last day of that month.

Do not use this medicine if you notice any visible signs of deterioration.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.