Drug Description
Each film-coated tablet contains 25 mg of agomelatine.Excipient: lactose monohydrate 61.84 mg

Presentation
Film-coated tablet [tablet].Orange-yellow, oblong, film-coated tablet with blue imprint of company logo on one side.

Indications
Treatment of major depressive episodes in adultsValdoxan is indicated in adults.

Adult Dosage
For cutaneous useAdults and Elderly MenThe recommended starting dose of Tostran is 3 g gel (60 mg of testosterone) applied once daily at approximately the same time each morning. Dose titration should be based on both serum testosterone levels and the existence of clinical signs and symptoms related to androgen deficiency. It should be taken into account that physiological testosterone levels decline with increasing age.The daily dose should not exceed 4 g of gel (80 mg testosterone).The dose can be applied to the abdomen (entire dose over an area of at least 10 by 30 cm), or to both inner thighs (one half of the dose over an area of at least 10 by 15 cm for each inner thigh). Daily rotation between the abdomen and inner thighs is recommended to minimise application site reactions.The gel should be applied to clean, dry, intact skin. It should be rubbed in gently with one finger until dry, then the application site should be covered, preferably with loose clothing. Hands should then be washed with soap and water.Each full depression of the canister piston delivers one half gram of gel (10 mg testosterone). To obtain a full first dose, it is necessary to prime the canister pump. To do so, with the canister in the upright position, slowly and fully depress the actuator 8 times to ensure that the pump is fully primed. The first few depressions may result in no discharge of gel. Discard the gel dispensed during priming (i.e., from the first eight depressions). It is only necessary to prime the pump before the first dose. The canister should be stored in an upright position between use.In Table 1 below the amount of gel dispensed once the pump is primed and the amount of testosterone which would be applied to the skin from a number of piston depressions are shown.TABLE 1: DOSE OF TOSTRAN DISPENSED AFTER PUMP PRIMINGNo of DepressionsAmount of Gel (g)Amount of Testosterone Applied to the Skin (mg)10.5102120424063608480Patients who wash in the morning should apply Tostran after washing, bathing or showering.Tostran must not be applied to the genitals.Treatment ControlSerum testosterone concentration should be measured approximately 14 days after initiation of therapy to ensure proper dosing. The blood sample for measurement of serum testosterone level should be obtained 2 hours after application of Tostran. If the serum testosterone concentration is between 5.0 and 15.0 µg/l, the dose should not be changed from 3 g/day. If the serum testosterone concentration is below 5.0 µg/l, the dose should be increased to 4 g/day (80 mg testosterone). If the testosterone concentration is above 15.0 µg/l, the dose should be reduced to 2 g/day (40 mg testosterone). Smaller 0.5 g gel (10 mg testosterone) dosage adjustment may be made if necessary.Because of the variability in analytical values amongst diagnostic laboratories, all testosterone measurements should be performed in the same laboratory.There is limited experience of treating men older than 65 years of age with Tostran.No formal studies have been conducted with the product in patients with renal or hepatic impairment.Children Tostran is not indicated for use in children and has not been clinically eva luated in males under 18 years of age.

Child Dosage
Valdoxan is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.

Elderly Dosage
Efficacy has not been clearly demonstrated in the elderly ( 65 years). Only limited clinical data is available on the use of Valdoxan in elderly patients 65 years old with major depressive episodes. Therefore, caution should be exercised when prescribing Valdoxan to these patients.

Contra Indications
Tostran 2% Gel is contraindicated in patients with:known or suspected carcinoma of the breast or the prostate known hypersensitivity to testosterone or any of the excipients

Special Precautions
Tostran should not be used to treat non-specific symptoms suggestive of hypogonadism if testosterone deficiency has not been demonstrated and if other aetiologies responsible for the symptoms have not been excluded. Testosterone deficiency should be clearly demonstrated by clinical features and confirmed by two separate blood testosterone measurements before initiating therapy with any testosterone replacement, including Tostran treatment.For the time being there is no consensus concerning age specific reference values for testosterone. However it should be taken into consideration that the physiological serum levels of testosterone decrease with age.To ensure proper dosing, serum testosterone concentrations should be measured.Tostran is not indicated for treatment of male sterility or sexual impotence.Prior to initiation of testosterone replacement therapy, all patients must undergo a detailed examination in order to exclude a risk of pre-existing prostatic cancer. Careful and regular monitoring of the prostate gland and breast must be performed in accordance with recommended methods (digital rectal examination and estimation of serum prostate specific antigen (PSA)) in patients receiving testosterone therapy at least annually and twice yearly in elderly patients and at risk patients (those with clinical or familial factors).Androgens may accelerate the progression of sub-clinical prostatic cancer and benign prostatic hyperplasia.Oedema with or without congestive heart failure may be a serious complication in patients with pre-existing cardiac, renal or hepatic disease. The treatment must be discontinued immediately if such complications occur. In addition, diuretic therapy may be required.There are no studies undertaken to demonstrate the efficacy and safety of this medicinal product in patients with renal or hepatic impairment. Therefore, testosterone replacement therapy should be used with caution in these patients.The treatment of hypogonadal men with testosterone may potentiate sleep apnoea in some patients, especially those with risk factors such as obesity or chronic lung disease.The following checks should be carried out periodically: full blood count (including haemoglobin and haematocrit to detect polycythaemia), lipid profile and liver function tests.Care should be taken in patients with skeletal metastases due to the risk of hypercalcaemia/hypercalcuria developing from androgen therapy. Regular monitoring of the serum levels of calcium in these patients is recommended.Testosterone may cause a rise in blood pressure and Tostran should be used with caution in men with hypertension.Tostran should be used with caution in patients with ischemic heart disease, epilepsy and migraine as these conditions may be aggravated.Improved insulin sensitivity may occur in patients treated with androgens who achieve normal testosterone plasma concentrations following replacement therapy.General: certain clinical signs may indicate excessive androgen exposure requiring dosage adjustment. The physician should instruct patients to report any of the following:Irritability, nervousness, weight gain. Too frequent or persistent erections of the penis. Any nausea, vomiting, changes in skin colour or ankle swelling. Breathing disturbances, including those associated with sleep. If the patient develops a severe application site reaction, treatment should be reviewed and discontinued if necessary.Athletes should be informed that Tostran contains an active substance (testosterone), which may give positive results in a doping test. Androgens are not suitable for enhancing muscular development in healthy individuals or for increasing physical ability.Tostran should not be used in women due to possible virilising effects.Potential for transferIf no precautions are taken, testosterone gel can be transferred to other persons by close skin to skin contact, resulting in increased testosterone serum levels and possibly adverse effects (e.g. growth of facial and/or body hair, deepening of the voice, irregularities of the menstrual cycle) in case of repeat contact (inadvertent androgenisation).The physician should inform the patient carefully about the risk of testosterone transfer and about safety instructions (see below). Tostran should not be prescribed in patients with a major risk of non-compliance with safety instructions (e.g. severe alcoholism, drug abuse, severe psychiatric disorders).This transfer is avoided by wearing clothes covering the application area or bathing or showering prior to contact.As a result, the following precautions are recommended:For the patient:wash hands with soap and water after applying the gel, over the application area with clothing once the gel has dried, bathe or shower before any situation in which this type of contact is foreseen. For the health care professional or carer:disposable gloves should be used if a health care professional or carer needs to apply the testosterone gel to the patient, the disposable gloves should be resistant to alcohols as the gel contains both ethanol and isopropyl alcohol, which facilitate the penetration of testosterone. For people not being treated with Tostran:in the event of contact with an application area which has not been washed or is not covered with clothing, wash the area of skin onto which testosterone may have been transferred as soon as possible, using soap and water, report the development of signs of excessive androgen exposure such as acne or hair modification. To guarantee partner safety the patient should be advised for example to observe a minimum of four hours between Tostran application and sexual intercourse, to wear clothing covering the application site, during contact period or to bathe or shower before sexual intercourse.Furthermore, it is recommended to wear clothing covering the application site during contact periods with children, in order to avoid a risk of contamination to children's skin.Pregnant women must avoid contact with Tostran application sites. In case of pregnancy of a partner, the patient must take extra care with the precautions for use described above.Absorption studies of testosterone conducted in patients treated with Tostran indicate that patients should wait at least two hours between gel application and bathing or showering.Tostran contains butylhydroxytoluene (E321) which may cause local skin reactions (eg contact dermatitis) or irritation of the eyes and mucous membranes. Tostran contains propylene glycol which may cause skin irritation.

Interactions
When androgens are given simultaneously with anticoagulants, the anticoagulant effect can increase. Patients receiving oral anticoagulants require close monitoring of their INR especially when the androgen treatment is started, stopped or the dose of Tostran changed.The concurrent administration of testosterone with ACTH or corticosteroids may increase the likelihood of oedema; thus these drugs should be administered with caution, particularly in patients with cardiac, renal or hepatic disease.Laboratory test interactions: Androgens may decrease concentrations of thyroxin-binding globulin, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4. Free thyroid hormone concentrations remain unchanged however, and there is no clinical evidence of thyroid dysfunction.

Adverse Reactions
The most commonly reported adverse reactions in a controlled clinical study (up to 4 g Tostran) were application site reactions (ASR; 26%) including; paresthesia, xerosis, pruritus and rash or erythema. The majority of these reactions were mild to moderate in severity and diminished or cleared, despite continued application.All adverse reactions reported with a suspected relationship are listed by class and frequency (very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100) and rare ( 1/10,000 to < 1/1,000)).Organ SystemVery Common( 1/10)Common( 1/100 to < 1/10)Blood and lymphatic system disordersIncrease in haemoglobin and haematocritEndocrine disordersIncrease in male pattern hair distributionVascular disordersHypertensionReproductive system and breast disordersGynaecomastiaGeneral disorders and administration site conditionsAdministration site reactionsPeripheral oedemaInvestigationsIncreased PSAHyperglycaemia was reported as an adverse event in two patients with a history of diabetes mellitus.Gynaecomastia develops in 1.5% of patients being treated with testosterone for hypogonadism and occasionally persists.According to the literature, other known undesirable effects have been reported following testosterone treatment and are listed in the following table:Organ SystemAdverse reactionsMetabolism and nutrition disordersWeight gain, electrolyte changes (retention of sodium, chloride, potassium, calcium, inorganic phosphate and water) during high dose and/or prolonged treatment.Nervous system disordersNervousness, hostility, depression.Respiratory, thoracic and mediastinal disordersSleep apnoeaGastrointestinal disordersNauseaHepatobiliary disordersIn very rare cases jaundice and liver function test abnormalities.Skin and subcutaneous tissue disordersVarious skin reactions may occur including acne, seborrhoea and balding (alopecia).Musculoskeletal and connective tissue disordersMuscle cramps, muscle painReproductive system and breast disordersLibido changes, increased frequency of erections; 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), prostate abnormalities, prostate cancer*, urinary obstruction.General disorders and administration site conditionsHigh dose or long-term administration of testosterone occasionally increases the occurrences of water retention and oedema; hypersensitivity reactions may occur.* Data on prostate cancer risk in association with testosterone therapy are inconclusive.Other rare known undesirable effects associated with excessive dosages of testosterone treatments include hepatic neoplasms.Because of the excipients (butylhydroxytoluene and propylene glycol) contained in the product, applications to the skin may cause irritation and dry skin which usually reduce over time.

Manufacturer
Servier Laboratories Limited

Updated
10 September 2010