SUMMARY OF PRODUCT CHARACTERISTICS

1 DENOMINATION OF THE MEDICINAL PRODUCT DELORAZEPAM ABC 1 mg/ml Oral drops, solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

DELORAZEPAM ABC 1 mg/ml Oral drops, solution 1 ml of solution contains: Active principle: delorazepam 1 mg

For the excipients, refer to 6.1.

3. Pharmaceutical form Oral drops, solution.

4. CLINIC INFORMATION 4.1 Therapeutical indications Dysphoria, Insomnia. The benzodiazepines are indicated only when the disorder is serious, disabling or the subject is submitted to serious uneasiness.

4.2 Posology and administration modality Anxiety trouble In general medicine -oral drops, solution: 13-26 drops, for 2-3 times a day.

In neuro-psychiatry - oral drops, solution: 26-50 drops, for 2-3 times a day.

The anxiety trouble treatment should be in terms of time as short as possible. The patient should be regularly re-valued and the necessity of a continued treatment should be attentively evaluated, particularly when the patient is without symptoms. The total treatment duration should not exceed, generally, 8-12 weeks, including a period of gradual suspension. In specific cases, the extension of treatment beyond the maximum period may be necessary; in such case, this should not occur without the patient condition re-evaluation.

Insomnia

-oral drops, solution: 13-26-52 drops, in the evening before going to sleep.

The insomnia treatment, in terms of time, should be as brief as possible. The treatment duration, generally, varies from a few day to two weeks up to a maximum of four weeks, including a period of gradual suspension. In specific cases it may be necessary the extension beyond the period of maximum treatment; in such case, this should not happen without a previous re-evaluation, by the physician, of the patient conditions. The treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded. It is recommended to take DELORAZEPAM ABC drops with a little water. A drop of DELORAZEPAM ABC contains 38,5 mcg of clordemetildiazepam; 13 drops= 0,5 mg. Because of the variability of the individual responses the individual and daily posology will have to be adapted to the age, to the general conditions and to the clinic context. The dose for the old people and for the patients with hepatic and/or renal altered function must be carefully established by the physician who will have to evaluate a contingent reduction of the above-mentioned dosages. The posology must be fixed within prudential limits for the debilitated subjects or particularly sensitive, and for those patients with organic cerebral modifications (especially of the arteriosclerotic kind) or with respiratory insufficiency. In these subjects it is suggested to start with low dosages and to adjust subsequently the posology on the basis of the results obtained. The patient should be regularly controlled at the start of the treatment to reduce, if necessary, the dose or the frequency of the taking, in order to prevent the hyper-dosage due to the accumulation.

4.3 Contraindications Hypersensitivity to the benzodiazepine. Hypersensitivity to the active principle or to any of the excipients. Myasthenia gravis. Severe respiratory distress syndrome. Hepatic insufficiency. Night apnea syndrome. Pregnancy and breast feeding (see 4.6)

4.4 Special cautions and suitable use precautions Tolerance . A certain loss of efficacy towards the benzodiazepine hypnotic effects may develop after a repeated use for some weeks. Dependence . The use of benzodiazepine may lead to the development of physical and psychical addiction to these medicines. The risk of addiction increases with the dose and treatment duration; this is higher in patients with a story of drug or alcohol addiction. Once the physical dependence has been developed, the treatment abrupt interruption will be accompanied by abstinence symptoms. These may consist in headache, muscular ache, extreme anxiety, tension, restlessness, confusion and irritability. In the serious cases the following symptoms may be evidenced: de-realization, de-personalization, hyperacusia, extremities numbness and formication, hypersensitivity to the light, to the noise and to the physical contact, hallucinations or epileptic crises. Insomnia and rebound anxiety: at the treatment suspension it may occur a temporary syndrome in which the symptoms that have led to the treatment with the benzodiazepine return in an aggravated form. It may be associated to other reactions, including mood changes, anxiety, restlessness or sleep troubles. Since the risk of abstinence or rebound symptoms is greater after an abrupt treatment suspension, we recommend to adopt a gradual reduction of the dosage. Treatment duration. The treatment duration should be as brief as possible (see “posology and modality of administration”) depending on the indication and should not exceed the four weeks for the insomnia and eight-twelve weeks in the case of the anxiety, including a period of gradual suspension. The extension of this therapy, beyond these periods, should not occur without re-evaluation of the clinic situation. It may be useful to inform the patient when the treatment is started that it twill be of limited duration and to precisely explain that the dosage will be gradually reduced. In addition, it is important that the patient be informed of the possibility of rebound phenomena, minimizing thus the anxiety towards these symptoms, whether these should become present at the suspension of the medicine. When using the DELORAZEPAM ABC (tablets and oral solution), long action duration benzodiazepine it is important to warn the patient that is not advisable the abrupt change with a brief action duration benzodiazepine, since an abstinence syndrome might arise. In case of prolonged treatment it is advisable to proceed to the blood test analysis and hepatic function control. Amnesia The benzodiazepine can induce anterograde amnesia. This happens quite often several hours after the medicine assumption and then, to reduce the risk, it must be ascertained that the patient could have an unbroken sleep of 7-8 hours (refer to “Undesired effects”). Psychiatric and paradoxical reactions . When using benzodiazepine it is well-known that reactions may occur as relentlessness, agitation, irritability, aggressiveness, delirium, anger, nightmares, hallucinations, psychosis, behavior alterations. Should this happen, the use of the drug should be suspended. Such reactions are more frequent in children and old patients. Specific groups of patients . The benzodiazepine should not be administered to children without an attentive evaluation of the real necessity of the treatment; the treatment duration must be as short as possible. The ancients should take a reduced dose (refer to “Posology and administration mode”). Similarly, a reduced dose is recommended for patients suffering with chronic respiratory insufficiency because of the risk of a respiratory depression. The benzodiazepines are not indicated in patients with serious hepatic insufficiency since they may precipitate the hepatic encephalopathy. The benzodiazepines are not suggested for the primary treatment of the psychotic disease. The benzodiazepine should not be used as the sole remedy for treating the depressive disorder or the anxiety connected with the depression (suicide may be precipitated in such patients). The benzodiazepine should be used with extreme attention in patients with a story of drug addiction or alcohol abuse.

DELORAZEPAM ABC in the 0,5 mg, 1 mg and 2 mg tablets confections contains lactose, therefore it is not fit for the subjects with deficit of lactase, galactosemia or glucose/galactose mal-absorption syndrome.

DELORAZEPAM ABC drops, oral solution contains 13% vol/vol ethanol (alcohol) i.e. up to 211 mg per dose, equivalent to 5,2 ml of beer and to 2.16 ml of wine per dose. Harmful for alcohol- dependent persons. To be taken into consideration in pregnant women and breast-feeding women, children and high-risk groups as for instance patients with hepatic disorder and epileptic patients.

4.5 Interactions with other medicines and other forms of interaction The concurrent assumption of alcohol must be avoided. The sedative effect may be increased when the medicinal is assumed concurrently with alcohol. This negatively influences the driving capacity or the use of machineries. Association with medicines depressing the SNC (Central Nervous System): the central depressive effect may be increased in the cases of concurrent use of anti-psychotic (neuroleptics), hypnotics, tranquillizers/sedatives, anti-depressives, analgesics narcotics, anti-epileptics, anesthetics and antihistamine sedatives. In the case of the analgesics narcotics there may have an increase of the euphoria which may lead to an increase of the psychic dependence. The association with other psycho-medicine requires particular caution and vigilance by the physician in order to avoid unexpected undesired effects caused by interaction.

Aggregates inhibiting determined hepatic enzymes (especially cytochrome P450) may increase the benzodiazepine activity. In a lower grade, this is applied also to the benzodiazepine which are metabolized only through conjugation.

4.6 Pregnancy and breast feeding. If the product is prescribed to a woman in fertile age, she will have to contact her own physician, either if she intend to initiate a pregnancy or if she suspect to be pregnant, as to what concerns the medicine interruption. The medicine must not be administered in the first quarter of pregnancy whilst in the further period only in case of real necessity and under direct physician’s control. If , for medical serious motivations, the product is administered during the last period of the pregnancy, or during the childbirth labor at the high doses, there may occur effects on the newborn such as hypothermia, hypotonia and moderate respiratory depression due to the medicine pharmacologic action. In addition to, newborn children born from mothers who have taken chronically benzodiazepine during the advanced phases of the pregnancy, may develop physical dependence and may present a certain risk of developing the abstinence symptoms in the post-born period. Since the benzodiazepine are excreted into the maternal milk, they should not be administered to the mother during the breast-feeding period.

4.7 Effects on the capacity of driving vehicles and of using machineries The sedation, the amnesia, the alteration of the concentration and of the muscular function as well, may negatively influence the driving capacity and of using machineries. If the sleep duration has been insufficient, the probability that the vigilance be altered may be increased (refer to "Interactions").

4.8 Undesired effects DELORAZEPAM ABC ABC is, generally, well tolerated. However, as with other benzodiazepine, undesired effects could appear such as sleepiness, dullward of the emotions, reduction of the vigilance, confusion, fatigue, headache, dizziness, muscular weakness, ataxia, double vision. These phenomena appear mainly at the start of the therapy and usually disappear with the subsequent administrations. Occasionally, other adverse reactions have been signaled, which comprise: gastrointestinal disorder, libido alterations and reactions on the dermis. Rare cases of constipation, urinary incontinence, tremors, cutaneous reactions, hypotension, paradoxical excitation conditions, nausea, disappear spontaneously in a few days or after having adjusted the posology. Amnesia . Anterograde amnesia may show up also at the therapeutic dosages; the risk increases at the higher dosages. The amnesia effects may be associated with behavior alterations (refer to ”Special cautions and use precautions”). Depression During the use of benzodiazepines may be unmasked a pre-existent depression state. The benzodiazepines and benzodiazepine-similar aggregates may cause reactions like: restlessness, agitation, irritability, aggressiveness, delirium, anger, nightmares, hallucinations, psychosis, behaviour alterations. Such reactions may be quite serious. They are more probable with children and old people. Dependence . The use of the benzodiazepines (also at the therapeutic doses) may lead to the development of physical dependence: the therapy suspension may cause rebound abstinence phenomena (refer to ”Specific cautions and precautions for use”). It may occur psychic dependence. It has been signaled the abuse of benzodiazepines.

4.9 Overdosage As for the other benzodiazepine, an excessive dose should not present a life risk, unless there is a concurrent assumption of other anti-depressive agents of the SNC (Central Nervous System) (including alcohol). In the over-dosage treatment of any medicine, it should be considered the possibility that other substances have also been concurrently taken. After an excessive dose of benzodiazepine for oral use it should be induced the emesis (within one hour) if the patient is conscious, or it should be carried out the gastric washing with protection of the respiratory tract if the patient is in a state lacking conscious awareness. If an improvement is not observed with the emptying of the stomach, it should be administered activated carbon in order to reduce the absorption. Special attention should be dedicated to the respiratory and cardiovascular functions in the urgency therapy. The benzodiazepine over-dosage usually occurs with various degree of central nervous system depression (SNC) which varies from the darkening of mind to the coma. In the light cases, the symptoms include mind obnubilation, mind confusion and lethargy. In the more serious cases, the symptoms nay include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and, very rarely, death. The “Flumazenil” may be useful as an antidote.

5. PHARMACOLOGIC PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutical category: tranquillizers, benzodiazepinic aggregates, code ATC: N05BA49. The clordemetildiazepam, like other benzodiazepines, possesses a tranquillizing activity, hypno-inducing, myo-relaxing and anti-convulsive agent. Studies of pharmacodynamics have proved that the presence of the chlorine atom in the 7 position of the clordemetildiazepam phenyl makes the molecules more active with respect to other benzodiazepines. The clordemetildiazepam has shown a very high affinity for the specific cerebral receptors (Ki 1.3+-0.1).

5.2 Pharmacokinetic properties The clordemetildiazepam is well absorbed after oral administration and the peak haematic time for the tablet formulation (1 mg) is 1,5 hours, whilst for the drops (equal to 1 mg) is 45 minutes. The haematic concentration corresponding to the peak are 12 ng/ml for the tablets concentration (1 mg) and 14,5 ng/ml for the oral solution (equal to 1 mg). The bioavailability of the oral forms, tablets and solution, is respectively 87% and 81,3% of the value obtained by intravenous injection. The elimination biological half-life varies as a function of the age. In the adults the biological half-life results to be about 99,7 hours (+/-22,3) for the tablets and 96,9 hours (+/-19,7) for the drops after administration of one individual 1 mg dose. In the children of the age comprised between 7 months and 12 years the oral dose (solution) of 30 µg/kg shows an elimination biological half-life of 40 hours for children of 7 months, 27 hours in subjects of age comprised between 2 and 3 years and 34 hours in children of greater age. The clordemetildiazepam may be, therefore, classified among the long biological half-life benzodiazepine. The average total clearance after oral administration of 2 mg is 0,11ml/min/kg and the distribution apparent total volume is 0,94 l/kg. A study carried out on hospitalized patients after administration of 0,5 mg of clordemetildiazepam twice a day has documented that the concentration at the steady state is reached after c.a. 20 days. The reaching time can be reduced by increasing the administration frequency. The clordemetildiazepam administration with food slow down the medicine absorption without modifying the quantity of dose absorbed with respect to the fasting condition. In patients with altered hepatic function it has been observed a clordemetildiazepam absorption relatively slower with a major bio-availability and a major molecule free fraction, whose clearance is equal to 1/5 with respects to the controls. The distribution volume of the clordemetildiazepam assumed per os by patients with hepatic functionality alteration is equal to the half of the one referred to sound patients. In patients with altered kidneys functionality in dialysis it has been observed a clordemetildiazepam absorption relatively slower with a good (82%) and a major molecule free fraction. The metabolic clordemetildiazepam degradation occurs through hydroxylation in position 3 with formation of 3-OH-clordemetildiazepam. The major inactive urinary metabolite is the glucuronide of the 3-OH- clormetildiazepam; in addition, other minor inactive metabolites are present.

5.3 Pre-clinic safety data The acute toxicity values expressed as DL50 after administration per os in the mouse and in the rat are resulted respectively equal to 1100 mg/kg and 2000 mg/kg. The chronic toxicity has been studied administering during 180 days the active principle per os in the rats (0,2-2 mg/kg/die) and in the dog (0,150 mg/kg/day). From the total data obtained a conclusion can be drawn that the clordemetildiazepam is well tolerated. Studies carried out administering per os the medicine during 104 weeks to rats Sprague-Dawley with dosages of 0,15, 1,20, and 9,60 mg/kg/day have demonstrated that the active principle does not possess carcinogenic properties and does not increment the insurgency frequency of spontaneous tumors. Tests in vitro have excluded that the medicinal drug posses mutagen properties.

6. PHARMACEUTICAL INFORMATION 6.1 Excipients list DELORAZEPAM ABC 1 mg/ml Oral drops, solution Ethanol 96 per cent, glycerol, depurated water, glycamil N, sodium saccharin, propylene glycol.

6.2 Incompatibility Data not available.

6.3 Validity period - Oral drops, solution: 5 years. The validity period after bottle first opening is 12 months.

6.4 Special precautions for the conservation No particular indications required for conservation modality

6.4 Nature and content of container Oral drops, solution: 20 ml glass bottle, with screw plug and drop-counter, enclosed into a cardboard sheath. Oral drops, solution: 30 ml glass bottle, with screw plug and drop-counter, enclosed into a cardboard sheath.

6.6 Use and manipulation instructions None.

7. MARKETING AUTHORIZATION HOLDER ABC FARMACEUTICI S.P.A. Corso Vittorio Emanuele II, 72 – 10121 Torino

8. NUMBERS OF THE MARKETING AUTHORIZATION DELORAZEPAM ABC 1 mg/ml oral drops, solution in 20 ml bottle: 039386012 DELORAZEPAM ABC 1 mg/ml oral drops, solution in 30 ml bottle: 039286024

9. FIRST AUTHORIZATION DATE – August 2011

10. TEXT REVISION DATE – August 2011