SUMMARY OF THE PRODUCT CHARACTERISTICS. ACICLOVIR ABC (Aciclovir)

Transcription

1 SUMMARY OF THE PRODUCT CHARACTERISTICS 1. DENOMINATION OF THE PRODUCT ABC ACICLOVIR 800 mg TABLETS ABC ACICLOVIR 8% ORAL SUSPENSION ACICLOVIR ABC (Aciclovir) 2. QUALITATIVE AND QUANTITATIVE COMPOSITION ABC Aciclovir tablets Each tablet contains: Active ingredient: Aciclovir 800 mg Excipients: Microcrystalline cellulose 127 mg, sodium starch glycolate 40 mg, polivinilpyrrolidon 25 mg, magnesium stearate 8 mg. ABC Aciclovir suspension Each 5 ml of suspension contains: Active ingredient: Aciclovir 400,0 mg Excipients: Sorbitol (70% not crystallisable) 2,250 g, glycerin 0,750 mg, dispersible cellulose 75,0 mg, metil p-hydroxybenzoate 5,0 mg, propil p-hydroxybenzoate 1,0 mg, sour-cherry flavour 4,0 mg, purified water q.s. to 5 ml. 3. PHARMACEUTICAL FORM 35 tablets 800 mg 1 oral suspension bottle 100 ml 8% 4. CLINICAL INFORMATION 4.1. THERAPEUTIC INDICATIONS ABC ACICLOVIR is indicated: - for treatment of Herpes Simplex infections of the skin and the membrane mucous, the primary and recurrent Herpes Genitalis included. - for the relapses suppression from Herpes Simplex in immune-competent patients. - for infections prophylaxis from Herpes Simplex in immune-compromised patients. - for Herpes Zoster treatment POSOLOGY AND METHOD OF ADMINISTRATION Treatment of Herpes Simplex infections in adults: Except for a different medical prescription, 200 mg (2.5 ml of suspension) is advisable 5 times a day at about 4 hours intervals omitting the night dose. The treatment must be continued for 5 days, but an extension can become necessary in serious primary infection cases. In immune-compromised patients (for ex. after a marrow transplantation) or in patients with a diminished intestinal absorption, the dosage can be doubled to 400 mg by using half a tablet or 5 ml of the suspension, or alternatively, the possibility of a medicine administration via intravenous route can be considered. The therapy must be started as soon as possible and in case of recurrent infections, preferably during the prodromic phase or at the first appearance of the wounds. Suppressive therapy of relapses of Herpes Simplex infections in immune-competent patients

2 Except for a different medical prescription, 200 mg (2.5 ml of the suspension) are advisable 4 times a day at 6 hours intervals. Many patients can be successfully treated with 400 mg administration corresponding to half a tablet or 5 ml of the suspension 2 times a day at 12 hours intervals. Dosages of 200 mg can also prove to be effective, 3 times a day at 8 hours intervals or 2 times a day at 12 hours intervals. In some patients infection relapses can occur with a total daily dose of 800 mg. The therapy should be interrupted periodically from 6 to 12 months intervals, in order to be able to observe possible changes in the natural history of the disease. Prophilaxis of Herpes Simplex infections in neo immune-compromised patients Except for a different medical prescription, 200 mg (2.5 ml of the suspension) are advisable 4 times a day at 6 hours intervals. In seriously immune-compromised patients (for ex. after a marrow transplantation) or in patients with a diminished intestinal absorption, the dosage can be doubled to 400 mg corresponding to half a tablet or 5 ml of the suspension or in alternative the possibility of a medicine administration via intravenous route can be considered. The prophilaxis length must be considered as connected to that of a risking period. Treatment of Herpes Zoster infections Except for a different medical prescription, 800 mg or 10 ml of suspension are advisable 5 times a day at about 4 hours intervals omitting the night dose. The treatment must be continued for 7 days. In seriously immune-compromised patients (for ex. after a marrow transplantation) or in patients with a diminished intestinal absorption, the possibility of a medicine administration via intravenous route can be considered. The therapy must be started immediately after the infection s appearance, in fact the treatment obtains better results if accomplished at the first appearance of the wounds. Children For the treatment of Herpes Simplex infections and for the prophilaxis of the same ones in the immune-compromised patients, in children over 2 years old the dosage is similar to the adult one. Under two years old the dosage is reduced to half. Old people In old people the total clearance decreases with the reduction of creatinine clearance associated to the advancement of age. In patients who take high doses of ABC ACICLOVIR via oral route an adequate hydration must be kept. A particular attention must be paid in considering the possibility of a dosage reduction in case of patients with a compromised renal functionality. Renal insufficiency In the treatment of Herpes Simplex infections, in patients with reduced renal functionality, the oral posology recommended should not cause an Aciclovir accumulation over the acceptable retained levels for the medicine administration via intravenous route. However, in patients with serious renal insufficiency (creatinine clearance lower than 10 ml/min), it is recommended to adapt the dose to 200 mg 2 times a day at 12 hours intervals. In the Herpes Zoster treatment it is recommended to modify the posology up to 800 mg given 2 times a day at about 12 hours intervals, in patients with serious renal insufficiency in case the creatinine clearance is lower than 10 ml/min; and to 800 mg 3 times a day at 8 hours intervals, in patients with moderate renal insufficiency in case the creatinine clearance is between 10 and 25 ml/min CONTRAINDICATIONS Hypersensitivity toward components. Breast feeding. Pregnancy SPECIAL WARNINGS AND PRECAUTIONS FOR USE Nothing

3 4.5. INTERACTIONS WITH OTHER DRUGS/MEDICINES AND OTHER FORMS OF INTERACTION The probenecid protracts the permanency time of Aciclovir in blood. Other medicines which interfere on renal functionality could modify the pharmacokinetics of Aciclovir. However, in clinical practice, other interactions with Aciclovir have not been observed PREGNANCY AND BREAST FEEDING As clinical data about the administration in pregnancy are limited, during such a period the product must be given only in cases of absolute necessity under the direct control of the doctor. The administration via systemic route of Aciclovir in rabbits or in rats has not produced any embryotoxic or teratogen effects. In an experimental test not included in the standard teratogenesis tests some fetus abnormalities have been observed after the administration of so high subcutaneous doses of Aciclovir to produce toxic effects to the mother. The clinical relevance of these results is uncertain. As a consequence of the administration via oral route of 200 mg 4 times a day the presence of Aciclovir in maternal milk has been observed, in concentrations equal to 0,6-4,1 times the corresponding plasmatic levels. Such levels would potentially expose the breast-fed children to doses of Aciclovir up to 0,3 mg/kg/die. Therefore, the use of ABC ACICLOVIR during breast feeding must be avoided. Fertility In rats and dogs reversible toxic effects have been noticed on the spermatogenesis only for remarkably higher dosages than the therapeutic ones. Studies on two generations of mice have not indicated any effects of Aciclovir on fertility, no data on fertility in women is available. ABC ACICLOVIR has not proved to have any effect on the number, the morphology and the motility of spermatozoons in men EFFECTS ON THE CAPACITY OF DRIVING AND USING MACHINERIES No negative effects of ABC ACICLOVIR on the capacity of driving and on the use of machineries are known ADVERSE EFFECTS After the administration of ABC ACICLOVIR via oral route in some patients skin eruptions, promptly disappeared with the therapy interruption, have been shown. At the digestive tube s expense symptoms such as nausea, vomiting, diarrhoea and abdominal ache have been signalled. Reversible neurological reactions, in particular vertigos, confusion states, hallucinations and sopor, have been reported occasionally and generally in patients suffering from renal insufficiency or other predisposing factors. A more rapid and more widespread loss of hair has always been reported on occasions. As this last one has been associated with a whole range of pathologies and with the intake of different drugs, the relationship with the aciclovir is uncertain. After the ABC ACICLOVIR intake via oral route, a modest and transitory rise of the bilirubin haematic values and of the hepatic enzymes has been seldom remarked. Besides moderate increases of the urea and of the creatinine, slight descents of the haematological indexes, headache, modest and reversible neurological disorders and asthenia have been signalled. 4.9 OVERDOSAGE The Aciclovir is only partially absorbed at the intestinal level. So it is unlikely that there are serious toxic effects even in the possibility that 5 grams of Aciclovir are swallowed only once. The data about the possible consequences of greater doses digestion is not available. Single doses of intravenous injection up to 80 mg/kg have been administered unintentionally without side effects. The patients, who have swallowed Aciclovir doses with more grams, must be kept under observation. The Aciclovir is dialyzable.

4 5. PHARMACOLOGICAL PROPERTIES 5.1 PHARMACODYNAMIC PROPERTIES The Aciclovir is an analogous synthetic purine nucleoside with inhibitory activity, in vitreous as well as lifelike manners, towards the human herpetic viruses including the Herpes Simplex Virus (HSV) of types 1 and 2 and the Varicella Zoster Virus (VZV). In cellular cultures, the Aciclovir has shown its greatest antiviral activity towards HSV-1, followed by HSV-2. The Aciclovir inhibitory activity towards HSV-1, HSV-2, is highly selective. The thymidine kinase enzyme of normal and not infected cells does not use efficaciously the Aciclovir as substrate; therefore the toxicity for the guest cells is meagre; on the contrary, the viral thymidine kinase turns the Aciclovir into monophosphate Aciclovir, an analogous nucleosidic, that is further on turned into di-phosphate and tri-phosphate through the action of cellular enzymes. The tri-phosphate Aciclovir interferes with the viral DNA polymerase and it inhibits the viral DNA replication, its incorporation into the viral DNA causes the interruption of the chain elongation process of this latter one. Extended or repeated cycles of Aciclovir in seriously immunecompromised patients can be associated with the selection of viral strains with reduced sensibility, that can not respond to the Aciclovir continuous treatment. Most isolated viral strains, with reduced sensibility, showed a relative deficit of thymidine kinase; however strains with thymidine kinase or altered viral DNA polymerase have been remarked too. Even the vitreous exposure of isolated HSV strains to Aciclovir can be associated with the appearance of less sensible strains. The actual relationship between the sensibility, determined in vitreous way, of the isolated HSV strains and the clinical response to the Aciclovir therapy is not clarified. 5.2 PHARMACOKINETIC PROPERTIES The Aciclovir is only partially absorbed at the intestinal level. The peak of the plasmatic concentrations, to the steady state (C max ), after 200 mg dose every 4 hours is of 3,1 µmol (0,7 µg/ml) and the minimal concentration (C min ) is of 1,8 µmol (0,4 µg/ml). After 400 mg and 800 mg doses every 4 hours the C max is respectively of 5,3 µmol (1,2 µg/ml) and of 8 µmol (1,8 µg/ml) and the C min is respectively of 2,7 µmol (0,6 µg/ml) and of 4 µmol (0,9 µg/ml). The drug half-life is of 2,9 hours about. Most drugs are excreta modified by kidney. The Aciclovir kidney clearance is considerably greater than the one of the creatinine, this indicates the fact that, besides the glomerular filtration, the tubular secretion, too, contributes to the renal elimination of the drug. The only important metabolite is the 9-carboxymethoxymethylguanine, that corresponds to about 10-15% of the excreta dose by urine. In the patients suffering from chronic renal insufficiency the average half-life is of 19,5 hours whereas, during haemodialysis, the Aciclovir average half-life is of 5,7 hours and the plasmatic levels come down on the average to about 60%. In the old the total clearance decreases with the age increase together with the creatinine clearance, however there are slight changes in the terminal average half-life. The drug levels in the liquor correspond to about 50% of the plasmatic ones. The bond to the plasmatic proteins is relatively poor (from 9 to 33%) and the pharmacological intercourses due to dislocations from the bond seat are not set. 5.3 PRECLINICAL SAFETY DATA The results of a wide number of vitreous and lifelike mutagenesis tests indicate that the Aciclovir does not involve genetic risks for men. In long-dated studies on the rat and the mouse, the Aciclovir is not resulted carcinogen. 6. PHARMACEUTICAL INFORMATION 6.1 EXCIPIENT LIST

5 ABC Aciclovir 800 mg tablets 35 tablets Microcrystalline cellulose, sodium starch glycolate, polyvinylpyrrolidone, magnesium stearate. ABC Aciclovir 8% oral suspension 100ml bottle of oral suspension Sorbite (70% non-crystallizable), dispersible cellulose, glycerol, methyl p-hydroxybenzoate, propyl p- hydroxybenzoate, sour black cherry aroma, purified water. 6.2 INCOMPATIBILITY Incompatibilities with other drugs are not known. 6.3 VALIDITY By integral pack: ABC Aciclovir 800 mg tablets 35 tablets: the stability of the product lasts 5 years ABC Aciclovir 8% oral suspension 100 ml bottle of oral suspension: the stability of the product lasts 3 years 6.4 SPECIAL PRECAUTIONS FOR STORAGE ABC Aciclovir tablets: keep in a dry place ABC Aciclovir oral suspension: none in particular 6.5 NATURE AND CONTENT OF THE TRAY ABC Aciclovir tablets: blister by 35 tablets of 800 mg ABC Aciclovir oral suspension: 100 ml glass bottle 6.6 DIRECTIONS None in particular 7. HOLDER OF THE MARKETING AUTHORIZATION ABC Farmaceutici S.p.A. Corso Vittorio Emanuele II, 72 Torino 8. NUMBER OF THE MARKETING AUTHORIZATION ABC Aciclovir 800 mg tablets 35 tablets: AIC /G ABC Aciclovir 8% oral suspension 100 ml bottle of oral suspension: AIC /G 9. FIRST AUTHORIZATION ISSUE DATE/RENEWAL Renewal: December TEXT (PARTIAL) REVISION DATE December 2004

6 SUMMARY OF THE PRODUCT CHARACTERISTICS 1. DENOMINATION OF THE PRODUCT ABC Aciclovir 5% cream tube by 10 g of cream ACICLOVIR ABC CREAM (Aciclovir) 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 1g of cream contains: Active ingredient: Aciclovir 50mg Excipients: Tefose 1500, glycerin, stearic acid, liquid paraffin, methylparaben, purified water. 3. PHARMACEUTICAL FORM 5% cream for topic use Tube of 10 g 4. CLINICAL INFORMATION 4.1 THERAPEUTIC SUBSCRIPTIONS ABC ACICLOVIR CREAM is subscribed in the dermatological infection treatment of Herpes Simplex such as: primary or recurrent genital Herpes and lip Herpes. 4.2 POSOLOGY AND METHOD OF ADMINISTRATION DOSE, WAY AND TIME OF ADMINISTRATION ABC ACICLOVIR CREAM is to be applied 5 times a day at about 4 hours intervals. ABC ACICLOVIR CREAM is to be applied on the lesions or the areas where these are developing as more precociously as possible after the infection beginning. It is particularly important to begin the treatment of recurrent episodes during the phase in which there are symptoms that precede the pathological condition setting up (prodroma) or to the first appearance of the lesions. The treatment has to be continued for 5 days at least and up to a maximum of 10 if there has been no healing. 4.3 CONTRAINDICATIONS Hypersensitivity to the components. Pregnancy and breast feeding. 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE The product is not to be applied on the eyes, neither it is advisable to apply it on the mucous membranes of mouth and vagina. Studies on animals indicate that the ABC ACICLOVIR CREAM application in vagina can cause reversible excitations. The especially extended use of the product can give rise to sensitisation phenomena, where it occurs it is necessary to interrupt the treatment and consult the family doctor. 4.5 INTERACTIONS WITH OTHER DRUGS/MEDICINES AND OTHER INTERACTION FORMS The probenecid extends the Aciclovir permanence time into the blood when this latter one is administered via systematic route. The clinical trial has not relieved interactions with other drugs. 4.6 PREGNANCY AND BREAST FEEDING As there is no clinical data about the ABC ACICLOVIR CREAM effects in pregnancy, during this period the drug is to be used only in case of absolute necessity under the direct doctor control.

7 The data about the Aciclovir levels, that could be found into the maternal milk after the ABC ACICLOVIR CREAM application during breast feeding is not available. 4.7 EFFECTS ON THE CAPACITY OF DRIVING AND USING MACHINERIES The ABC ACICLOVIR CREAM negative effects on the capacity of driving and using machines are not known. 4.8 ADVERSE EFFECTS Soon after the cream application, sometimes there can be transitory burn and ache. Rubescence or moderate dryness and peeling of the skin have been remarked in a small percentage of cases. In any case the patient is invited to communicate to his doctor or chemist any adverse effect that should occur during the therapy, even if it is not described in this package leaflet. 4.9 OVERDOSAGE OVERDOSAGE Even in the case that the whole content of the cream tube is swallowed, there should be no undesirable effects as single doses by 600 mg and daily doses up to 3600 mg have been administered via oral route without giving rise to adverse effects. Single doses of intravenous injection up to 80 mg/kg have been administered unintentionally without side effects. In any case a possible luxus of Aciclovir can be removed from the blood by dialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 PHARMACODYNAMIC PROPERTIES The Aciclovir is an analogous synthetic purine nucleoside with inhibitory activity, in vitreous as well as lifelike manners, towards the human herpetic viruses including the Herpes Simplex Virus (HSV) of 1 and 2 types and the Varicella Zoster Virus (VZV). Most isolated viral strains, with reduced sensibility, showed a relative deficit of thymidine kinase; however strains with thymidine kinase or altered viral DNA polymerase have been remarked too. Even the vitreous exposure of isolated HSV strains to Aciclovir can associate with the appearance of less sensible strains. The actual relationship between the sensibility, determined in vitreous way, of the isolated HSV strains and the clinical response to the Aciclovir therapy is not clarified. 5.2 PHARMACOKINETIC PROPERTIES After entering the cells infected by the Herpes, the Aciclovir is turned into the active compound, the triphosphate aciclovir; the viral thymidine kinase turns the Aciclovir into monophosphate Aciclovir, an analogous nucleosidic, that is further on turned into di-phosphate and tri-phosphate through the action of cellular enzymes. The Aciclovir inhibitory activity towards HSV- 1, HSV-2, is highly selective. The thymidine kinase enzyme of normal and not infected cells does not use efficaciously the Aciclovir as substrate; therefore the toxicity for the guest cells is meagre. The tri-phosphate Aciclovir interferes with the viral DNA polymerase and it inhibits the viral DNA replication, its incorporation into the viral DNA causes the interruption of the chain elongation process of this latter one. 5.3 PRECLINICAL SAFETY DATA The (oral) DL50 in the mouse is > mg/kg; in the rat it is > mg/kg. The results of a wide number of vitreous and lifelike mutagenesis tests indicate that the Aciclovir does not involve genetic risks for men. In long-dated studies on the rat and the mouse, the Aciclovir is not resulted carcinogen. 6. PHARMACEUTICAL INFORMATION 6.1 EXCIPIENT LIST Tefose 1500, glycerin, stearic acid, liquid paraffin, methylparaben, purified water.

8 6.2 INCOMPATIBILITY Incompatibilities with other drugs are not known 6.3 VALIDITY By integral pack: 36 months 6.4 SPECIAL PRECAUTIONS FOR STORAGE Keep at a temperature not higher than 25 C 6.5 NATURE AND CONTENT OF THE TRAY AND PRICES 5% cream for topic use Tube of 10 g 6.6 DIRECTIONS None in particular 7. HOLDER OF THE MARKETING AUTHORIZATION ABC Farmaceutici S.p.A. Corso Vittorio Emanuele II, 72 Torino 8. NUMBER OF THE MARKETING AUTHORIZATION ABC Aciclovir 5% cream tube of 10 g of cream: AIC n /G 9. FIRST AUTHORIZATION ISSUE DATE/RENEWAL Renewal: June TEXT (PARTIAL) REVISION DATE June 2004