NEOTIGASON NAME OF THE MEDICINE. acitretin

Transcription

1 NAME OF THE MEDICINE NEOTIGASON acitetin CAS Registy Numbe: DESCRIPTION NEOTIGASON (acitetin) is a etinoid fo the oal teatment of sevee cases of psoiasis and disodes of keatinisation. It is available in 10 and 25 mg capsules. The chemical name of acitetin is all-tans-9-(4-methoxy-2,3,6-timethylphenyl)-3,7-dimethyl- 2,4,6,8-nonatetanoic acid. Its empiical fomula is C 21 H 26 O 3 with a molecula weight of Acitetin is a metabolite of etetinate and is elated to both etinoic acid and etinol (Vitamin A). Acitetin is a geen-yellow cystalline powde. It is vitually insoluble in wate (< 0.1 mg/100 ml). The pka is appoximately 5. It is pesent in the capsules as a spay-died powde. PHARMACOLOGY Phamacodynamics NEOTIGASON eveses the epidemal polifeation and inceased keatinisation seen both in chemically induced epithelial tumous in animals and in hypekeatotic disodes in man. Vitamin A (etinol and its estes) can beneficially influence hypekeatotic changes in the skin o metaplasias of the mucous membanes. Phamacokinetics Absoption and Bioavailability Acitetin eaches peak plasma concentation 1-5 hous afte ingestion of the medicine. Bioavailability of oally administeed acitetin is best when the medicine is taken togethe with food. Bioavailability of a single dose is appoximately 60%, but this may vay consideably fom one patient to anothe (36-95%). Afte administation of a single 50 mg oal dose of acitetin to 18 healthy subjects, maximum plasma concentations anged fom 196 to 728 ng/ml (mean 416 ng/ml) and wee achieved in 2 to 5 hous (mean 3.5 hous). The oal absoption of acitetin is linea and popotional with inceasing doses fom 25 to 100 mg. Following multiple doses, acitetin plasma concentations eached steadystate conditions within two weeks and accumulation was 0.5 to 2.6-fold highe than afte a single dose. In patients with psoiasis, mean steady-state tough concentations of acitetin inceased in a popotional manne and anged between 6 and 7 ng/ml, 11 and 14 ng/ml, and 19 and 25 ng/ml ove an eight week peiod at daily oal doses of 10 mg, 25 mg and 50 mg, espectively. In this same NEOTIGASON PRODUCT INFORMATION APPROVED 21 ST JANUARY (11)

2 study, acitetin plasma concentations wee non-measuable (< 4-6 ng/ml) in all patients whee blood samples wee dawn thee weeks afte cessation of theapy. Distibution Acitetin is highly lipophilic and penetates eadily into body tissues. Potein binding of acitetin exceeds 99%. In animal studies, acitetin passed the placental baie in quantities sufficient to poduce foetal malfomations. Due to its lipophilic natue, it can be assumed that acitetin passes into beast milk in consideable quantities. Metabolism Acitetin is metabolised by isomeisation into its 13-cis isome (cis acitetin), by glucuonidation and cleavage of the side chain. Both acitetin and its 13-cis isome ae eliminated fom the body pimaily by metabolism to chain-shotened beakdown poducts and conjugates that ae ultimately exceted in the faeces (35-45%) and uine (48-61%). The fomation of the 13-cis isome elative to paent compound is not alteed by dose o fed/fasted conditions of oal administation of acitetin. The elimination of the 13-cis isome is essentially paallel to that of acitetin afte multiple doses. Thee was no detectable fomation of etetinate when a single 100 mg oal dose of acitetin was administeed without concuent ethanol ingestion. Although the fomation of etetinate without concuent ethanol ingestion cannot be excluded, only 7.5% of 240 evaluated psoiatic patients on acitetin theapy (5-60 mg/day) in contolled and uncontolled clinical tials wee found to have measuable etetinate concentations (5 ng/ml). Of these patients, the last measuable etetinate concentation was obseved at two months afte cessation of acitetin theapy. Animal studies confim the possibility that, in the at at least, metabolism of acitetin to etetinate in the absence of alcohol can occu. Elimination Multiple-dose studies in patients aged yeas showed an elimination half-life of appoximately 50 hous fo acitetin and 60 hous fo its main metabolite in plasma, cis acitetin, which is also a teatogen. Fom the longest elimination half-life obseved in these patients fo acitetin (96 hous) and cis acitetin (123 hous), and assuming linea kinetics, it can be pedicted that moe than 99% of the dug is eliminated within 36 days afte cessation of long-tem theapy. Futhemoe, plasma concentations of acitetin and cis acitetin dopped below the sensitivity limit of the assay (< 6 ng/ml) within 36 days following cessation of teatment. Acitetin is exceted entiely in the fom of its metabolites, in appoximately equal pats via the kidneys and the bile. Special Populations Plasma concentations of acitetin wee significantly lowe in end stage enal failue subjects (n = 6) when compaed to age-matched contols following single 50 mg oal doses. Howeve, acitetin was not emoved by haemodialysis in these subjects. In a multiple-dose study in healthy young (n = 6) and eldely (n = 8) subjects, inceased acitetin plasma concentations wee seen in eldely subjects although the elimination half-life did not change. NEOTIGASON PRODUCT INFORMATION APPROVED 21 ST JANUARY (11)

3 CLINICAL TRIALS Use of NEOTIGASON in psoiatic patients esults in impovement manifested by a decease in scale, eythema and thickness of lesions, and deceased inflammation in the epidemis. INDICATIONS Acitetin may be used fo the teatment of: Sevee intactable psoiasis in all its foms Sevee foms of disodes of keatinisation such as hypekeatosis palmais et plantais pustulosis palmais et plantais ichthyosis keatosis folliculais (Daie's disease) lichen planus affecting the skin o the mucosae pityiasis uba pilais CONTRAINDICATIONS NEOTIGASON is teatogenic and must not be used by patients who ae pegnant o who intend to become pegnant duing theapy o fo 2 yeas afte cessation of theapy. NEOTIGASON is also containdicated in people who ae hypesensitive to acitetin o othe ingedients in NEOTIGASON capsules o to othe etinoids. Women of childbeaing potential must not eceive blood fom patients being teated with NEOTIGASON. Donation of blood by a patient being teated with NEOTIGASON is pohibited duing and fo one yea afte completion of teatment with NEOTIGASON. NEOTIGASON is containdicated in patients with seveely impaied live o kidney function and in patients with chonic abnomally elevated blood lipid values. Since both NEOTIGASON and tetacyclines can cause inceased intacanial pessue, thei combined use is containdicated. An inceased isk of hepatitis has been epoted to esult fom combined use of methotexate and Tigason (active ingedient: etetinate). Consequently, the combination of methotexate with NEOTIGASON is also containdicated. Concomitant administation of NEOTIGASON and vitamin A o othe etinoids is containdicated due to the isk of hypevitaminosis A. NEOTIGASON PRODUCT INFORMATION APPROVED 21 ST JANUARY (11)

4 PRECAUTIONS Use in Pegnancy: Categoy X NEOTIGASON should only be pescibed by physicians who ae expeienced in the use of systemic etinoids and undestand the isk of teatogenicity associated with acitetin theapy. NEOTIGASON must not be used by females who ae pegnant o who may become pegnant while undegoing teatment. Thee have been no epots of biths whee thee had been foetal exposue to NEOTIGASON. Howeve, acitetin is a metabolite of etetinate and majo human foetal abnomalities have been epoted with the administation of etetinate and could be expected with NEOTIGASON. Potentially any exposed foetus can be affected. Acitetin has been shown to be embyotoxic and/o teatogenic in mice, ats and abbits at doses appoximately 3, 15 and 0.5 times the maximum ecommended theapeutic dose, espectively. NEOTIGASON is containdicated in women of childbeaing potential unless the patient meets all of the following conditions: has sevee psoiasis o disode of keatinisation is unesponsive to o intoleant of standad non-teatogenic theapies is eliable in undestanding and caying out instuctions is capable of complying with the mandatoy contaceptive measues has eceived both oal and witten wanings of the hazads of foetal exposue to NEOTIGASON and the isk of possible contaception failue and has acknowledged he undestanding of these wanings has had a negative seum o uine pegnancy test within two weeks pio to beginning theapy will begin theapy only on the second o thid day of the next nomal menstual peiod. It is ecommended that a pesciption should not be issued until a epot of a negative pegnancy test has been obtained and the patient has begun he menstual peiod. It is also ecommended that pegnancy testing and contaception counselling be epeated on a egula basis. Acitetin is a metabolite of etetinate. Majo human foetal abnomalities elated to etetinate administation have been epoted, including meningomyelocele, meningoencephalocele, multiple synostoses, facial dysmophia, syndactylies, absence of teminal phalanges, malfomations of hip, ankle and foeam, low set eas, high palate, deceased canial volume, and alteations of the skull and cevical vetebae on x-ay. Fatalities elated to some of these malfomations have been epoted. Effective contaception must be used fo at least one month befoe beginning NEOTIGASON theapy and thoughout theapy. The fomation of etetinate has been obseved in cetain patients teated with NEOTIGASON. Until this phenomenon has been fully explained, the phamacokinetic behaviou of etetinate must be taken into account. Since the elimination half-life of etetinate is appoximately 120 days, contaceptive measues must be taken fo two yeas following discontinuation of theapy even whee thee has been a histoy of infetility, unless due to hysteectomy. Women who have taken Tigason ecommendations fo Tigason. (etetinate) must continue to follow the contaceptive NEOTIGASON PRODUCT INFORMATION APPROVED 21 ST JANUARY (11)

5 If pegnancy does occu, the physician and patient should discuss the desiability of continuing the pegnancy. Use in Lactation NEOTIGASON must not be given to nusing mothes. Hepatic Toxicity Elevated tansaminase and alkaline phosphatase levels have been noted in a numbe of patients eceiving acitetin. Seveal cases of hepatitis have been noted in association with etetinate. Hepatic function should be monitoed befoe and evey one to two weeks fo the fist two months afte stating teatment with NEOTIGASON and then evey thee months duing teatment. If pathological values fo hepatic function ae found, monitoing should be epeated at weekly intevals. If hepatotoxicity is suspected duing NEOTIGASON teatment the dug must be discontinued and the aetiology futhe investigated. Lipids Blood lipid deteminations should be pefomed befoe NEOTIGASON is administeed and again at intevals of one to two weeks until the lipid esponse to the dug is established, which is usually within fou to eight weeks. Appoximately 65% of patients eceiving NEOTIGASON duing clinical tials expeienced an elevation in tiglyceides. Appoximately 30% developed a decease in high density lipopoteins (HDL). The mean cholesteol level of the study population ose slightly with time but neve exceeded the nomal ange, although some individual patients did exceed the nomal ange. These effects of NEOTIGASON wee evesible upon cessation of theapy. Patients with an inceased tendency to develop hypetiglyceidaemia include those with diabetes mellitus, obesity, inceased alcohol intake o a familial histoy of these conditions. Hypetiglyceidaemia and loweed HDL may incease a patient's cadiovascula isk status. Theefoe, evey attempt should be made to contol significant elevations of tiglyceides o HDL deceases by eduction of weight o estiction of dietay fat and alcohol intake while continuing NEOTIGASON theapy. Use in Diabetes In diabetics, etinoids can eithe impove o wosen glucose toleance. Blood suga levels must theefoe be checked moe fequently than usual in the ealy stages of teatment. Paediatic Use Skeletal changes in pematue epiphysial ossification ae seen in young animals teated with etetinate. These effects have not been obseved in man but only a limited numbe of childen have been studied. Because of the uncetain effects of acitetin on gowth and skeletal development, the dug should only be used in those unde 18 in the following situations: life-theatening cicumstances whee othe theapy cannot be used o is not effective; and in sevee foms of the NEOTIGASON PRODUCT INFORMATION APPROVED 21 ST JANUARY (11)

6 disode fo which thee is no altenative theapy. Gowth paametes and bone development must be closely monitoed in all patients on long-tem theapy, by egula measuement and X-ay. In view of possible sevee advese effects associated with long-tem teatment, the isk should be caefully weighed against the theapeutic benefit. Acitetin should be used only when altenative theapies have been exhausted. Pseudotumou Ceebi NEOTIGASON and othe etinoids administeed oally have been associated with cases of pseudotumou ceebi (benign intacanial hypetension). Ealy signs and symptoms include papilloedema, headache, nausea and vomiting, and visual distubances. Patients with these signs and symptoms should be examined fo papilloedema and, if pesent, should discontinue NEOTIGASON immediately and be efeed fo neuologic evaluation and cae. Hypeostosis In clinical tials with NEOTIGASON, patients wee pospectively evaluated fo evidence of development o change in bony abnomalities of the vetebal column. Of 262 patients teated with NEOTIGASON, 7% had pe-existing abnomalities of the spine, which showed new changes o pogession of pe-existing findings. Changes included degeneative spus, anteio bidging of spinal vetebae, diffuse idiopathic skeletal hypeostosis, and naowing and destuction of a cevical disc space. These existing abnomalities may be in some pat attibutable to the undelying psoiasis and/o the patient's age. No bone changes wee seen in patients who had nomal pe-teatment X-ays. A substantially highe incidence of hypeostosis has been obseved with oal administation of othe etinoids also involving patients without pe-existing abnomalities of the spine. In adults eceiving long-tem teatment with NEOTIGASON, appopiate examinations should be peiodically pefomed in view of possible ossification abnomalities (see ADVERSE EFFECTS). If such disodes aise, the continuation of theapy should be discussed with the patient on the basis of a caeful isk/benefit analysis. Patients should be advised that a tansient incease in psoiasis is sometimes seen duing the initial teatment peiod. Patients should be advised that they may expeience deceased toleance to contact lenses duing the initial teatment peiod. It is ecommended that patients do not donate blood duing and fo two yeas following theapy. Cacinogenicity Cacinogenicity studies caied out with acitetin showed an incease in the fequency of blood vessel tumous (haemangiomas and haemangiosacomas) in male mice. NEOTIGASON PRODUCT INFORMATION APPROVED 21 ST JANUARY (11)

7 Inteactions with Othe Medicines Peliminay studies indicated that acitetin does not intefee with the actions of oestogenpogesteone oal contaceptives. In a study of ten healthy male voluntees, acitetin did not intefee with the hypopothombinemic effect of the coumain-type anticoagulant, phenpocoumon. Pogestogen-only oal contaceptives ( Minipills ) should be avoided as a contaceptive measue because thei efficacy may be educed by etinoid teatment. In a study of twelve healthy male subjects, the concomitant administation of digoxin and acitetin did not alte the phamacokinetics of eithe dug. In a study of ten healthy men, the concomitant administation of cimetidine and acitetin did not alte the phamacokinetics of eithe dug. In concuent teatment with phenytoin, it must be emembeed that NEOTIGASON patially educes the potein binding of phenytoin. Concomitant administation of alcohol may cause inceased levels of etetinate, which is much slowe than acitetin to be eliminated fom the body. Clinical evidence has shown that etetinate can be fomed with concuent ingestion of acitetin and ethanol. In a 2-way cossove study, all 10 subjects fomed etetinate with concuent ingestion of a single 100 mg oal dose of acitetin duing a 3 hou peiod of ethanol ingestion (total ethanol ~1.4 g/kg body weight). A mean peak etetinate concentation of 59 ng/ml (ange: ng/ml) was obseved and extapolation of AUC values indicated that the fomation of etetinate in this study was compaable to a single 5 mg oal dose of etetinate. Ethanol must not be ingested duing teatment with NEOTIGASON by women of childbeaing age, as clinical evidence has shown that etetinate can be fomed with concuent ingestion of acitetin and ethanol. The mechanism of this metabolic pocess has not been defined, so it is not clea whethe othe inteacting agents ae also possible. Ethanol should be avoided fo two months afte cessation of acitetin theapy. Thee appeas to be no phamacokinetic inteaction between acitetin and cimetidine, digoxin, phenpocoumon, oal contaceptives o glybuide. Ability to Dive and Use Machines Deceased night vision has been epoted with NEOTIGASON theapy. Patients should be advised of this potential poblem and waned to be cautious when diving o opeating any vehicle at night. Visual poblems should be caefully monitoed. ADVERSE EFFECTS Advese effects ae seen in most patients eceiving NEOTIGASON. Howeve, they usually disappea when the dosage is educed o the dug withdawn. An initial wosening of the disease symptoms is sometimes seen. Most of the advese effects occuing in association with systemic etinoids including NEOTIGASON esemble those of excessive vitamin A intake. NEOTIGASON PRODUCT INFORMATION APPROVED 21 ST JANUARY (11)

8 Skin and Appendages Vey Common: dy skin, puitus, eythema, ash, scaling paticulaly on palms and soles, skin fagility, thinning of skin, sticky skin, alopecia, nail fagility, paonychia. Common: bullous euption, abnomal hai textue. Uncommon: photosensitivity eactions. Rae: etinoid dematitis (occasionally povoking psoiatic lesions), uticaia. Ocula Vey Common: dy eyes, eye iitation, intoleance of contact lenses, xeophthalmia, conjunctivitis. Common: blued vision, impaied night vision. Rae: keatitis, coneal eosions, abasion and iegulatiites leading to coneal opacities, papilloedema. Special Senses Othe Common: tinnitus, taste pevesion. Uncommon: deafness. Respiatoy Common: epistaxis, hinitis. Cadiovascula Common: flushing. Musculoskeletal Common: athalgia, athitis, muscle, joint and bone pain. In chonic hypevitaminosis A syndome, deminealisation and aefaction of bone, cotical hypeostosis, peiosteal calcification, pematue epiphyseal closues (see Pecautions, Paediatic Use). In long-tem teatment, ievesible hypeostosis and exta-skeletal calcification e.g. spinal hypeostosis and calcification of spinal ligaments esulting in spinal cod compession (see Pecautions, Hypeostosis). Rae: elevated seum ceatine kinase (CK); myalgia in the case of maked CK elevation. Neuological and Psychiatic Common: headache, fatigue, depession, solmnolence. Uncommon: lassitude, vetigo, distubance of consciousness, abnomal thinking, emotional lability, aggessive feelings. Rae: pseudotumou ceebi (see Pecautions, Pseudotumou Ceebi). Endocine Rae: gynaecomastia. NEOTIGASON PRODUCT INFORMATION APPROVED 21 ST JANUARY (11)

9 Metabolic and Nutitional Vey Common: elevated seum cholesteol and tiglyceides (see Pecautions, Hepatic Toxicity). Rae: oedema, thist. Live and Biliay System Vey Common: elevated seum tansaminases and alkaline phosphatase (see Pecautions, Lipids). Uncommon: jaundice, hepatitis. Gastointestinal Vey Common: cheilitis, hagades of cone of mouth, dy mouth. Common: somatitis, gingivitis. Uncommon: gastitis, heatbun, inflammatoy bowel disodes. Rae: panceatitis. Genitouinay Rae: metohagia. Immunological Uncommon: vulvovaginitis due to Candida albicans. DOSAGE AND ADMINISTRATION Adults Because thee ae diffeences in the absoption and ate of metabolism of acitetin, the dosage must be individually adjusted. The capsules should be taken pefeably once daily with meals, o with milk. An initial dosage of 25 mg o 30 mg fo about two to fou weeks may give satisfactoy theapeutic esults. The maintenance dose must be based on clinical efficacy and toleance. In geneal, a daily dosage of mg taken fo a futhe six to eight weeks achieves optimal theapeutic esults. Theapy can be teminated in patients with psoiasis whose lesions have esolved sufficiently. Relapses should be teated as descibed above. In disodes of keatinisation, a continuous maintenance is mostly needed with the dose at the lowest possible level. This may be less than 20 mg and should not exceed 50 mg daily. NEOTIGASON PRODUCT INFORMATION APPROVED 21 ST JANUARY (11)

10 Childen The dosage should be established on a weight basis. The daily dosage is about 0.5 mg/kg. Highe doses up to 1 mg/kg o 35 mg daily may be necessay in some cases fo limited peiods. Maintenance doses should be kept as low as possible in view of possible long tem advese effects. Combined Teatment When NEOTIGASON is used in combination with othe types of theapy, it may be possible, depending on the patient's individual esponse, to educe the dosage of NEOTIGASON (see PRECAUTIONS Inteactions with Othe Medicines). Standad topical teatments can geneally be continued and do not intefee with NEOTIGASON. OVERDOSAGE In the event of acute ovedosage, NEOTIGASON must be withdawn at once. Symptoms of ovedose ae identical to an acute hypevitaminosis A, i.e. headache and vetigo. The acute oal toxicity (LD 50 ) of acitetin in both mice and ats was geate than 4000 mg/kg. Teatment of ovedose should consist of geneal suppotive measues. Contact the Poisons Infomation Cente fo advice on management of ovedose. PRESENTATION AND STORAGE CONDITIONS NEOTIGASON 10 mg had gelatine capsules have a white opaque body and a bown opaque cap with the wod ROCHE pinted in black ink on both body and cap. NEOTIGASON 25 mg had gelatine capsules have a yellow opaque body and a bown opaque cap with the wod ROCHE pinted in black ink on both body and cap. Capsules 10 mg, catons of 100 Capsules 25 mg, catons of 100 Stoe below 25 o C The poduct is sensitive to moistue, theefoe, stoe in the oiginal package. POISON SCHEDULE OF THE MEDICINE Schedule 4 Pesciption only medicine NEOTIGASON PRODUCT INFORMATION APPROVED 21 ST JANUARY (11)

11 NAME AND ADDRESS OF THE SPONSOR Roche Poducts Pty Limited ABN Inman Road DEE WHY NSW 2099 TGA Appoval Date: 21 st Januay 2008 NEOTIGASON PRODUCT INFORMATION APPROVED 21 ST JANUARY (11)