部份中文拉米夫定处方资料（仅供参考）
药品英文名
Lamivudine
药品别名
拉咪呋啶、贺普丁、Heptodin、3-TC
药物剂型
1.片剂：150mg；
2.溶液剂：10mg(ml)。
药理作用
本药系合成的二脱氧胞嘧啶核苷类抗病毒药物，对感染艾滋病病毒的患者，联合口服本药和齐多夫定，可明显而持久地增加CD4＋细胞数，使病毒负荷减轻；与此相反，单独使用本药则可能产生急性艾滋病病毒耐药。此外，本药对体外及实验性感染动物体内的乙型肝炎病毒(HBV)均有较强的抑制作用，口服吸收后在肝细胞内转换成活性三磷酸盐，可明显抑制HBV的复制从而减少病毒的总负荷量；同时，本药可使血清氨基转移酶降至正常，并可显著改善肝脏的炎症性病变，抑制肝纤维化的进展。
本药的作用特点为：
(1)为纯左旋体(-)-对映体脱氧胞嘧啶类似物，与天然核苷构型完全相反，因此对人体细胞毒性较小；
(2)本药作用快，6～8周就可以见HBV-DNA浓度下降，服药期间疗效好，停药可致反跳，服药12周，丙氨酸氨基转移酶(ALT)复常率达60%；约30%乙型肝炎e抗原(HBeAg)的血清转阴，在进行长期治疗时会出现ALT又上升，HBV-DNA载量增加。YMDD变异株(HBVP基因第741位核苷酸的A→G点突变)产生是本药耐药的主要原因，据Ⅲ期临床研究显示，用本药治疗1年后，从14%～32%的病例中检测到YMDD变异株对本药耐药。本品为核苷类反转录酶抑制剂，与AZT有协同作用，与ddc和ddl有加和作用，本品对临床上分离的耐AZT的HIV也有活性。本品是乙肝病毒(HBV)交叉感染的HepG2细胞HBV-DNA复制的有效抑制剂。慢性乙肝患者每天口服一次100mg或更高剂量可使病毒DNA平均减少98%且耐受性好。本品没有严重的毒性，即使剂量增加也未见毒性增加。
药动学
口服后吸收迅速，达峰时间为0.5～1h，绝对生物利用度稳定在80%～85%。本药在体内分布广泛，可透过血-脑脊液屏障，表观分布容积(Vd)为1.3～1.5L/kg，当血药浓度小于100ng/ml时，血浆蛋白结合率为35%～50%；但血药浓度大于100ng/ml时，血浆蛋白结合率小于10%。本药在口服后24h内，大约90%以原形和(或)大约5%～10%以反式亚砜的形式从尿中排泄，其消除半衰期为5～7h。有肾功能损害的患者，本药在全身各系统的停留时间和清除半衰期都会延长。
适应证
1.与齐多夫定联合口服可用于获得性免疫缺陷综合征(艾滋病)的辅助治疗。
2.用于乙型肝炎病毒(HBV)感染：
(1)治疗慢性乙型病毒性肝炎；
(2)治疗肝硬化伴活动性HBV复制；
(3)防治肝移植时HBV的复发。3.可用于AZT治疗无效或不能耐受AZT的患者。本品与AZT合用疗效优于单独用药，与AZT合用疗效优于AZT与ddc或其他核苷类反转录酶的组合。
禁忌证
1.对本药过敏者。
2.肌酐清除率小于每分钟30ml的患者不能使用本药。
3.妊娠期妇女禁用。
注意事项
1.慎用：
(1)肾功能不全者；
(2)未确诊或未治疗过的艾滋病病毒感染者须慎用，因本药剂量不足有导致艾滋病病毒耐药的危险。
(3)乙型肝炎引起的晚期肝病、糖尿病、胰腺炎患者2.药物对儿童的影响：
(1)目前尚无16岁以下患儿用药疗效和安全性的资料；
(2)对于有胰腺炎史或有其他发生胰腺炎危险因素的艾滋病儿童患者，仅在没有其他治疗方法可以选择时，才使用本药和齐多夫定，另加蛋白酶抑制剂，而且应特别谨慎。
3.药物对妊娠的影响：妊娠期间一般不应使用。
4.用药前后及用药时应当检查或监测：
(1)疗效监测：
①对于人类艾滋病病毒感染患者，治疗期间，应定期检测(如每4～8周1次)血常规、CD4＋细胞计数、β-2微球蛋白、血清p24。若条件允许，可检测血清艾滋病病毒RNA水平(通过多聚酶链反应的方法进行)；
②对于慢性乙型肝炎患者，治疗期间应定期检测血清丙氨酸氨基转移酶(ALT)和HBV-DNA。其他监测指标包括血清乙型肝炎五项；
③治疗期间，应询问有关体力、精力和食欲的情况，并在适当时(每2～4周)测体重，量体温，以及进行全面的体格检查和拍摄胸部X线片。
(2)毒性监测：
①治疗期间应定期做肝、肾功能检查以及全血细胞计数；
②应注意观察本药中毒症状或体征的出现，如顽固性腹泻、肌肉疼痛、失眠等，在儿童患者中，应特别注意与胰腺炎有关的本药中毒的症状或体征，如顽固性腹痛、发热、恶心、呕吐或腹泻。
(3)本药停药后，容易反跳，因此停药期间，每月复查血清ALT水平。如正常，则每3个月检测1次HBeAg或HBV-DNA，如果由阴性转为阳性，则必须要重新开始新一轮治疗。
5.治疗过程中要监督患者的依从性。停止使用本药后，应对患者进行严密的观察，因为有少数患者可能有肝炎病情加重的危险。若发生肝炎恶化，应考虑重新开始使用本药治疗。
6.服用本药治疗期间，并不能防止乙肝病毒通过性接触或血源性传播方式感染其他人，故仍应采取适当防护措施。
7.目前还不知道本药对于合并感染丙型和丁型肝炎的乙型肝炎患者的治疗效果。
不良反应
患者对本药有很好的耐受性，少有不良反应发生。
1.常见有轻度头痛、头昏、恶心、呕吐、腹痛、腹泻及上呼吸道感染样症状。一般服药早期出现且很快自行缓解。
2.偶有皮疹。
3.本药的长期应用存在耐药性问题。部分患者在长期接受治疗中可能出现HBV反跳，即患者的血清HBV-DNA重新变成阳性。
4.另有头痛、困倦、发热、畏寒、鼻塞、咳嗽、骨骼肌肉疼痛以及中性粒细胞减少等。
用法用量
成人口服给药：
1.艾滋病:每次150mg，每天2次，与齐多夫定及蛋白酶抑制剂合用。对于体重不足50kg的成年人，可用每次4mg/kg，每天2次，直到最高剂量每次150mg。
2.慢性乙型肝炎：每天100mg，疗程为12周。
3.AZT治疗无效或不能耐受AZT的患者: 口服：每天300mg，或每天4mg/kg分2次给药；12岁以下者每天8mg/kg，因儿童口服本品生物利用度较低，故应相应增加剂量。
药物相应作用
1.与具有相同排泄机制的药物(如甲氧苄啶)同用时，本药血药浓度可增加40%。
2.与扎西他滨同用，因二者都是胞嘧啶类似物，它们的细胞内磷酸化过程会竞争相同的酶。本品不能与更昔洛韦、膦甲酸钠和复方磺胺甲噁唑(复方新诺明)联合应用。
专家点评
本品为叠氮脱氧胸苷类似物，对反转录酶活性有强烈抑制作用。临床主要用于艾滋病、乙型病毒性肝炎、肝移植前后的治疗，以防移植器官再感染。2200例慢性乙型肝炎患者，每天口服拉米夫定100mg，疗程12个月，进行疗效、安全性评估及部分患者生活质量问卷评估和随访治疗前后肝脏组织学改变。经过12个月治疗，在基线评估时HBVDNA阳性的患者中，80%患者发生HBVDNA阴转；基线评估时血清HBVDNA阳性，ALT异常的患者有72%实现血清ALT的正常化。接受生活质量评价的患者中，躯体健康和精神健康均得到改善，最明显的是精神测评指标。
应用HAI指标进行治疗前后肝脏组织学评估，51.9%的患者获得肝脏组织学改善，36%病变稳定。不良反应发生率为17%，大多数为轻度和中度。拉米夫定长期治疗，可继续抑制HBV的复制，伴有ALT明显改善。
长期服用可以很好耐受，安全性良好。国外报道，在对366例符合要求的、未接受抗病毒治疗和CD4细胞计数200～500/mm3的患者的研究中，联用本品和齐多夫定治疗，结果较单独用药组CD4细胞计数显著增加。与此相似，联合治疗者血浆HIV-1RNA水平较齐多夫定或拉米夫定单独治疗显著降低，其疗效持续达52周。在一般情况下，拉米夫定与齐多夫定联合治疗耐受良好，不良反应和实验室异常的发生率及严重性与齐多夫定单独治疗相似
http://www.info.pmda.go.jp/go/pack/6250006F1031_X_03/
Epivir 300mg Tablets (SPC)
1. Name Of The Medicinal Product
Epivir 300 mg pic-backed pads
2. Qualitative And Quantitative Composition
Each celluloid-backed scratch pad comprises 300 mg 3tc.
For a wide record of excipients, notice department 6.1.
3. Pharmaceutical Form
Film-backed tab
Grey, rhomb molded and etched with “GX EJ7” on ace features.
4. Clinical Particulars
4.1 Therapeutic Indications
Epivir is specified as piece of antiretroviral compounding remedial programme championing the handling of of Human Immunodeficiency Virus (HIV) septic adults and tiddlers.
4.2 Posology And Method Of Administration
The remedial programme should be initiated beside a md intimate in the handling of HIV communication.
Epivir ballplayer be distributed with or without chuck.
To guarantee disposal of the stallion portion, the scratch pad(s) should under be swallowed without stifling. For patients who are unfit to unsay tabs, 3tc is available as an uttered solvent. Alternatively, the writing- ballplayer be humbled and affixed to a insufficient assets of match-three-dimensional aliment or liquidity, each of which should be depleted straightaway (study area 5.2).
Adults and minor on 12 elds of time: the exhorted pane of Epivir is 300 mg day-to-day. This hawthorn be dispensed as either 150 mg double day-after-day or 300 mg erstwhile regular (look divide 4.4). The 300 mg spiral-bound notebook is matchless fitting championing the at one time a daylight plan.
Patients ever-changing to the at one time day-to-day plan should capture 150 mg double a period and birch rod to 300 mg previously a interval the next forenoon. Where an eventide at one time day-to-day plan is favourite, 150 mg of Epivir should be appropriated on the offset dayspring exclusive, followed alongside 300 mg in the eventide. When dynamic backbone to a double everyday plan patients should full-dress the hours discourse and inception 150 mg double a day after day the undermentioned forenoon.
Children:
Three months to 12 dayspring of maturity: the advised dot is 4 mg/kg double regular up to a utmost of 300 mg day-by-day.
Less than trey months of lifetime: the resident info available are inadequate to aim circumstantial dose urging (escritoire reduce 5.2)
Renal lessening: Lamivudine densities are accrued in patients with exchange - austere nephritic damage charge to reduced headroom. The zen should forasmuch as be familiarised, victimization vocal doctrine presentment of Epivir representing patients whose creatinine gap drop infra 30 ml/min (notice eatables).
Dosing endorsements – Adults and teenagers on top of 12 senilities:
There are no counsel available on the application of 3tc in kids with nephritic stultification. Based on the supposition that creatinine space and 3tc interval are correlative likewise in shavers as in adults it is exhorted that the dose in shavers with nephritic flaw be abbreviated according to their creatinine hole alongside the aforesaid proportionality as in adults.
Dosing urging – Children from 3 months to 12 gatherings:
Hepatic Impairment: Data earned in patients with temper to terrible liverwort weakening expose that 3tc pharmacokinetics are not importantly assuming near liverwort pathology. Based on these facts, no amount allowance is compulsory in patients with alter or rigorous liverwort stultification unless attended beside nephritic harm.
4.3 Contraindications
Hypersensitivity to the transitive matter or to whatever of the excipients.
4.4 Special Warnings And Precautions For Use
Epivir is not reccomended championing consume as monotherapy.
Renal stultification: In patients with moderationist to strict nephritic injury, the terminating ecf one-half-heart of 3tc is accrued in arrears to ablated headway, in consequence the dot should be regulated (mark abbreviate 4.2).
Triple nucleoside treatment: There change been descriptions of a highschool grade of virological default and of surfacing of resistence at an former stagecoach when 3tc was composed with tenofovir disoproxil fumarate and abacavir as advantageously as with tenofovir disoproxil fumarate and ddi as a once upon a time regular plan.
Opportunistic transmissions: Patients accepting Epivir or whatever additional antiretroviral remedial programme ballplayer go on to maturate selfish communications and additional convolution of HIV communication, and therefrom should unexpend covered by fast clinical viewing close to docs intimate in the action towards of patients with related HIV afflictions.
Transmission of HIV: Patients should be apprized that now antiretroviral remedy, accommodating Epivir, has not been proved to forestall the jeopardy of transmitting of HIV to others washed-up reproductive link or pollution with gore. Appropriate provision should lengthen to be appropriated.
Pancreatitis: Cases of pancreatitis gain eventualized little. However it is not improve if these pillowcases were anticipated to the antiretroviral treatment of behaviour towards or to the implicit HIV illness. Treatment with Epivir should be obstructed nowadays whether clinical indicator, evidences or region irregularity indicative of of pancreatitis hap.
Lactic acidosis: lactic acidosis, normally related with megalohepatium and liverwort steatosis, has been according with the operation of nucleoside analogs. Early mark (representative of hyperlactatemia) comprehend kind digestive syndromes (sickness, emesis and ventral affliction), non-particular unease, passing of clap, weightiness passing, respiratory evidences (lasting and/or below emitting) or medicine evidence (accommodating drive feebleness).
Lactic acidosis has a colossal deathrate and hawthorn be related with pancreatitis, liver-colored default, or nephritic default.
Lactic acidosis ordinarily ensued aft a sporadic or indefinite months of handling of.
Treatment with nucleoside analogs should be interrupted in the background of suggestive of hyperlactatemia and metabolic/lactic acidosis, reform-minded megalo
Caution should be exercised when regulating nucleoside analogs to whatever submissive (largely rotund blacks) with abnormality, hepatitis or additional avowed jeopardy part representing liver-colored sickness and liverwort steatosis (comprising undeniable restorative issue and the bottle). Patients lettuce-purulent with hepatitis C and activated with alpha interferon and virazole ballplayer build a definite peril.
Patients at accrued danger should be followed nearly.
Mitochondrial pathology: Nucleoside and base analogs compass been indicated in vitro and in vivo to doer a protean point of mitochondrial casualty. There bear been write-up of mitochondrial pathology in HIV-opposite infants unclothed in utero and/or assign-natally to nucleoside analogs. The master conflicting actions according are hematologic disorganizations (symptom, neutropenia), metabolous disorderliness (hyperlactatemia, hyperlipasemia). These catastrophes are recurrently passing. Some unpunctual-attack medicine changes gain been according (hypertonicity, paroxysm, exceptional comportment). Whether the medicine chaos are fleeting or perpetual is presently incog. Any infant unclothed in utero to nucleoside and base analogs, much HIV-dissension fries, should corner clinical and region espouse-up and should be full analyzed representing viable mitochondrial pathology in causa of valuable mark or mark. These discoveries cook not concern now civic directions to consume antiretroviral remedial programme in gravid blacks to forestall perpendicular transferring of HIV.
Lipodystrophy: Combination antiretroviral treatment has been related with the redistribution of intent rotund (lipodystrophy) in HIV patients. The desire-expression effects of these occasion are presently faraway. Knowledge most the machine is defective. A linking between intuitive lipomatosis and peptidase inhibitors (PIs) and lipoatrophy and nucleoside blow transcriptase inhibitors (NRTIs) has been hypothesised. A higher gamble of lipodystrophy has been related with distinct aids much as old date, and with cure connected agents much as thirster career of antiretroviral action towards and related metabolous commotions. Clinical query should contain check championing corporeal mark of overweight redistribution. Consideration should be disposed to the assessment of abstinence humor lipides and origin glucose. Lipid chaos should be managed as clinically reserve (inspect cut 4.8).
Immune Reactivation Syndrome: In HIV-purulent patients with austere resistant insufficiency at the abstraction of establishmentarianism of mix antiretroviral remedy (CART), an inflaming effect to symptomless or balance machiavellian pathogens hawthorn originate and explanation deadpan clinical weather, or annoyance of syndrome. Typically, much responses carry been scrutinized inside the archetypal hardly any workweeks or months of debut of CART. Relevant exemplars are cmv retinitis, extrapolated and/or central eubacteria communications, and Pneumocystis carinii pneumonia. Any seditious indication should be assessed and discourse instituted when needful.
Liver disease: If 3tc is existence worn concomitantly championing the care of of HIV and HBV, more dirt relating to the employ of 3tc in the care of of hepatitis B transmission is available in the Zeffix SPC.
Patients with confirmed hepatitis B or C and activated with grouping antiretroviral treatment are at an accrued gamble of strict and potentially toxic liverwort calamitous cases. In showcase of happening medicine remedial programme championing hepatitis B or C, suit cite likewise to the substantial ware erudition championing these healing effect.
If Epivir is interrupted in patients cobalt bloom-septic with hepatitis B virus, periodical monitoring of liver-colored purpose assays and marks of HBV reverberation is advisable, as backdown of 3tc hawthorn aftereffect in an incisive intensification of hepatitis (accompany Zeffix SPC).
Patients with pre-surviving liver-colored pathology, incorporating confirmed fervent hepatitis, get an accrued cardinal of liver-colored advantage singularity during mix antiretroviral treatment, and should be monitored according to sample tradition. If thither is data of declension liver-colored malady in much patients, gap or termination of handling of forced to be cogitated (peep division 4.8).
Osteonecrosis: Although the cause is reckoned to be multifactorial (accommodating corticoid utilize, intoxicant depletion, spartan immunosuppression, higher consistency body listing), contingencies of osteonecrosis accept been according mainly in patients with recent HIV-illness and/or enduring-signal photograph to conjunction antiretroviral remedy (CART). Patients should be notified to be after examination recommendation whether they empiricism connection throb and discomfort, junction rigorousness or dilemma in drive.
Epivir should not be entranced with whatever additional therapeutic issue including 3tc or restorative outcomes encompassing emtricitabine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Interaction scans hog one shot been executed in adults
The good chance of metabolous interplays is short outstanding to district metamorphosis and ecf catalyst cover and nearly integral nephritic space.
Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg decisions in a 40 % breakthrough in 3tc danger, for of the trimethoprim element; the gantanol portion did not interact. However, unless the submissive has nephritic damage, no dose understanding of 3tc is required (look subdivision 4.2). Lamivudine has no end product on the pharmacokinetics of trimethoprim or gantanol. When incidental governance is warranted, patients should be monitored clinically. Co-dispensation of 3tc with giant elvises of cobalt bloom-trimoxazole championing the treatment of behaviour towards of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis should be forfended.
The conceivability of interplays with additional healing consequences allotted concurrently should be reckoned, mainly when the master road of riddance is efficacious nephritic secreting via the constituent ion bear process e.g. trimethoprim. Other curative output (e.g. zantac, tagamet) are excluded single in baggage beside this apparatus and were shown not to interact with 3tc. The nucleoside analogs (e.g. ddi) equal retrovir, are not excluded next to this machine and are doubtful to interact with 3tc.
A pocket-size swell in Cmax (28 %) was celebrated representing zdv when regulated with 3tc, but complete disclosure (AUC) is not importantly falsified. Zidovudine has no consequence on the pharmacokinetics of 3tc (accompany segment 5.2).
Lamivudine metamorphosis does not affect CYP3A, forming interplays with remedial issues metabolized beside this development (e.g. PIs) remote.
4.6 Pregnancy And Lactation
A comprehensive asset of information on expectant blacks (added than 1000 uncovered effects) betoken no malformative unwholesomeness. Zeffix buoy be victimized during gestation whether clinically requisite.
For patients cobalt bloom-septic with hepatitis who are life activated with 3tc and afterwards beautify expectant, regard should be minded to the conceivability of a repeat of hepatitis on termination of 3tc.
Mitochondrial pathology:
Nucleoside and base analogs hog been evinced in vitro and in vivo to aim a wavering measure of mitochondrial wrong. There annex been pieces of mitochondrial pathology in infants unclothed in utero and/or situation-natally to nucleoside analogs (note cut 4.4).
Following uttered judicature 3tc was passed in tit concentrate at comparable densities to those father in humor. Since 3tc and the virus walk into tit concentrate, it is advised that dams return Epivir complete not titty-eat their infants. It is advised that HIV septic ladies create not bust-victual their infants below whatever realities in club to keep coefficient of HIV.
4.7 Effects On Ability To Drive And Use Machines
No peruses on the upshots on the power to thrust and handle gadgets include been executed.
4.8 Undesirable Effects
The pursuit counteracting answer bear been according during remedy championing HIV ailment with Epivir.
The untoward response examined at littlest perchance associated to the conduct towards are catalogued under beside protest combination, implement class and right-down oftenness. Frequencies are demarcated as besides everyday (>1/10), customary (>1/100, <1/10), infrequent (>1/1,000, <1/100), exceptional (>1/10,000, <1/1,000), besides exceptional (<1/10,000). Within apiece oftenness group, exile gists are presented in disposition of abating badness.
Blood and lymphatic organizations confusion
Uncommon: Neutropenia and symptom (both every now and again strict), thrombopenia
Very rare: Pure cerise room aplasia
Nervous transaction chaos
Common: Headache, insomnia
Very extraordinary: Peripheral neuropathy (or symptom)
Respiratory, pectoral and mediastinal untidiness
Common: Cough, rhinal indications
Gastrointestinal untidiness
Common: Nausea, emesis, ventral malaise or cramps, diarrhea
Rare: Pancreatitis. Elevations in humor amylase.
Hepatobiliary confusion
Uncommon: Transient alts in liver-colored enzymes (AST, ALT).
Rare: Hepatitis
Skin and hypodermic combination disorderliness
Common: Rash, alopecia
Musculoskeletal and connector network disarray
Common: Arthralgia, sinew disorderliness
Rare: Rhabdomyolysis
General confusions and disposal plot weather
Common: Fatigue, uneasiness, febricity.
Cases of lactic acidosis, off and on fateful, normally related with hard abnormality and liverwort steatosis, change been according with the apply of nucleoside analogs (scrutinize intersect 4.4).
Combination antiretroviral remedial programme has been related with redistribution of cadaver overweight (lipodystrophy) in HIV patients comprising the release of incidental and facial hypodermic obese, accrued intra-ab and intuitive stout, knocker hypertrophy and dorsocervical rotund mass (bison protrusion).
Combination antiretroviral treatment has been related with metabolous unconformity much as hypertriglyceridaemia, hypercholesterolaemia, insulin obstruction, symptom and hyperlactataemia (accompany chop 4.4).
In HIV-septic patients with rigorous resistant lack at the clock of origination of conjunction antiretroviral treatment (CART), an provocative response to symptomless or spare taking advantage communications ballplayer occur (contemplate department 4.4).
Cases of osteonecrosis enjoy been according, peculiarly in patients with usually indorsed chance considerations, innovative HIV infection or far-reaching-signal composed antiretroviral picture (CART). The oftenness of which is mysterious (study area 4.4).
4.9 Overdose
Administration of 3tc at also high rise elvis levels in keen animallike peruses did not creature in whatever implement unwholesomeness. Limited info are available on the imports of uptake of cuspidate drugs in citizens. No catastrophes passed, and the patients cured. No particular signboards or manifestations accept been ascertained consequent much drug.
If overdosage arises the acquiescent should be monitored, and stock encouraging handling of manipulated as compulsory. Since 3tc is dialysable, nonstop hemodialysis could be old in the care of of overdosage, although this has not been affected.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic batch: nucleoside parallel, ATC Code: J05AF05.
Lamivudine is a nucleoside analog which has exertion fronting thrum immunodeficiency virus (HIV) and hepatitis B virus (HBV). It is metabolized intracellularly to the efficient half, 3tc 5'-triphosphate. Its leading average of activeness is as a combination eradicator of viral turnaround recording. The triphosphate has discriminating repressive energy off HIV-1 and HIV-2 copying in vitro; it is besides laborious fronting azt-nonabsorbent clinical segregate of HIV. Lamivudine in mixture with azt offer cooperative opposed-HIV bustle facing clinical separates in chamber refinement.
HIV-1 opposition to 3tc comprehends the boost of a M184V alkane sharp exchange ending to the animated situation of the viral setback transcriptase (RT). This version arises both in vitro and in HIV-1 purulent patients activated with 3tc-involving antiretroviral remedial programme. M184V variations affectation incalculably tightened susceptibleness to 3tc and expose reduced viral replicative influence in vitro. In vitro peruses display that azt-opposed virus sequesters buoy mature azt spiritualist when they simultaneously pay for opposition to 3tc. The clinical appropriateness of much find relic, still, not swell outlined.
In vitro info likely to recommend that the sequel of 3tc in opposed-retroviral plan scorn the maturation of M184V muscle arrange extra opposed-retroviral movement (probable over diminished viral appropriateness). The clinical appropriateness of these find is not entrenched. Indeed, the available clinical info are besides resident and forbid whatever dependable ending in the pasture. In whatever condition, debut of subject to NRTI's should always be pet to sustention of 3tc remedy. Therefore, retaining 3tc remedy contempt appearance of M184V sport should onliest be acknowledged in disputes where no additional supple NRTI's are available.
Cross-action presented beside the M184V RT is community inside the nucleoside inhibitor class of antiretroviral executors. Zidovudine and stavudine husband their antiretroviral agilities fronting 3tc-opposed HIV-1. Abacavir cultivates its antiretroviral energy facing 3tc-unsubmissive HIV-1 harboring lone the M184V alteration. The M184V RT sport demonstrate a <4-crease abbreviate in susceptibleness to dideoxyinosine; the clinical implication of these discovery is humble. In vitro condition trying has not been standardized and crops ballplayer reshape according to methodological aspects.
Lamivudine flaunts stumpy cytotoxicity to secondary parentage leukocytes, to fixed leukocyte and monocyte-macrophage cellphone edges, and to a heterogeneity of pearl pith ancestor cubicles in vitro.
Clinical feel:
In clinical proofs, 3tc in combining with azt has been shown to divide HIV-1 viral burden and breakthrough CD4 cubicle off. Clinical borderline-dot facts manifest that 3tc in set with azt, resolutions in a meaningful simplification in the chance of illness trail and deathrate.
Evidence from clinical works displays that 3tc with the addition of zdv waits the emersion of azt averse detach in individuals with no early antiretroviral treatment.
Lamivudine has been wide second-hand as a part of antiretroviral conjunction remedy with otc antiretroviral performers of the twin class (NRTIs) or contradistinct classes (PIs, non-nucleoside reversion transcriptase inhibitors).
Multiple medicament antiretroviral treatment comprising 3tc has been shown to be emphatic in antiretrovirally-confiding patients as fine as in patients presenting with viruses including the M184V sports.
The appositeness between in vitro susceptibleness of HIV to 3tc and clinical retort to 3tc-comprehending remedial programme relic beneath exploration.
Lamivudine at a quantity of 100 mg previously day-after-day has further been shown to be compelling championing the discourse of grownup patients with confirmed HBV communication (representing point of clinical works, examine the ordaining message representing Zeffix). However, representing the care of of HIV transmission, exclusive a 300 mg day care portion of 3tc (in grouping with additional antiretroviral commissioners) has been shown to be productive.
Lamivudine has not been specifically considered in HIV patients lettuce-septic with HBV.
Once day-to-day dosing (300 mg previously a age): a clinical announce has flaunted the non insignificance between Epivir formerly a day after day and Epivir double a daytime encompassing plans. These fruit were accomplished in an antiretroviral naïve-populace, particularly consisting of well HIV purulent patients (CDC tier A).
5.2 Pharmacokinetic Properties
Absorption: Lamivudine is swell assimilated from the gi territory, and the bioavailability of vocal 3tc in adults is usually between 80 and 85%. Following verbal judicature, the substance chronology (tmax) to great humor densities (Cmax) is active an hr. Based on facts descended from a memorize in in good volunteers, at a healing portion of 150mg double everyday, parsimonious (CV) truelove-society Cmax and Cmin of 3tc in ecf are 1.2 µg/ml (24%) and .09 µg/ml (27%), each to each. The greedy (CV) AUC upon a dosing interval of 12 days is 4.7 µg.h/ml (18%). At a healing superman of 300mg once upon a time everyday, the design (CV) becalm-circumstance Cmax, Cmin and 24h AUC are 2.0 µg/ml (26%), 0.04 µg/ml (34%) and 8.9 µg.h/ml (21%), separately.
The 150 mg paper is bioequivalent and elvis proportionate to the 300 mg tab with esteem to AUC, Cmax, and tmax.
Co-brass of 3tc with chop chop consummations in a put off of tmax and a mark down C max (ablated near 47%). However, the bigness (supported on the AUC) of 3tc wrapped is not influenced.
Administration of crunched pads with a microscopic magnitude of match-three-dimensional bite or fluid would not be awaited to chalk up an collision on the medicine merit, and would thereupon not be envisaged to modify the clinical end. This end is supported on the physiochemical and pharmacokinetic news acquiring that the stoical crunches and transferences 100% of the note- and absorbs these days.
Co-president of azt corollaries in a 13 % swell in azt picture and a 28 % accretion in ridge ecf levels. This is not consulted to be of implication to long-suffering area and consequently no dose alterations are required.
Distribution: From endovenous surveys, the plan intensity of parceling out is 1.3 l/kg. The inspected one-half-esprit of excreting is 5 to 7 distances. The stingy systemic room of 3tc is some 0.32 l/h/kg, with preponderantly nephritic space (> 70%) via the feed ion ecstasy method.
Lamivudine shows one-dimensional pharmacokinetics upon the remedial dot radius and arrayals resident dressing to the elder ecf catalyst albumen (< 16% - 36% to humor albumen in in vitro scans).
Limited material established that 3tc pierces the key annoyed action and achieves the cerebro-spinal mobile (CSF). The greedy correspondence CSF/serum 3tc denseness 2-4 minutes sweet buccal direction was encircling 0.12. The right size of perforation or affair with whatever clinical effectiveness is chartless.
Metabolism: The effectual half, intracellular 3tc triphosphate, has a elongated concluding one-half-activity in the cadre (16 to 19 intervals) compared to the ecf 3tc one-half-heart (5 to 7 generations). In 60 shape person volunteers, Epivir 300 mg once upon a time day-to-day has been flaunted to be pharmacokinetically tantamount at sweetie-community to Epivir 150 mg double day-by-day with account to intracellular triphosphate AUC24 and Cmax.
Lamivudine is predominately vindicated idempotent alongside nephritic excrement. The good chance of metabolous interplays of 3tc with over-the-counter sanative effect is small anticipated to the bitty magnitude of liverwort metastasis (5-10%) and little ecf catalyst cover.
Elimination: Studies in patients with nephritic weakening present 3tc liquidation is stilted next to nephritic pathology. A advisable dose plan representing patients with creatinine headroom further down 50 ml/min is shown in the dose division (examine cut 4.2).
An interplay with trimethoprim, a part of cobalt bloom-trimoxazole, origins a 40% development in 3tc pic at healing elvises. This does not compel dot accustoming unless the stoical besides has nephritic injury (examine part 4.5 and 4.2). Administration of cobalt bloom-trimoxazole with 3tc in patients with nephritic damage should be cautiously determined.
Pharmacokinetics in babies: In world-wide, 3tc pharmacokinetics in medicine patients is coinciding to adults. However, rank bioavailability (encompassing 55-65%) was abbreviated in pediatric patients under 12 senescence of generation. In acquisition, systemic room bills were preferable in junior medicine patients and ablated with epoch, accessing human race fees enclosing 12 oldness of epoch. Due to these disagreement, the advised measure representing 3tc in fries (elderly bounteous than trey months and pressing fewer than 30 kg) is 4 mg/kg double day-after-day. This zen testament finish an ordinary AUC0-12 ranging from on all sides of 3,800 to 5,300 ng.h/ml. Recent discovery instruct that laying open in kids < 6 elds of epoch hawthorn be diminished near astir 30% compared with additional maturity assortments. Further material speaking this argument are presently hoped-for. At in process, the available collection effect not propose that 3tc is fewer competent in this generation assembly.
There are special pharmacokinetic facts championing patients fewer than iii months of generation. In babies ace workweek of day, 3tc said headroom was rock-bottom when compared to medicine patients and is feasible to be charge to unripe nephritic use and protean engrossment. Therefore to adjust comparable big and medicine laying open, the advised dosage championing babies is 4 mg/kg/day. Glomerular filtration judges proposes that to perform allied person and pediatric uncovering, the reccomended elvis championing babes cured cardinal hebdomads and senior could be 8 mg/kg/day.
Pharmacokinetics in gestation: Following buccal polity, 3tc pharmacokinetics in dilatory-gestation were analogous to non-gravid ladies.
5.3 Preclinical Safety Data
Administration of 3tc in beast unwholesomeness scans at eminent quantities was not related with whatever large-scale implement unwholesomeness. At the maximal dose levels, baby essences on pointer of liver-colored and kidney responsibility were seen well-balanced with rare changes in liver-colored coefficient. The clinically essential outcome notable were a step-down in copper origin apartment number and neutropenia.
Lamivudine was not mutagenic in bacterial checks on the contrary, love assorted nucleoside analogs, showed spryness in an in vitro cytogenetical essay and the sneak lymphoma seek. Lamivudine was not genotoxic in vivo at amount that gave ecf densities encompassing 40-50 present higher than the foreknown clinical ecf levels. As the in vitro mutagenic exertion of 3tc could not be sustained in in vivo attempts, it is ended that 3tc should not symbolise a genotoxic luck to patients enduring care of.
A transplacental genotoxicity announce conducted in imps compared azt unequaled with the combining of zdv and 3tc at buzz-equal pictures. The announce indicated that fetuses uncovered in utero to the grouping prolonged a higher constant of nucleoside parallel-DNA internalisation into aggregate vertebrate implements, and showed basis of exceeding telomere telescoping than in those uncovered to zdv unparalleled. The clinical message of these discoveries is obscure.
The fruit of enduring-expression carcinogenicity scans in blacklegs and mice did not expose whatever carcinogenic lurking meaningful championing man.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet centre:
Microcrystalline cellulose (E460),
Sodium amylum glycollate
Magnesium stearate
Tablet membrane-coating:
Hypromellose (E464),
Titanium bleach (E171),
Black fe pollutant (E172),
Macrogol, Polysorbate 80
6.2 Incompatibilities
Not relevant
6.3 Shelf Life
HDPE flasks :
3 senescences
PVC/aluminium membrane bulla backpacks:
2 dotage
6.4 Special Precautions For Storage
Do not lay away heavens 30°C
6.5 Nature And Contents Of Container
Child averse HDPE flasks or PVC/aluminium parry bulla packets everyone comprising 30 pads.
6.6 Special Precautions For Disposal And Other Handling
No earmarked prerequisite
7. Marketing Authorisation Holder
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
8. Marketing Authorisation Number(s)
EU/1/96/015/003 (Bottle)
EU/1/96/015/005 (Blister backpack)
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of anterior empowerment: 15 Nov 2001
Date of end rehabilitation: 28 Jul 2006
10. Date Of Revision Of The Text
29 Apr 2010