SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS Page 1 of 10

2 1. NAME OF THE MEDICINAL PRODUCT Aciclovir 400 mg Tablets 1 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 400 mg Aciclovir For a full list of excipients, see section PHARMACEUTICAL FORM White to off white, oval, biconvex bevelled edge tablet debossed with C on left side of the break line and M on right side of the break line on one side of the tablet and a break line on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Aciclovir 400 mg Tablets are indicated for the treatment of the following infections in HIV/AIDS patients (see sections 4.2, 4.4 and 5.1): herpes simplex virus infections of the skin and mucous membranes including initial and recurrent genital herpes (excluding neonatal HSV and severe HSV infections in immunocompromised children) varicella (chickenpox) and herpes zoster (shingles) infections Aciclovir 400 mg Tablets are indicated in HIV/AIDS patients for the prophylaxis of the following infections (see sections 4.2, 4.4 and 5.1): recurrent herpes simplex infections in immunocompetent patients herpes simplex infections in immunocompromised patients 4.2 Posology and method of administration Posology Therapy should be prescribed by a health care provider experienced in the management of HIV-1 infection. Treatment of herpes simplex infections: 200 mg (½ tablet) five times daily at approximately 4-hourly intervals omitting the night time dose for 5-10 days 400 mg (1 tablet) three times daily at approximately 8-hourly intervals for 5-10 days Dosing should begin as early as possible after the start of an infection; for recurrent episodes this should preferably be during the prodromal period or when lesions first appear. Treatment of varicella and herpes zoster infections: 800 mg (2 tablets) five times daily at approximately 4- hourly intervals, omitting the night time dose for 7 days Dosing should begin as early as possible after the start of an infection: Treatment of herpes zoster yields better results if initiated as soon as possible after the onset of the rash. Treatment of chickenpox in immunocompetent patients should begin within 24 hours after onset of the rash. Children Treatment of herpes simplex infections: Children aged 2 years: adult dosage Children aged <2 years: half the adult dosage 1 Trade names are not prequalified by WHO. This is the national medicines regulatory agency s responsibility. Throughout this WHOPAR the proprietary name is given as an example only. Page 2 of 10

3 For treatment on neonatal herpes virus infections, intravenous aciclovir is recommended. Treatment of varicella infection: 6 years and over: 800 mg (2 tablets) four times daily 2-5 years: 400 mg (1 tablet) four times daily Under 2 years: 200 mg (½ tablet) four times daily Treatment should continue for 5 days. No specific data are available on the suppression of herpes simplex infections or the treatment of herpes zoster infections in immunocompetent children. Prophylaxis Prophylaxis of recurrent herpes simplex infections in immunocompetent patients: 200 mg (½ tablet) four times daily at approximately 6-hourly intervals. Many patients may be conveniently managed on a regimen of 400 mg twice daily at approximately 12- hourly intervals. Dosage titration down to 200 mg three times daily at approximately 8-hourly intervals or two times daily at approximately 12-hourly intervals may prove effective. Some patients may experience break-through infection on total daily doses of 800 mg. Therapy should be interrupted periodically at intervals of six to twelve months, in order to observe possible changes in the natural history of the disease. Prophylaxis of herpes simplex infections in immunocompromised patients: 200 mg (½ tablet) four times daily at approximately 6-hourly intervals. In severely immunocompromised patients or in patients with impaired absorption from the gut, the dose can be doubled to 400 mg, or alternatively, intravenous dosing could be considered. The duration of prophylactic administration is determined by the duration of the period at risk. Children Prophylaxis of herpes simplex infections in immunocompromised patients: Children aged 2 years: adult dosage Children aged <2 years: half the adult dosage Special populations Elderly The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly. Adequate hydration of elderly patients taking high oral doses of aciclovir should be maintained. Renal impairment Caution is advised when administering aciclovir to patients with impaired renal function. Adequate hydration should be maintained. Creatinine clearance Dosage ml/minute Treatment of herpes zoster infections 800 mg three times daily at approximately 8-hourly intervals <10 ml/minute Treatment of herpes simplex infections 200 mg two times daily at approximately 12-hourly intervals Page 3 of 10

4 Treatment of herpes zoster infections 800 mg two times daily at approximately 12-hourly intervals Hepatic impairment No dose adjustment is required in patients with impaired hepatic function. Method of administration: Aciclovir 400 mg Tablets should be swallowed with water, with or without food. For children younger than 6 years of age who experience difficulty in swallowing, the tablets may be crushed and added to small amount of semi-solid food or liquid, all of which should be consumed immediately. Missed dose and vomiting after a dose It is important that the patient takes the medicine regularly as prescribed. Missing doses can increase the risk of resistance to aciclovir and reduce its efficacy. When advising patients on missed doses, the health care provider should take into account the prescribed dosage interval. For doses taken four times daily or more, the patient can omit the missed dose and take the next dose when it is due. For doses taken twice daily, the patient should take the missed dose if it is less than 6 hours from when it was due. If it is more than 6 hours since the dose was due, the patient should omit the missed dose and take the next dose at the usual time. Patients should be advised not to take a double dose to make up for a missed dose. If the patient vomits within 1 hour of taking a dose, the patient should take an extra dose. If vomiting occurs more than an hour after taking the dose, the patient does not need to take an extra dose and can take the next dose as usual when it is due. 4.3 Contraindications Aciclovir 400 mg Tablets are contra-indicated in patients known to be hypersensitive to aciclovir or valaciclovir, or to any of the excipients. 4.4 Special warnings and precautions for use In patients with severe infections and in severely immunocompromised patients or in patients with impaired absorption from the gut, intravenous dosing should be considered. Use in patients with renal impairment and in elderly patients: Aciclovir is eliminated by renal clearance, therefore the dose must be adjusted in patients with renal impairment (see section 4.2). Elderly patients are likely to have reduced renal function and therefore the need for dose adjustment must be considered in this group of patients. Both elderly patients and patients with renal impairment are at increased risk of developing neurological side effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see section 4.8). Concomitant use with nephrotoxic drugs Caution should be exercised when administering aciclovir to patients receiving potentially nephrotoxic agents since this may increase the risk of renal impairment and/or reversible central nervous system symptoms (see sections 4.5 and 4.8). Hydration status: Care should be taken to maintain adequate hydration in patients receiving high oral doses of aciclovir. Use in immunocompromised patients Prolonged or repeated courses of aciclovir in severely immunocompromised individuals, e.g. patients who have AIDS, may result in the selection of virus strains with reduced sensitivity, which may not respond to Page 4 of 10

5 continued aciclovir treatment (see section 5.1). The possibility of viral resistance to aciclovir should be considered in patients who show poor clinical response during therapy. Transmission of infections Patients should be informed on the risk of transmission of the infection. Patients should be advised to avoid contact with lesions or intercourse when symptoms of herpes infection are present even if treatment has been initiated to prevent transmission. Varicella zoster infections The data currently available from clinical studies is not sufficient to conclude that treatment with aciclovir reduces the incidence of chickenpox-associated complications in immunocompetent patients. 4.5 Interaction with other medicinal products and other forms of interaction Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that reduce renal function or compete for active tubular secretion (e.g. emtricitabine, tenofovir disoproxil, entecavir) may increase plasma concentrations of aciclovir and/or the coadministered drugs. Probenecid and cimetidine also increase the AUC of aciclovir by this mechanism, and reduce aciclovir renal clearance. Similarly increases in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplant patients have been shown when the drugs are coadministered. However no dosage adjustment is necessary because of the wide therapeutic index of aciclovir. A small study indicates that concomitant therapy with aciclovir increases AUC of totally administered theophylline by approximately 50%. It is recommended to measure plasma concentrations during concomitant therapy with aciclovir. 4.6 Fertility, pregnancy and lactation Fertility Adverse effects on spermatogenesis at high doses in rats and dogs were reported, but no effect was seen in two generation studies in mice (see section 5.3). There is no information on the effect of aciclovir on human female fertility. In a study of 20 male patients with normal sperm count, oral aciclovir administered at doses of up to 1g per day for up to six months has been shown to have no clinically significant effect on sperm count, motility or morphology. Pregnancy A post-marketing aciclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of aciclovir. The registry findings have not shown an increase in the number of birth defects amongst aciclovir exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause. A more recent retrospective cohort study in Denmark found that the risk of major birth defects during the first year of life was not increased by exposure to aciclovir during the first trimester of pregnancy. Findings from preclinical studies do not indicate a risk of the use of aciclovir during pregnancy (see section 5.3). Aciclovir can be used during pregnancy if clinically needed. Breast-feeding Following oral administration of 200 mg aciclovir five times a day, aciclovir has been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding plasma levels. These levels would potentially expose nursing infants to aciclovir dosages of up to 0.3 mg/kg/day. Caution is therefore advised if aciclovir is to be administered to a nursing woman. 4.7 Effects on ability to drive and use machines There are no data on the effect of aciclovir on the ability to drive or use machines. The clinical status and the adverse events profile of aciclovir should be taken into account when considering the patient s ability to drive or use machines. Page 5 of 10

6 4.8 Undesirable effects The frequency categories associated with the adverse events below are estimates. For most events, suitable data for estimating incidence were not available. In addition, adverse events may vary in their incidence depending on the indication. The following convention has been used for the classification of adverse events in terms of frequency: Very Common 1/10, common 1/100 and <1/10, uncommon 1/1000 and <1/100, rare 1/10,000 and <1/1000, very rare <1/10,000. Blood and lymphatic system disorders very rare anaemia, leukopenia, thrombocytopenia leukocytoclastic vasculitis, lymphadenopathy Immune system disorders rare anaphylaxis Musculoskeletal and connective tissue disorders myalgia Psychiatric disorders very rare agitation, confusion, hallucinations, psychotic symptoms aggressive behaviour, delirium Nervous system disorders common headache, dizziness very rare tremor, ataxia, dysarthria, convulsions, somnolence, encephalopathy, coma paraesthesia The above events are generally reversible and usually reported in patients with renal impairment or with other predisposing factors (see section 4.4). Respiratory, thoracic and mediastinal disorders rare dyspnoea Gastrointestinal disorders common nausea, vomiting, diarrhoea, abdominal pain gastrointestinal distress Hepatobiliary disorders rare very rare reversible increases in bilirubin and liver related enzymes hepatitis, jaundice Skin and subcutaneous tissue disorders common pruritus, rashes (including photosensitivity) uncommon urticaria, accelerated diffuse hair loss Accelerated diffuse hair loss has been associated with a wide variety of disease processes and medicines, the relationship of the event to aciclovir therapy is uncertain. rare angioedema erythema multiforme, peripheral oedema, Stevens-Johnson syndrome, toxic epidermal necrolysis Renal and urinary disorders rare increases in blood urea and creatinine very rare acute renal failure, renal pain haematuria Renal pain may be associated with renal failure and crystalluria. General disorders and administration site conditions Page 6 of 10

7 common fatigue, fever Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Health care providers are asked to report any suspected adverse reactions to the marketing authorisation holder, or, if available, via the national reporting system. 4.9 Overdose Symptoms Aciclovir is only partly absorbed in the gastrointestinal tract. Patients have ingested overdoses of up to 20 g aciclovir on a single occasion, usually without toxic effects. Accidental, repeated overdoses of oral aciclovir over several days have been associated with gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion). Overdosage of intravenous aciclovir has resulted in elevations of serum creatinine, blood urea nitrogen and subsequent renal failure. Neurological effects including confusion, hallucinations, agitation, seizures and coma have been described in association with intravenous overdosage. Treatment Patients should be observed closely for signs of toxicity. Treatment is symptomatic and supportive, including general supportive measures such as monitoring of vital signs, as well as observation of the clinical status of the patient. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered in the event of symptomatic overdose. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group Direct acting antivirals, Nucleosides and nucleotides excl. reverse transcriptase inhibitors ATC-Code: J05AB01 Mechanism of action: Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including herpes simplex virus (HSV) types I and II and varicella zoster virus (VZV). The inhibitory activity of aciclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts aciclovir into aciclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, aciclovir triphosphate stops replication of herpes viral DNA. TK of normal, uninfected cells does not use aciclovir effectively as a substrate. Aciclovir triphosphate interferes with the viral DNA polymerase and inhibits viral DNA replication with resultant chain termination following its incorporation into the viral DNA. Aciclovir has greater antiviral activity against HSV compared to VZV due to its more efficient phosphorylation by the viral TK. Mechanism of resistance: Resistance generally results from viral TK-deficiency. However, strains with altered viral TK or viral DNA polymerase have also been reported. Prolonged or repeated courses of aciclovir in severely immune-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued aciclovir treatment. The relationship between the in vitro determined sensitivity of HSV isolates and clinical response to aciclovir therapy is not clear. A review published in 2011 reported HSV resistance to aciclovir to be low (<1%) in immunocompetent patients. Resistance to aciclovir was more prevalent in immunocompromised patients, ranging from 3.5%- Page 7 of 10

8 10% and 3.5%-7% in patients with HIV infection, specifically. Most of the infections caused by resistant HSV were observed in AIDS patients. Generally, such infections did not result in severe generalized infections, but were associated with extensive mucocutaneous lesions. 5.2 Pharmacokinetic properties Absorption and bioavailability: Aciclovir is only partially absorbed from the gut. Following single dose administration of Aciclovir 400 mg Tablets in 28 healthy volunteers, the mean (±SD) C max value was 669 (±268) µg/ml and the corresponding value for AUC 0-inf was 4258 (±1247) µg.h/ml. The median aciclovir t max value was 2.0 (±0.8) hours. There was no effect of food on the absorption of aciclovir. Distribution: Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels. Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not anticipated. Aciclovir is distributed well in tissue and body fluids. Metabolism/Elimination: In adults the terminal plasma half-life of aciclovir after administrations of intravenous aciclovir is about 2.9 hours. Most of the drug is excreted unchanged by the kidney by both tubular secretion and glomerular filtration. 9-carboxymethoxymethylguanine is the only significant metabolite of aciclovir, and accounts for approximately 10-15% of the administered dose recovered from the urine. Special populations Renal impairment: In patients with chronic renal failure the mean terminal half-life was found to be 19.5 hours. The mean aciclovir half-life during haemodialysis was 5.7 hours. Plasma aciclovir levels dropped approximately 60% during dialysis. Elderly patients: In the elderly, total body clearance falls with increasing age associated with decreases in creatinine clearance although there is little change in the terminal plasma half-life. Paediatric population: See special dosage regimens (see section 4.2). 5.3 Preclinical safety data Mutagenicity: The results of a wide range of mutagenicity tests in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man. Carcinogenicity: Aciclovir was not found to be carcinogenic in long term studies in the rat and the mouse. Teratogenicity: Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rats, rabbits or mice. In a non-standard test in rats, foetal abnormalities were observed, but only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain. Fertility: Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of aciclovir greatly in excess of those employed therapeutically. Two generation studies in mice did not reveal any effect of aciclovir on fertility. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Croscarmellose sodium Magnesium stearate Microcrystalline cellulose Polyvinyl pyrrolindone (povidone) Sodium lauryl sulfate 6.2 Incompatibilities Page 8 of 10

9 Not applicable. 6.3 Shelf life 24 months 6.4 Special precautions for storage Do not store above 30 C. Store tablets in blister in the provided carton. 6.5 Nature and contents of container The primary packs are blister cards of 10 tablets (comprised of PVC-Aluminium and PVC/PVDC- Aluminium foil). Each blister card is packed in a carton. Pack size: 10 tablets. 6.6 Instructions for use and handling and disposal No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. SUPPLIER Mylan Laboratories Limited Plot No.564/A/22, Road No. 92, Jubilee Hills Hyderabad Telangana India 8. WHO REFERENCE NUMBER (PREQUALIFICATION PROGRAMME) HA DATE OF FIRST PREQUALIFICATION/RENEWAL OF THE PREQUALIFICATION 30 June DATE OF REVISION OF THE TEXT January 2018 Page 9 of 10

10 References European Aids Clinical Society (EACS) guidelines for the treatment of adult HIV-positive persons. Available at Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents:recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children.Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Department of Health and Human Services. Available at WHO guidelines for the Treatment of Genital Herpes Simplex Virus, World Health Organization 2016, available at UK SmPC, Zovirax 200 mg tablets, available at FDA label, Zovirax, available at Dutch SmPC, Zovirax 200 mg/5 ml, suspensie voor oraal gebruik, available at Further references relevant to sections of the SmPC include: Section 4.5 University of Liverpool, HIV Drug interactions, available at: University of Liverpool, HEP Drug interactions, available at: Section 4.6 Pasternak B and Hviid A. Use of Acyclovir, Valacyclovir, and Famciclovir in the First Trimester of Pregnancy and the Risk of Birth Defects. JAMA. 2010; 304(8): Section 5.1 Piret J and Boivin G. Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management. Antimicrob Agents Chemother. 2011; 55(2):