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Uses and Administration Adverse Effects Profile Profile Profile Uses

Uses and Administration Adverse Effects Profile Profile Profile Uses

Penciclovir/Raltegravir 1009

disorders. Peptide T has also been tried in the treatment of clinical studies to date the FDA considers that it may rarely References. psoriasis. cause or serious skin reactions. As with other 1. Hirayama C, et al. Propagermairlum: a nonsped.fic immune modulator for chronic B. J Gastroenterol 2003; 38: 525-32. inhibitors, neurologic and behavioral symptoms have been infrequently reported. For further (USAN, r/NN} information on neurological and other adverse effects �r.��.��!�Oseltamivir, p. I 007 .2. Patients with known or suspected renal insufficiency Single-ingredient Preparations.Jp n: Serocion. should have a baseline creatinine clearance measurement before taking peramivir. Dosage adjustments may be necessary in patients with renal impairment.

�.��P.�.��.!�<>.��...... (details are given in Volume B) Uses and Administration ProprielaryPreparations Single-ingredient Preparations.Jp n: Rapiacta. Peramivir is a that is given intravenously; it is being evaluated in phase 3 clinical studies for the treatment of (see p. 960.2). Although it has not yet been approved for marketing, the FDA has authorised the emergency use of peramivir in the USA to treat certain adult and paediatric patients with suspected or laboratory-confirmed (HINI) 2009 influenza, or infection due to nonsubtypable influenza A suspected to be 2009 HINI based on community epidemiology. The recommended dose for patients from 18 years of age is 600 mg given intravenously over 30 minutes once daily for s to 10 days. Dose adjustments are needed in patients with renal impairment, see below. For details of doses in children, see below. Profile Administration in children. Peramivir may be given to is an antiviral with activity against a range of children in the treatment of pandemic (HINI) 2009 influ­ picomaviruses. It has been investigated for the oral enza, similarly to adults (see above). Doses may be given treatment of viral meningitis and encephalitis, upper intravenously over 60 minutes once daily for S to 10 days Uses and Administration respiratory-tract viral infections, and other enteroviral according to age as follows: Raltegravir is an inhibitor of HIV integrase, an enzyme infections. However, there have been concerns over birth to 30 days old: 6 mg/kg essential for insertion of viral DNA into the host genome, • efficacy, viral resistance, and interactions with oral 31 to 90 days old: 8 mg/kg and thus for replication. It is used with other antiretrovirals • contraceptives. Development of an intranasal formulation 91 to 180 days old: I 0 mg/kg for treatment of HIV infection and AIDS (p. 957.2) and is • for the has also been investigated. • 18I days old to S years of age: 12 mg/kg licensed for use in both treatment-naive and treatment­ 6 to 17 years of age: I 0 mg/kg References. experienced patients. • l. The maximum daily dose is 600 mg. For details of dose Nowak·Wegrzyn A. et al. Successful treatment of infection It is given orally as the potassium salt but doses are with the use of pleconaril in 2 infants with severe combined adjustments in children with renal impairment, see below. immunodefidency. Clin Infect Dis 2001; 32: El3-E l4. expressed in terms of the base; 434 mg of raltegravir 2. Rotbart HA, Webster Treatment of potentially life-threatening AD. potassium is equivalent to about 400 mg of raltegravir. The Administration in renol impairment. Intravenous doses of enterovirus infections with pleconaril. Clin Infect Dis 2001; 32: 228-35. usual dose is the equivalent of 400 mg of raltegravir twice 3. Aradottir E, et al. Severe neonatal enteroviral hepatitis treated with peramivir should be reduced in patients with renal impair­ daily, with or without food. For details of doses in children pleconaril. Pediatr Infect Dis J 2001; 20: 457-9. ment, according to creatinine clearance (CC): 4. Starlin R, et al. Acute flaccid paralysis syndrome associated with and adolescents, see below. Adultsfrom years of age. echovirus 19, managed with pleconaril and intravenous immunoglobu­ Doses of raltegravir may need to be amended when given lin. Clin Infect 2001; 33: 730-2. • CC 31 to18 49 mL/minute: ISO mg daily Dis with : a dose of 800 mg twice daily has been CC 10 to 30mL/minute: IOOmg daily 5. Hayden FG, et al. Oral pleconaril treatment of -associated suggested. • viral respiratory illness in adults: efficacy and tolerability in phase II CC less than IOmL/minute: IOOmg on day I, then ISmg • clinical trials. Antivir Ther 2002; 7: 53--65. References. daily thereafter 6. Abzug MJ, et al. Double blind placebo-controlled trial of pleconaril in 1. Iwamoto M, et al. Safety, tolerability, and of infants with enterovirus meningitis. Pediatr Infect Dis J 2003; 22: 335-41. • Intermittent haemodialysis: IOOmg on day I, and 2 raltegravir after single and multiple doses in healthy subjects. Clin hours after the end of each dialysis session 7. Hayden FG, et al. Efficacy and safety of oral pleconaril for treatment of Pharmacol Ther 2008; 83: 293-9. colds due to in adults: results of 2 double-blind, 2. Croxtall JD, et al. Raltegravir. Druos 2008; 68: 131-8. Infantsand children. 36: randomized, placebo-controlled trials. Clin Infect Dis 200?; 1523-32. 3. Croxtall JD, Kearn SJ. Raltegravir: a review of its use in the management • CC 31 to 49 mL/minute per !.73m2: 8. Webster AD. Pleconaril-an advance in the treatment of enteroviral of infection in treatment-experienced patients. 2009; 69: infection in immuno-compromised patients. J Clin Virol 2005; 32: 1-6. mv • l.S mg/kg daily in those from birth to 30 days old 1059-75. 2 mg/kg daily in those from 31 to 90 days old 9. Desmond RA, et al. Enteroviral meningitis: natural history and outcome 4. Hicks C, Gulick RM. Raltegravir: the first HIV type 1 . • of pleconaril therapy. Antimicrob Agents Chemother 2006; 50: 2409-14. 48: 2.5 mg/kg daily in those from 91 to 180 days old Clin Infect Dis 2009; 931-9. • 5. Lennox JL, et al. Safety and efficacy of raltegravir-based versus • 3 mg/kg daily in those from 181 days old to S years of efavirenz-based combination therapy in treatment-naive piltients with age HIV-1 infection: a multicentre, double-blind randomised controlled trial. C12U Lancet 2009; 374: 796-806. Correction. ibid.; 786. • 2.S mg/kg daily in those from 6 to I7 years of age 6. Croxtall JD, Scott Raltegravir: in treatment-naive patients with HIV- CC 10 to 30mL/minute per !.73m2: IJ. • 1 infection. Druos 2010; 70: 631-42. ' • I mg/kg daily in those from birth to 30 days old 7. Steigbigel RT, et al. BENCHMRK Study Teams. Long-term efficacy and • 1.3mg/kg daily in those from 31 to 90 days old safety of raltegravir combined with optimized background therapy in treatment-experienced patients with -resistant mv infection: week • 1.6mg/kg dally in those from 91 to 180 days old Profile 96 results of the BENCHMRK 1 and 2 phase trials. Clin Infect Dis 2010; I.9 mg/kg daily in those from 181 days old to S years m • Poly I.poly CI2U is a synthetic mismatched polymer of 50: 605-12. of age double-stranded RNA with antiviral and immunomodula­ 8. Ramkumar K, Neamati N. Raltegravir: the evidence of its therapeutic 1.6 mg/kg daily in those from 6 to 17 years of age value in HIV-1 infection. Core Evid2010 ; 4: 131-47. • tory activity (see also Poly I. Poly C, p. 2S94. 1). It is under 2 9. Ski est DJ, et al. Similar efficacy of raltegravir when used with or without • CC less than IOmL/minute per !.73m : investigation in the treatment of HIV infection, and also in I mg/kg on day I, then O.IS mg/kg daily in those from a protease inhibitor in treatment-experienced patients. HN Clin Trials • renal cell carcinoma, chronic syndrome, invasive 2011; 12: 131-40. birth to 30 days old melanoma, and and C. 10. Brainard DM, et al. Clinical profile of raltegravir, an IDV-1 51: • 1.3 mg/kg on day I, then 0.2 mg/kg dally in those integrase strand transfer inhibitor. J Clin Pharmaco/ 2011; 1376-1402. from 31 to 90 days old 11. Rokas KEE, et al. Role of raltegravir in HIV-1 management. Ann Pharmacother 2012; 46: 578-89. • 1.6 mg/kg on day I, then 0.2S mg/kg daily in those �r.��.�?.!�bioavailability compared with the rum­ day I, and then 2 hours after each dialysis session: coated tablets. Doses are based on body-weight. In children from 2 years (and weighing at least 10 kg) to • I mg/kg for those from birth to 30 days old less than 12 years of age, the following dose recommenda­ • I.3 mg/kg for those from 31 to 90 days old lions are made for chewable tablets: • 1.6mg/kg for those from 91 to 180 days old I 0 to less than 14 kg: 7 S mg twice daily • I.9 mg/kg for those from 181 days to S years of age • 14 to less than 20 kg: 100 mg twice daily • 1.6 mg/kg for those from 6 to 17 years of age • Profile • 20 to less than 28 kg: ISO mg twice daily AdverseEffects • 28 to less than 40 kg: 200 mg twice daily Propagermanium is an immunomodulator that has been • at least 40 kg: 300 mg twice daily (maximum dose) Safety and efficacy data for peramivir are limited. The most used in chronic hepatitis B infections. Acute exacerbation of Film-coated tablets may be given to children from 6 years of commonly reported adverse events have been diarrhoea, hepatitis, including some fatalities, has been reported in age (and weighing at least 2S kg) and adolescents; the usual nausea, , and neutropenia. Although not seen in patients receiving propagermanium. oral dose is 400 mg twice daily.

The symbol denotes a preparation no longer actively marketed t 1010 Antivirals

Profile Copegus (Roche) is used in the UK with alfa-2a or Adverse Effects and Precautions peginterferon alfa-2a and in the USA with peginterferon On the basis of limited data, raltegravir appears to be well is an immune response modifier that has been alfa-2a. tolerated; non -specific adverse effects associated with investigated for the topical treatment of genital herpes, The following doses are used with peginterferon alfa-2a raltegravir-based regimens include rash, insomnia, abnor­ common warts, and actinic keratosis. It is also being studied for mono-infection in genotype l or 4: mal dreams, , abdominal pain, diarrhoea, nausea, as a potential adjunct therapy for improving the immune • adults up to 75 kg: 400 mg in the morning and 600 mg in vomiting, asthenia, fatigue, dizziness, and vertigo. Rarely, response to certain vaccines. the evening more serious adverse effects such as immune reconstitution • over 75 kg: 600mg both in the morning and in the syndrome, gastritis, hepatitis, renal failure, neutropenia, References. evening thrombocytopenia, and hypersensitivity and severe skin I. Spruance SL, et al. Application of a topical immune response modifier, resiquimod gel, to modify the recurrence rate of recurrent genital For mono-infection in genotype 2 or 3 (with reactions such as Stevens-Johnson Syndrome and toxic herpes: a pilot study . .JInfect Dis 2001; 184: 196-200. peginterferon alfa-2a): epidermal necrolysis have occurred. Psychiatric distur­ 2. Mark KE, et al. Topical resiquimod 0.01% gel decreases • all adults: 400 mg both in the morning and in the evening bances, including anxiety, depression, paranoia, and virus type 2 genital shedding: a randomized, controlled trial. J Infect Dis The following doses are used with interferon alfa-2a for suicidal ideation have also been reported, particularly in 2007; 195: 1324-3 1. 3. Szeimies RM, et al. A phase IIdose-ranging study of topical resiquimod to mono-infection in genotype l to 4: those with a pre-existing history of mental illness. treat actinic keratosis. Br J Dermatol 2008; 159: 205-10. • adults up to 7 5 kg: 400 mg in the morning and 600 mg in Abnormal creatine phosphokinase values may occur and 4. Igartua M, Pedraz JL Topical resiquimod: a promising adjuvant for the evening myopathy and rhabdomyolysis have been reported vaccine development? Expert Rev Vacdnes 2010; 9: 23-7. • over 7 5 kg: 600 mg both in the morning and in the although a causal relationship has not been established; evening nonetheless, caution is advised in patients at increased risk For co-infection with HIV: of these conditions. Increased transaminases and • all adults: 800 mg daily, irrespective of genotype serum triglyceride concentrations may also occur. !BAN. usAN r!NNI Dose reductions of ribavirin may be necessary in patients Ribavirilni; . Ribavirina; Ripavirinas; Ril:Javlrine; who develop low haemoglobin concentrations. Ribavirin is Interactions Ribavirilium;tCN'1229; Tribavirin; contra-indicated in patients with a creatinine clearance less . than 50 mL!rninute. Raltegravir is not a substrate for cytochrome P450 .1-j: rD-Ribqfu ranosy.. RTCA; l-1 H-1.2,4-triaPV16as>�p14K.zo le+carbwxa mide. isoenzymes, and does not appear to interact with drugs Reviews. Inetabolised by this mechanism. However, rifampicin CsH";2N.05=2;14.2 1. Gish RG. Treating HCV with ribavirin analogues and ribavirin-like molecules. J Antimicrob Chemother 2006; 57: 8-13. induces the glucuronidase responsible for raltegravir .CAS4(( � 36791-04'5. 2. Gambarin-Gelwan M, Jacobson IM. Optimal dose of peginterferon and

metabolism (UGT!Al) and reduces plasma concentrations ...:... . J05flB04� ribavirin for treatment of chronic . J Viral Hepatitis 2008; 15: of raltegravir; if use with rifampicin cannot be avoided, ATCI/et QJ05AB04. 623-33. --c' 3. Reddy KR, et al. Ribavirin: current role in the optimal clinical increasing the dose of raltegravir may be considered (see IJN!i 49;tl7AW06K. Pharmacopoeias. In Chin., Eur. management of chronic hepatitis C. J Hepatol 2009; 50: 402-l l. Uses and Administration, p. 1009.3). 4. Shiffman ML. What future for ribavirin? Liver Int 2009; 29 (suppl l): 68- Ph, Eur, 8: (Ribavirin). A white or almost white crystalline 73. Antivirals. Plasma concentrations of raltegravir were mod­ powder. It exhibits polymorphism. Freely soluble in water; 5. Brok J, et al. Ribavirin monotherapy for chronic hepatitis C. Available in estly increased by atazanavir and -boosted ataza­ slightly soluble in alcohol; slightly soluble or very slightly The Database of Systematic Reviews; Issue 4. Chichester; John Wiley; 2009 (accessed 22/0l/10). navir in healthy subjects; this increase is not considered to soluble in dichloromethane. A 2% solution in water has a 6. Aghemo A, et al. IFN ·a 2a and ribavirin in the treatment of be clinically significant.1 pH of 4.0 to 6.5. Protect from light. hepatitis C. Ther 2009; 7: 925-35. In a pharmacokinetic study, use of raltegravir and USP 36: (Ribavirin). A white crystalline powder. Freely 7. Gluud LL, et Peginterferon plus ribavirin for chronic hepatitis C in maraviroc together resulted in decreased plasma concentra­ patients with human immunodeficiency virus. Am J Gastroenterol 2009; soluble in water; slightly soluble in dehydrated alcohol. 104: 2335-4 1. lions of both drugs, although these changes were also not Store in airtight containers. 8. Ventre K, Randolph A. Ribavirin for respiratory syncytial virus infection thought to be clinically significant.2 of the lower respiratory tract in infants and young children 1. Iwamoto M, et a!. Atazanavir modestly increases plasma levels of [withdrawn]. Available in The Cochrane Database of Systematic raltegravir in healthy subjects. Clin Infect Dis 2008; 47: 137-40. Reviews; Issue 5. Chichester: John Wiley; 2010 (accessed 18/08110). 2. Andrews E, et a!. Assessment of the pharmacokinetics of co-administered Uses and Administration maraviroc and raltegravir. Br J Clin Pharmaco/ 2010; 69: 51-7. Ribavirin is a synthetic structurally Administration. Relerence1 to the intravenous use of riba­ related to . It is given by aerosol in the treatment of virin. Gastrointestinal drugs. The solubility of raltegravir is pH­ RSV infections (p. 961.3); this route appears to give better l. Riner A, et al. Intravenous ribavirin-review of the FDA's Emergency dependent. and use of omeprazole has been noted to results than the oral route although its efficacy is Jnve;tiJ;atHonal New Drug Database (1997-2008) and literature review. increase plasma concentrations of raltegravir in healthy questionable. It is used orally with an interferon alfa or 121: 139-46. subjects.1 However, some HIV-infected patients (and parti­ peginterferon alfa in the treatment of chronic hepatitis C cularly those with AIDS) have increased gastric pH relat­ (p. 990.3 ), including HlV co-infection. Ribavirin has been Administration in children. Preparations of ribavirin are ing to their illness, and data from IITV-infected patients tried in haemorrhagic , such as haemorrhagic available for aerosol administration to infants and children suggests acceptable safety and only modest pharmacoki­ with renal syndrome and Lassa fever (p. 1011.1), and in with severe RSV infection via a small particle aerosol gen­ netic interaction when gastric-acid reducing drugs are SARS (p. 962.2), erator. Solutions containing 20 mg/mL are used; 300 mL, used with raltegravir .1 US licensed product information for For details of doses in children, see below. representing 6 g of ribavirin, is delivered over a 12-to 18- raltegravir therefore suggests that no dose adjustment is Ribavirin is used, with an interferon alia or peginterferon hour period by aerosol at an average concentration of needed when raltegravir is used with gastric-acid reducing alfa, for the treatment of chronic hepatitis C. For 190 micrograms/litre of air. Treatment is given for 3 to 7 drugs, although UK licensed information has advised that information on the dose of interferon alia used in the days, such combinations should be avoided unless considered treatment of chronic hepatitis C see under Interferon Alfa, Ribavlrin is used, with an interferon alia or peginterferon essential. p. 989.2. Doses of ribavirin depend upon the product used, alfa, for the treatment of chronic hepatitis C. Doses of et at. L Iwamoto M, Effects of omeprazole on plasma levels of raltegravir. but are given orally, usually twice daily, and are determined ribavirin depend upon the product used, but are given Clin Infect Dis 2009; 48: 489-92. according to body-weight. Duration of treatment, and orally, usually twice daily, and are determined according to sometimes also dose, may be influenced by the genotype of body-weight. Duration of treatment, and sometimes also Pharmacokinetics the hepatitis C virus. In those with hepatitis C infection dose, may be influenced by the genotype of the hepatitis C alone (mono-infection), patients with viral genotype 1, and virus. In hepatitis C mono-infection, patients with viral Raltegravir is absorbed on oral dosage and peak genotype 1 should be treated for 48 weeks and those with concentrations occur after 3 hours. There is considerable probably genotype 4, should generally be treated for 48 weeks and those with genotype 2 or 3 lor 24 weeks; data on genotype 2 or 3 for 24 weeks. interindividual variation in the pharmacokinetics. It is Rebeto/ (Schering-Plough) is used, with interferon alfa-2b or metabolised via glucuronidation, catalysed by the enzyme genotypes 5 or 6 are insufficient to make recommendations. In co-infe ction with HIV, peginterferon alfa-2b, for hepatitis C. diphosphate glucuronosyltransferase 1A1 treatment should generally be given The following doses are recommended in the UK for (UGTIA1 ), and excreted in both urine and faeces as for 48 weeks regardless of genotype. Rebetol (Schering-Plough) is used, with interferon alfa-2b or children 3 years of age and older: unchanged drug and metabolites. peginterferon alfa-2b for hepatitis C. • less than 4 7 kg: 15 mg/kg daily in 2 divided doses The following doses are recommended in the UK: • 47 to 49 kg: 200 mg in the morning and 400 mg in the evening • adults up to 65 kg: 400 mg both in the morning and in the details are given in Volume B) ProprietaryPreparations evening • 50 to 65 kg: 400 mg both in the morning and in the ( 65 to 80 kg: 400 mg in the morning and 600 mg in the evening Single-ingredient Preparations. Austral.: Isentress; Austria: !sen­ • tress; Belg.: Isentress; Braz.: Isentress; Canad.: Isentress; Chile: evening • over 65 kg: tbe adult dose (above) Isentress; China: Isentress Cz. : Isentress; Denm.: !sen­ • from 81 to 105 kg: 600 mg both in the morning and in the In the USA, ribavirin is licensed for use with interferon tress; Fr.: Isentress; Ger.: Isentress;Cit1:t=,f); Gr.: Isentress; Hong Kong: evening alfa-2b and peginterferon alfa-2b, for the treatment of Isentress; Hung.: Isentress; Irl.: Isentress; Israel: Isentress; Ital. : • over 105 kg: 600 mg in the morning and 800 mg in the children from 3 to 17 years of age. The recommended Isentress; Malaysia: Isentress; Neth.: Isentress; Norw. : Isentress; evening doses of ribavirin are: NZ: Pol.: Port.: Rus.: Isentress; Isentress; Isentress; Isentress In the USA, the dose of ribavirin given with interferon • less than 47 kg: 15mg/kg daily (HceHTpecc); Singapore: Isentress; Spain: Isentress; Swed. : !sen­ alfa-2b is: • 47 to 59kg: 400 mg both in the morning and in the tress; Switz.: Isentress; Thai.: Isentress; UK: Isentress; Ukr.: adults up to 7 5 kg: 400 mg in the morning and 600 mg in evening Isentress (HceHTpecc); USA: Isentress. • the evening • 60 to 73 kg: 400 mg in the morning and 600 mg in the • over 75 kg: 600 mg both in the morning and in the evening evening • over 73 kg: 600 mg both in the morning and in the Resiquimod lriNNI The following doses are used with peginterferon alfa-2b: evening Copegus (Roche) is not licensed for use in those less than 18 Rc848; ResiqLlimod: R&.�iq

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