Drug-Drug Interactions Between Protease Inhibitors and Statins and Proton Pump Inhibitors: a Systematic Review Charles Orido, Samantha Mckinnon and DR

Total Page:16

File Type:pdf, Size:1020Kb

Drug-Drug Interactions Between Protease Inhibitors and Statins and Proton Pump Inhibitors: a Systematic Review Charles Orido, Samantha Mckinnon and DR Drug-drug interaction between Protease inhibitors and statins and Proton pump inhibitors Item Type text; Electronic Report Authors Orido, Charles; McKinnon, Samantha Publisher The University of Arizona. Rights Copyright © is held by the author. Download date 28/09/2021 12:23:53 Item License http://rightsstatements.org/vocab/InC/1.0/ Link to Item http://hdl.handle.net/10150/636245 Drug-Drug Interactions between Protease Inhibitors and Statins and proton Pump inhibitors: A Systematic Review Charles Orido, Samantha McKinnon and DR. Dan Malone PharmD University of Arizona College of Pharmacy BACKGROUND RESULTS RESULTS • . Protease inhibitors (PIs) are HIV and Hepatitis C drugs that block a protease from Characteristics and Outcomes of Included Studies making protein by competitive inhibition. The are CYP3A4 inhibitors. • Recent studies suggest that when PIs are given with Statins (primarily metabolized by Table 1 Studies of simvastatin and Protease inhibitors Fig. 1: Chemical structures of HMG-CoA reductase inhibitors (statins). The lactone CYP3A4) especially Simvastatin and Lovastatin, they increases the AUC and Cmax of Reference Design Patient n Reference Protease Inhibitor Statin AUC Cmax Comments statins which leads to serious adverse events and even death. population regimen ring is underlined in green and the efficacious acid moiety is underlined in red. Hsyu et al. 2001 Open-label, sequential, Healthy 32 Simvastatin 20 mg Nelfinavir 1250 mg Simvastatin co-administered ↑ 505 % ↑517 % ADE: • Atazanavir (ATV) is a potent, well-tolerated, once daily, HIV protease Inhibitor [1] multiple-dose, single BID with NFV after 14 days on Diarrhea center study Simvastatin alone Rash extensively studied in naïve and experienced patients. Migraine headache ↓Fasting cholesterol • ATV exhibits pH-dependent solubility, previous data have indicated that ATV ↓LDL bioavailability is sensitive to gastric PH. Is a moderate Inhibitor of CYP2C19 in vitro Fichtenbaum et al Randomized phase 1, HIV Serone- 67 Simvastatin 40 Atazanavir/ Simvastatin 40mg/day ↑59% ↑328% ADE: 2002 open label, multiple gative mg/day ritonavir 300 mg BID administered with RTV after 14 Diarrhea • Proton Pump Inhibitors (PPIs) are primarily metabolized by CYP2C19, suppresses acid dose Sequinavir 400 days or simvastatin alone GI upset mg/day BID Simvastatin 40 mg/day Concentration increased secretion and increases gastric PH. administered with SQV after 14 30-fold days of simvastatin alone. Methaneethorn et Open-label, sequential, Healthy Simvastatin 20 Nelfinavir Simvastatin co-administered Concentration Increased al 2014 multiple dose, single mg/day with NFV after 14 days on 6-fold. OBJECTIVE center Simvastatin alone Hare et al 2002 Case report HIV 1(70-year-old Simvastatin 80 mg Nelfinavir 750 mg TID Simvastatin concurrent with Muscle weakness The purpose of this article is to provide a systematic review of the pharmacokinetic and white male /day Nelfinavir Diarrhea Acute renal failure clinical data on drug-drug interactions between protease inhibitors (PIs) and statins, Oliguria Metabolic acidosis atazanavir and proton pump inhibitors (PPIs) and discuss their clinical relevance. Elevated troponin-1 Elevated creatine kinase Rhabdomyolysis Death METHODS Ginelle et al 2007 Case report HIV 1(72-year-old Simvastatin 80 Atazanavir 400 mg at Simvastatin concurrent with Weakness white male mg/day bedtime Atazanavir 27days and Fatigue Amiodarone 400 mg amiodarone for 7 days Muscle pain Search Strategy & Study Selection daily for 7 days then Increased creatine kinase 200 mg daily. Dark orange urine Oliguric renal failure • A literature search was performed using Medline, EMBASE, and google scholar, Cheng et al 2002 Case report HIV 1(51-year-old Simvastatin 20 Indinavir 800 mg BID Simvastatin concurrent with Elevated aspartate transaminase, LDH, abstracts from 1970 to 2019 of major conferences were searched and currently white woman mg/day Ritonavir 100 mg BID Indinavir and ritonavir. Ritonavir alanine transaminase. added 1 week before admission Rhabdomyolysis. available FDA drug information package inserts was examined. • Articles were eligible for inclusion if they were: AM, morning; ATV, atazanavir; AUC, area under the curve; bid, twice a day; Cmax, maximum concentration; CO, cross-over; d, day(s); DB, double-blind; DRV, darunavir; FPV, fosamprenavir; DISCUSSION & CONCLUSION h, hour; IDV, indinavir; LPV/r, lopinavir/ritonavir; n, number of participants; OL, open label: PM, evening; PG, parallel group; PK, pharmacokinetics; qd, once a day; R, randomized; TV or r, ritonavir; SQV, saquinavir; BID, two times a day; TPV, tipranavir. 1. Published in English between January 1970 and October 2019 • Protease Inhibitors increased the AUC and Cmax of simvastatin by approximately 2. Healthy individuals or persons with HIV/AIDS of any ages Table 2Studies of Proton Pump Inhibitors and Protease Inhibitors 500% and 517 respectively. 3. Reported any incidence pharmacokinetic or pharmacodynamics • Therefore, simvastatin and Lovastatin are not recommended co-administration with Reference Design Patient n Reference regimen Protease Inhibitor Statin AUC Cmax Comments population a Protease Inhibitors. Zhu et al 2011 Cohort Healthy 56 Atazanavir 400mg qd ATV 400 mg qd OMP 20 mg QAM 12 h ↓38 % • Two independent authors screened titles and abstracts, and then extracted data ATV/r 300/100 mg before ATV/r ↓42 % • Other statins can be used like atorvastatin, rosuvastatin and pravastatin which is qd OMP 20 mg QAM 1 h before ↓37 % following a full-text review of included articles ATV/r 400/100 mg ATV/r the main statin recommended. qd OMP 20 mg 12 h after ATV/r • Atazanavir can be administered with PPIs but if possible, change of an acid Agarwala et al. Randomized, parallel Healthy 48 Atazanavir/ ATV/r 300/100 mg OMP 40 mg qd, 2 h before ↓76% ↓72% 2005 group, open label, ritonavir 300/100 mg qd ATV/r reducing agent may be warranted. multiple doses. qd ATV/r 300/100 mg OMP 40 mg qd, 2 h before qd1cola ATV/r ↓70% ↓66% • Providers should keep a close eye to those patients taking atazanavir and PPIs Risk of Bias ATV/r 400/100 mg OMP 40 mg qd, 2 h before qd ATV/r and consider a change to H2RA. ↓61% ↓66% Instrument and data collection: Case reports were assessed using the called Drug Interaction Luber et al. 2006 Randomized, Cross Healthy 19 ATV/r 300/100 mg qd ATV/r 300/100 mg OMP 20 mg single dose . Probability Scale (DIPS) developed by Horn et. al. to evaluate the quality of DDI case Over, Open Label, AM qd Am PM multiple doses, ATV/r 300/100 mg OMP 20 mg qd PM reports. If the total DIPs score is >8 then it is suggestive of a (highly probable) drug interaction. qd ↓27% ↓33% AM REFERENCES Lower values of 5-8 probable of drug interaction, 2-4 possible of drug interaction, and <2 Tomilo et al. Cross Over, Open Healthy 9 ATV 400 mg single ATV 400 mg single LANS 60 mg qd x 2 ↓94% ↓91% Standard Lansoprazole dose is 30mg doubtful of drug interaction. 2006 Label, dose dose doses 1. Béïque, L, et al. “Interactions between Protease Inhibitors and Acid-Reducing Agents: a Systematic Review.” HIV Medicine, vol. 8, no. 6, 2007, Agarwala et al. R, PG, OL, multiple Healthy 48 ATV 400 mg qd ATV 400 mg qd OMP40 mg qd, 2 h before ↓94% ↓96% pp. 335–345., doi:10.1111/j.1468-1293.2007.00482. x. Accessed November 1028 2005 doses ATV 400 mg qd 1 ATV 2. Chastain, Daniel B., et al. “Evidence-Based Review of Statin Use in Patients with HIV on Antiretroviral Therapy.” Journal of Clinical & Study Selection Cola OMP 40 mg qd, 2h before Translational Endocrinology, vol. 8, 2017, pp. 6–14., doi: 10.1016/j.jcte.2017.01.004. Accessed November 2018 ATV/r 300/100 qd ATV ↓93% ↓94% 3. Hsyu, P.-H., et al. “Pharmacokinetic Interactions between Nelfinavir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Records Records Full-text OMP 40 mg qd, 2 h before Atorvastatin and Simvastatin.” Antimicrobial Agents and Chemotherapy, vol. 45, no. 12, 2001, pp. 3445–3450., doi:10.1128/aac.45.12.3445- Records Studies ATV/r ↓50% ↓73% 3450.2001. Accessed November 2018 identified after articles 4. Al, Fichtenbaum Et. “Pharmacokinetic Interactions between Protease Inhibitors and Statins in HIV Seronegative Volunteers.” Aids, vol. 17, no. after included in Klein et al. 2006 R, PG, OL, multiple Healthy 10 ATV/r 300/100 mg qd ATV/r 300/100 mg OMP 40 mg qd, 1.5 h 62 59 RTV AUC ↓ 16%, through duplicate assesse Supplement 4, 2003, pp. 109–110., doi:10.1097/00002030-200317004-00017. Accessed November 2018. inclusion systematic [//] doses qd before ATV/r Cmax and Cmin no change 5. Schmidt, G. A., et al. “Severe Rhabdomyolysis and Acute Renal Failure Secondary to Concomitant Use of Simvastatin, Amiodarone, and database s d for Atazanavir.” The Journal of the American Board of Family Medicine, vol. 20, no. 4, 2007, pp. 411–416., doi:10.3122/jabfm.2007.04.060187. criteria review Faber et al 2016 Ranndomized, single- Healthy 8 Atazanavir/ atazanavir/ Rebeprazole 200 mg BID + ↓70% ↓35% searching removed eligibility Accessed November 2018 [//] dose, 3 period, Ritonavir 300/100 mg ritonavir 300/100 atazanavir/ritonavir 300/100 6. Agarwala S, Gray K, Eley T, Wang Y, Hughes E, Grasela D. Pharmacokinetic interaction between atazanavir and omeprazole in healthy crossover mg mg (n=34) (n=14) subjects. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil, 24–27 July 2005 [Abstract study (n=246) (n=24) (n=24) WePe3.3C08]. The ‘multiple doses’ design indicates that all agents are given for multiple doses, except where otherwise specified. 7. Klein C, Chiu YL, Cai Y et al. Lack of effect of acid reducing agents on the pharmacokinetics of lopinavir/ritonavir tablet formulation. 13th AM, morning; ATV, atazanavir; AUC, area under the curve; bid, twice a day; Cmax, maximum concentration; CO, cross-over; d, day(s); DB, double-blind; DRV, darunavir; ESO, esomeprazole; FPV, fosamprenavir; h, hour; IDV, Conference on Retroviruses and Opportunistic Infections.
Recommended publications
  • Pharmacokinetic Interactions Between Herbal Medicines and Drugs: Their Mechanisms and Clinical Relevance
    life Review Pharmacokinetic Interactions between Herbal Medicines and Drugs: Their Mechanisms and Clinical Relevance Laura Rombolà 1 , Damiana Scuteri 1,2 , Straface Marilisa 1, Chizuko Watanabe 3, Luigi Antonio Morrone 1, Giacinto Bagetta 1,2,* and Maria Tiziana Corasaniti 4 1 Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, Section of Preclinical and Translational Pharmacology, University of Calabria, 87036 Rende, Italy; [email protected] (L.R.); [email protected] (D.S.); [email protected] (S.M.); [email protected] (L.A.M.) 2 Pharmacotechnology Documentation and Transfer Unit, Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy 3 Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 981-8558 Sendai, Japan; [email protected] 4 School of Hospital Pharmacy, University “Magna Graecia” of Catanzaro and Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0984-493462 Received: 28 May 2020; Accepted: 30 June 2020; Published: 4 July 2020 Abstract: The therapeutic efficacy of a drug or its unexpected unwanted side effects may depend on the concurrent use of a medicinal plant. In particular, constituents in the medicinal plant extracts may influence drug bioavailability, metabolism and half-life, leading to drug toxicity or failure to obtain a therapeutic response. This narrative review focuses on clinical studies improving knowledge on the ability of selected herbal medicines to influence the pharmacokinetics of co-administered drugs. Moreover, in vitro studies are useful to anticipate potential herbal medicine-drug interactions.
    [Show full text]
  • Indinavir Sulfate Capsule Merck & Co., Inc
    CRIXIVAN - indinavir sulfate capsule Merck & Co., Inc. ---------- CRIXIVAN® (INDINAVIR SULFATE) CAPSULES DESCRIPTION CRIXIVAN1 (indinavir sulfate) is an inhibitor of the human immunodeficiency virus (HIV) protease. CRIXIVAN Capsules are formulated as a sulfate salt and are available for oral administration in strengths of 100, 200, 333, and 400 mg of indinavir (corresponding to 125, 250, 416.3, and 500 mg indinavir sulfate, respectively). Each capsule also contains the inactive ingredients anhydrous lactose and magnesium stearate. The capsule shell has the following inactive ingredients and dyes: gelatin, titanium dioxide, silicon dioxide and sodium lauryl sulfate. The chemical name for indinavir sulfate is [1(1S,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-[2-[[(1,1­ dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D-erythro-pentonamide sulfate (1:1) salt. Indinavir sulfate has the following structural formula: Indinavir sulfate is a white to off-white, hygroscopic, crystalline powder with the molecular formula C36H47N5O4• H2SO4 and a molecular weight of 711.88. It is very soluble in water and in methanol. 1 Registered trademark of MERCK & CO., Inc. COPYRIGHT © 1996, 1997, 1998, 1999, 2004 MERCK & CO., Inc. All rights reserved MICROBIOLOGY Mechanism of Action HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Indinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles.
    [Show full text]
  • Hormone Therapy for Gender Transitioning Revised September 2017 Page 1 of 2 for Personal Use Only
    www.hiv-druginteractions.org Hormone Therapy for Gender Transitioning Revised September 2017 Page 1 of 2 For personal use only. Not for distribution. For personal use only. Not for distribution. For personal use only. Not for distribution. Estrogen and anti-androgen preparations for use in male to female gender reassignment therapy HIV drugs with no predicted effect HIV drugs predicted to HIV drugs predicted to inhibit metabolism induce metabolism RPV, MVC, DTG, RAL, NRTIs ATV/cobi, DRV/cobi, EVG/cobi ATV/r, DRV/r, FPV/r, IDV/r, LPV/r, Estrogens (ABC, ddI, FTC, 3TC, d4T, TAF, TDF, ZDV) SQV/r, TPV/r, EFV, ETV, NVP Starting dose 2 mg/day 1 mg/day Increase estradiol dosage as needed Estradiol oral Average dose 4 mg/day 2 mg/day based on clinical effects and Maximum dose 8 mg/day 4 mg/day monitored hormone levels. Estradiol gel Starting dose 0.75 mg twice daily 0.5 mg twice daily Increase estradiol dosage as needed (preferred for >40 y Average dose 0.75 mg three times daily 0.5 mg three times daily based on clinical effects and and/or smokers) Maximum dose 1.5 mg three times daily 1 mg three times daily monitored hormone levels. Estradiol patch Starting dose 25 µg/day 25 µg/day* Increase estradiol dosage as needed (preferred for >40 y Average dose 50-100 µg/day 37.5-75 µg/day based on clinical effects and and/or smokers) Maximum dose 150 µg/day 100 µg/day monitored hormone levels. Starting dose 1.25-2.5 mg/day 0.625-1.25 mg/day Increase estradiol dosage as needed Conjugated Average dose 5 mg/day 2.5 mg/day based on clinical effects and estrogen† Maximum dose 10 mg/day 5 mg/day monitored hormone levels.
    [Show full text]
  • Indinavir PK Fact Sheet Reviewed March 2016 Page 1 of 2 for Personal Use Only
    www.hiv-druginteractions.org Indinavir PK Fact Sheet Reviewed March 2016 Page 1 of 2 For personal use only. Not for distribution. For personal use only. Not for distribution. For personal use only. Not for distribution. Details Generic Name Indinavir Trade Name Crixivan® Class Protease Inhibitor Molecular Weight 711.88 (as sulphate) Structure HO OH N N H H SO N N 2 4 O HN O H3C CH3 H3C Summary of Key Pharmacokinetic Parameters Plasma half life 1.8 ± 0.4 h Cmax 8.97 ± 2.87 µg/ml (800 mg every 8 hours) Cmin 0.146 µg/ml (800 mg every 8 hours) AUC 21.82 ± 8.11 µg/ml.h (800 mg every 8 hours) Bioavailability Approx 65% Absorption Administration of indinavir with a meal high in calories, fat, and protein resulted in a blunted and reduced absorption with an approximate 80 % reduction in AUC and an 86 % reduction in Cmax. Administration with light meals (e.g., dry toast with jam or fruit conserve, apple juice, and coffee with skimmed or fat–free milk and sugar or corn flakes, skimmed or fat–free milk and sugar) resulted in plasma concentrations comparable to the corresponding fasted values. Protein Binding ~60% Volume of Distribution ~1.74 L/kg [1] CSF:Plasma ratio 0.14 [2] Semen:Plasma ratio 1.9 [2] Renal Clearance <20% as unchanged drug Renal Impairment Safety in patients with impaired renal function has not been studied; less than 20% of indinavir is excreted in the urine as unchanged drug or metabolites. Hepatic Impairment Safety and efficacy of indinavir has not been established in patients with significant underlying liver disorders and should be used with caution.
    [Show full text]
  • Drug-Drug Interaction Between Protease Inhibitors and Statins and Proton Pump Inhibitors
    Drug-drug interaction between Protease inhibitors and statins and Proton pump inhibitors Item Type text; Electronic Report Authors Orido, Charles; McKinnon, Samantha Publisher The University of Arizona. Rights Copyright © is held by the author. Download date 01/10/2021 01:48:07 Item License http://rightsstatements.org/vocab/InC/1.0/ Link to Item http://hdl.handle.net/10150/636245 Group 47 :Orido/Samantha 1 Drug-drug interaction between Protease inhibitors and statins and Proton pump inhibitors Course Title: PhPr 862 Date: April 3, 2019 Faculty Advisor: Dr. Dan Malone Students: Charles Orido, Samantha McKinnon Pharm.D. Candidates, Class of 2019 Group 47 :Orido/Samantha 2 Objective The purpose of this article is to provide a systematic review of the pharmacokinetic and clinical data on drug-drug interactions between protease inhibitors (PIs) and statins, atazanavir and proton pump inhibitors (PPIs)and their clinical relevance. Methods A literature search was performed using Medline, EMBASE and google scholar, abstracts from 1970 to 2019 of major conferences were searched and FDA drug information package inserts of the manufacturer of every currently available PI was looked at. All data was summarized and verified by at least two investigators. Results A total of 246 references were identified, 8 of which were studies of pharmacokinetic and pharmacodynamics interactions between simvastatin, lovastatin and protease inhibitors and an additional 7 articles that provided pharmacokinetic of proton pump inhibitors and Atazanavir. Conclusions Protease inhibitors increases the AUC and Cmax of simvastatin by approximately 500% and 517% respectively. Therefore, simvastatin and Lovastatin are not recommended for a co-administration with a protease inhibitor.
    [Show full text]
  • Crixivan (Indinavir Sulfate)
    XXXXXXX CRIXIVAN® (INDINAVIR SULFATE) CAPSULES DESCRIPTION CRIXIVAN* (indinavir sulfate) is an inhibitor of the human immunodeficiency virus (HIV) protease. CRIXIVAN Capsules are formulated as a sulfate salt and are available for oral administration in strengths of 100, 200, and 400 mg of indinavir (corresponding to 125, 250, and 500 mg indinavir sulfate, respectively). Each capsule also contains the inactive ingredients anhydrous lactose and magnesium stearate. The capsule shell has the following inactive ingredients and dyes: gelatin and titanium dioxide. The chemical name for indinavir sulfate is [1(1S,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-1H­ inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2­ (phenylmethyl)-D-erythro-pentonamide sulfate (1:1) salt. Indinavir sulfate has the following structural formula: Indinavir sulfate is a white to off-white, hygroscopic, crystalline powder with the molecular formula C36H47N5O4 • H2SO4 and a molecular weight of 711.88. It is very soluble in water and in methanol. MICROBIOLOGY Mechanism of Action: HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Indinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Antiretroviral Activity In Vitro: The in vitro activity of indinavir was assessed in cell lines of lymphoblastic and monocytic origin and in peripheral blood lymphocytes. HIV-1 variants used to infect the different cell types include laboratory-adapted variants, primary clinical isolates and clinical isolates resistant to nucleoside analogue and nonnucleoside inhibitors of the HIV-1 reverse transcriptase.
    [Show full text]
  • The Role of Highly Selective Androgen Receptor (AR) Targeted
    P h a s e I I S t u d y o f I t r a c o n a z o l e i n B i o c h e m i c a l R e l a p s e Version 4.0: October 8, 2014 CC# 125513 CC# 125513: Hedgehog Inhibition as a Non-Castrating Approach to Hormone Sensitive Prostate Cancer: A Phase II Study of Itraconazole in Biochemical Relapse Investigational Agent: Itraconazole IND: IND Exempt (IND 116597) Protocol Version: 4.0 Version Date: October 8, 2014 Principal Investigator: Rahul Aggarwal, M.D., HS Assistant Clinical Professor Division of Hematology/Oncology, Department of Medicine University of California San Francisco 1600 Divisadero St. San Francisco, CA94115 [email protected] UCSF Co-Investigators: Charles J. Ryan, M.D., Eric Small, M.D., Professor of Medicine Professor of Medicine and Urology Lawrence Fong, M.D., Terence Friedlander, M.D., Professor in Residence Assistant Clinical Professor Amy Lin, M.D., Associate Clinical Professor Won Kim, M.D., Assistant Clinical Professor Statistician: Li Zhang, Ph.D, Biostatistics Core RevisionHistory October 8, 2014 Version 4.0 November 18, 2013 Version 3.0 January 28, 2013 Version 2.0 July 16, 2012 Version 1.0 Phase II - Itraconazole Page 1 of 79 P h a s e I I S t u d y o f I t r a c o n a z o l e i n B i o c h e m i c a l R e l a p s e Version 4.0: October 8, 2014 CC# 125513 Protocol Signature Page Protocol No.: 122513 Version # and Date: 4.0 - October 8, 2014 1.
    [Show full text]
  • Ongoing Living Update of Potential COVID-19 Therapeutics: Summary of Rapid Systematic Reviews
    Ongoing Living Update of Potential COVID-19 Therapeutics: Summary of Rapid Systematic Reviews RAPID REVIEW – July 13th 2020. (The information included in this review reflects the evidence as of the date posted in the document. Updates will be developed according to new available evidence) Disclaimer This document includes the results of a rapid systematic review of current available literature. The information included in this review reflects the evidence as of the date posted in the document. Yet, recognizing that there are numerous ongoing clinical studies, PAHO will periodically update these reviews and corresponding recommendations as new evidence becomes available. 1 Ongoing Living Update of Potential COVID-19 Therapeutics: Summary of Rapid Systematic Reviews Take-home messages thus far: • More than 200 therapeutic options or their combinations are being investigated in more than 1,700 clinical trials. In this review we examined 26 therapeutic options. • Preliminary findings from the RECOVERY Trial showed that low doses of dexamethasone (6 mg of oral or intravenous preparation once daily for 10 days) significantly reduced mortality by one- third in ventilated patients and by one fifth in patients receiving oxygen only. The anticipated RECOVERY Trial findings and WHO’s SOLIDARITY Trial findings both show no benefit via use of hydroxychloroquine and lopinavir/ritonavir in terms of reducing 28-day mortality or reduced time to clinical improvement or reduced adverse events. • Currently, there is no evidence of benefit in critical outcomes (i.e. reduction in mortality) from any therapeutic option (though remdesivir is revealing promise as one option based on 2 randomized controlled trials) and that conclusively allows for safe and effective use to mitigate or eliminate the causative agent of COVID-19.
    [Show full text]
  • ISENTRESS (Raltegravir) for Oral Suspension ------CONTRAINDICATIONS ------Initial U.S
    HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use --------------------- DOSAGE FORMS AND STRENGTHS --------------------- ISENTRESS safely and effectively. See full prescribing information Film-Coated Tablets: 400 mg (3). for ISENTRESS. Film-Coated Tablets: 600 mg (3). ISENTRESS® (raltegravir) film-coated tablets, for oral use Chewable Tablets: 100 mg scored and 25 mg (3). ® ISENTRESS HD (raltegravir) film-coated tablets, for oral use For Oral Suspension: Single-use packet of 100 mg (3). ISENTRESS® (raltegravir) chewable tablets, for oral use ® ISENTRESS (raltegravir) for oral suspension ------------------------------- CONTRAINDICATIONS ------------------------------- Initial U.S. Approval: 2007 None (4). ----------------------------INDICATIONS AND USAGE ---------------------------- ----------------------- WARNINGS AND PRECAUTIONS ----------------------- Adult Patients: Severe, potentially life-threatening and fatal skin reactions have been ISENTRESS and ISENTRESS HD are human immunodeficiency virus reported. This includes cases of Stevens-Johnson syndrome, integrase strand transfer inhibitors (HIV-1 INSTI) indicated in hypersensitivity reaction and toxic epidermal necrolysis. Immediately combination with other antiretroviral agents for the treatment of HIV-1 discontinue treatment with ISENTRESS or ISENTRESS HD and infection in adult patients (1). other suspect agents if severe hypersensitivity, severe rash, or rash Pediatric Patients: with systemic symptoms or liver aminotransferase
    [Show full text]
  • Clinically Relevant Drug Interactions with Antiepileptic Drugs
    British Journal of Clinical Pharmacology DOI:10.1111/j.1365-2125.2005.02529.x Clinically relevant drug interactions with antiepileptic drugs Emilio Perucca Institute of Neurology IRCCS C. Mondino Foundation, Pavia, and Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy Correspondence Some patients with difficult-to-treat epilepsy benefit from combination therapy with Emilio Perucca MD, PhD, Clinical two or more antiepileptic drugs (AEDs). Additionally, virtually all epilepsy patients will Pharmacology Unit, Department of receive, at some time in their lives, other medications for the management of Internal Medicine and Therapeutics, associated conditions. In these situations, clinically important drug interactions may University of Pavia, Piazza Botta 10, occur. Carbamazepine, phenytoin, phenobarbital and primidone induce many cyto- 27100 Pavia, Italy. chrome P450 (CYP) and glucuronyl transferase (GT) enzymes, and can reduce Tel: + 390 3 8298 6360 drastically the serum concentration of associated drugs which are substrates of the Fax: + 390 3 8222 741 same enzymes. Examples of agents whose serum levels are decreased markedly by E-mail: [email protected] enzyme-inducing AEDs, include lamotrigine, tiagabine, several steroidal drugs, cyclosporin A, oral anticoagulants and many cardiovascular, antineoplastic and psy- chotropic drugs. Valproic acid is not enzyme inducer, but it may cause clinically relevant drug interactions by inhibiting the metabolism of selected substrates, most Keywords notably phenobarbital and lamotrigine. Compared with older generation agents, most antiepileptic drugs, drug interactions, of the recently developed AEDs are less likely to induce or inhibit the activity of CYP enzyme induction, enzyme inhibition, or GT enzymes. However, they may be a target for metabolically mediated drug epilepsy, review interactions, and oxcarbazepine, lamotrigine, felbamate and, at high dosages, topira- mate may stimulate the metabolism of oral contraceptive steroids.
    [Show full text]
  • Proposal to Waive in Vivo Bioequivalence Requirements for the Who Model List of Essential Medicines Immediate Release, Solid Oral Dosage Forms
    Working document QAS/04.109/Rev.1 page 1 WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE PROPOSAL TO WAIVE IN VIVO BIOEQUIVALENCE REQUIREMENTS FOR THE WHO MODEL LIST OF ESSENTIAL MEDICINES IMMEDIATE RELEASE, SOLID ORAL DOSAGE FORMS This document has been revised by Professor Jennifer B. Dressman, Institut für Pharmazeutische Technologie, Biozentrum, Johann Wolfgang Goethe-Universität, Frankfurt/Main, Germany. It has followed the steps given in the schedule on page 2 herein. It has been very widely distributed and numerous comments have been incorporated. Please address any comments and/or corrections you may have to Dr S. Kopp, Quality Assurance and Safety: Medicines, Medicines Policy and Standards, World Health Organization, 1211 Geneva 27, Switzerland, fax: (+41 22) 791 4730 or e-mail: [email protected] (with a copy to [email protected]) by 20 October 2005. © World Health Organization 2005 All rights reserved. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations’ concerned staff and member organizations) without the permission of WHO. The draft should not be displayed on any website. Please send any request for permission to: Dr Sabine Kopp, Quality Assurance & Safety: Medicines (QSM), Department of Medicines Policy and Standards (PSM), World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; e-mails: [email protected]; [email protected] The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
    [Show full text]
  • Crixivan, INN-Indinavir Sulphate
    SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion for the approval of Crixivan. This scientific discussion has been updated until 1 October 2004. For information on changes after this date, please refer to module 8B. 1. Chemical, pharmaceutical and biological aspects The active substance of Crixivan, indinavir, is used as the sulphate salt ethanolate. One gram of anhydrous freebase corresponds to 1.25 grams of the sulphate salt ethanolate. This form is freely soluble in aqueous solutions, but the solubility decreases at higher pH. Indinavir is highly hygroscopic at relative humidities above 60 %. It has two pKa values, 6.2 and 3.8, and the partition coefficient octanol/water (log P) is 2.7 at pH 7. The primary degradation pathway for indinavir sulphate for both solid state and solution is amide bond hydrolysis to form lactone and aminoindanol. The degradation is humidity and temperature dependent. Indinavir is a chiral molecule with 5 stereogenic centres and is used as a single isomer. It is stereoselectively prepared from chiral starting materials. The enantiomeric purity is ascertained by a combination of controls during the synthesis. The only stereoisomer observed in the drug substance is the 4-(R)-epimer, which is controlled by the impurity method for drug substance. The drug substance is very pure. The limit for any single impurity is not more than 0.1 % and the limit for the sum of all impurities is not more than 0.5 %. However, due to the high doses to be given in clinical use (> 2 g/day), the qualification threshold as defined in the ICH guideline on impurities, is 0.05 %.
    [Show full text]