Raltegravir is primarily metabolised via glucuronidation by UGT1A1 enzyme. Individuals with genetic polymorphisms of *28/*28 genotype are known to have reduced activity of UGT1A1 enzyme.
EMA and FDA-approved drug labels for raltegravir cited that there is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinically meaningful extent even with UGT1A1 as the main enzyme involved in its elimination. Therefore, dose adjustments are not necessary for individuals with reduced UGT1A1 activity due to genetic polymorphism. However, the UGT1A1 catalytic activity is negligible at birth and matures after birth. The recommended dose for neonates <4 weeks of age takes into consideration the rapidly increasing UGT1A1 activity and drug clearance from birth to 4 weeks of age.
Some clinical studies, including that of a cohort of Caucasian and African HIV-1 infected patients demonstrated a higher raltegravir exposure among carriers of UGT1A1*28/*28 compared to UGT1A1*1/*1 and this effect appeared to be allele-dose dependent. In the study, it was emphasized that genetic screening for UGT1A1*28 may help improve raltegravir therapy. However, further clinical studies are still required.
Pharmacogenetic testing prior to raltegravir treatment initiation has not been addressed by other currently available references.
May be taken with or without food.
Granules for oral suspension: Mix the entire contents (100 mg) of a single-use packet with 10 mL of water in the provided mixing cup then gently swirl until suspended to make a final concentration of 10 mg/mL. Do not shake or invert the cup. Immediately measure the prescribed dose using the provided oral syringe and administer within 30 minutes of reconstitution. Discard the remaining suspension.
Hypersensitivity. Pre-term neonates. Lactation.
Patients with history of depression or psychiatric illness; history of or risk factors for rhabdomyolysis or myopathy; risk factors for increased serum creatine kinase (CK), pre-existing liver dysfunction (e.g. chronic hepatitis B or C coinfection). Severe hepatic impairment. Children and full-term neonates. Pregnancy.
Significant: Depression (including suicidal ideation and behaviour), rhabdomyolysis, myopathy, increased serum creatine kinase, osteonecrosis, fat redistribution or accumulation (e.g. central obesity, buffalo hump, peripheral and facial wasting, breast enlargement, cushingoid appearance), immune reconstitution syndrome (e.g. activation of Graves’ disease, polymyositis, Guillain-Barré syndrome), hypersensitivity reactions (e.g. rash, constitutional symptoms). Blood and lymphatic system disorders: Anaemia, neutropenia, thrombocytopenia. Cardiac disorders: Palpitations, sinus bradycardia, ventricular extrasystoles. Ear and labyrinth disorders: Tinnitus. Eye disorders: Visual impairment. Gastrointestinal disorders: Abdominal distention or pain, diarrhoea, flatulence, nausea, vomiting, dyspepsia, gastritis, gastroenteritis. General disorders and admin site conditions: Asthenia, fatigue, pyrexia, oedema. Hepatobiliary disorders: Hepatitis. Infections and infestations: Herpes zoster. Investigations: Atypical lymphocytes, increased ALT/AST, blood triglycerides, lipase, pancreatic amylase, and blood bilirubin. Metabolism and nutrition disorders: Decreased appetite, hyperglycaemia, dyslipidaemia. Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, back pain. Neoplasms benign, malignant and unspecified: Skin papilloma. Nervous system disorders: Dizziness, headache, psychomotor hyperactivity, vertigo. Psychiatric disorders: Insomnia, abnormal behaviour or dreams, nightmare, anxiety, paranoia, confusional state. Renal and urinary disorders: Nephritis, nocturia, renal failure. Reproductive system and breast disorders: Erectile dysfunction, menopausal symptoms, genital herpes. Respiratory, thoracic and mediastinal disorders: Dysphonia, epistaxis, nasal congestion. Skin and subcutaneous tissue disorders: Pruritus, hyperhidrosis, lipodystrophy acquired. Vascular disorders: Hot flush, hypertension. Potentially Fatal: Stevens-Johnson syndrome, toxic epidermal necrolysis, organ dysfunction (e.g. hepatic failure).
This drug may cause dizziness, if affected, do not drive or operate machinery.
Monitor viral load, CD4 count, CBC, renal and hepatic function at baseline and periodically thereafter. Assess for signs and symptoms of depression, suicidal ideation, and skin rash.
Reduced plasma concentration with potent UGT1A1 inducers (e.g. rifampicin), Al- and Mg-containing antacids. Plasma levels may be increased by UGT1A1 inhibitors (e.g. atazanavir, indinavir, saquinavir). Rate of absorption may be increased by agents that increase gastric pH (e.g. omeprazole, famotidine). Increased risk of myopathy or rhabdomyolysis with HMG-CoA reductase inhibitors (e.g. simvastatin), fenofibrate, gemfibrozil, zidovudine.
Description: Raltegravir inhibits the catalytic activity of HIV-1 integrase, an enzyme essential for the covalent insertion of unintegrated linear viral DNA into the host cell genome, thereby preventing the propagation of the HIV-1 provirus. Pharmacokinetics: Absorption: Rapidly absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 3 hours (400 mg film-coated tab); approx 1.5-2 hours (600 mg film-coated tab). Distribution: Crosses the placenta. Plasma protein binding: Approx 83%. Metabolism: Metabolised in the liver via glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Excretion: Mainly via faeces (approx 51% as unchanged drug); urine (approx 32%; 9% as unchanged drug, 23% as glucuronide metabolite). Elimination half-life: Approx 9 hours.
J05AJ01 - raltegravir ; Belongs to the class of integrase inhibitors. Used as direct acting antiviral in the systemic treatment of viral infections.
Belkhir L, Seguin-Devaux C, Elens L et al. Impact of UGT1A1 Polymorphisms on Raltegravir and its Glucuronide Plasma Concentrations in a Cohort of HIV-1 Infected Patient. Scientific Reports. 2018 May;8:7359. doi: 10.1038/s41598-018-25803-z. Accessed 11/09/2019Annotation of EMA Label for Raltegravir and UGT1A1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 04/09/2019.Annotation of FDA Label for Raltegravir and UGT1A1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 04/09/2019.Anon. Raltegravir. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 04/09/2019.Anon. Raltegravir. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/09/2019.Buckingham R (ed). Raltegravir. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/09/2019.Isentress Tablet, Film Coated; Tablet, Chewable; Granule, for Suspension (Merck Sharp & Dohme Corp.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 04/09/2019.Joint Formulary Committee. Raltegravir. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/09/2019.