Adult: As conventional tab: Initially, 50 or 100 mg once daily at bedtime, adjust dose within 3-4 weeks of therapy according to clinical response up to Max 300 mg daily. Doses >150 mg should be given in 2 or 3 divided doses.
Oral Obsessive compulsive disorder
Adult: As conventional tab: Initially, 50 mg once daily at bedtime gradually increase up to Max 300 mg daily. Doses >150 mg should be given in 2 or 3 divided doses. As extended-release tab: Initially, 100 mg once daily at bedtime, increase if necessary in increments of 50 mg at weekly intervals up to Max 300 mg once daily. Child: As conventional tab: >8 years Initially, 25 mg once daily, increase as tolerated in increments of 25 mg every 4-7 days until an effective dose is achieved. Max: 200 mg daily. Dose >50 mg should be given in 2 divided doses. If the 2 divided doses are not equal, give the larger dose at bedtime.
Special Patient Group
Fluvoxamine is metabolised mainly by CYP2D6 isoenzyme to its inactive metabolites. CYP2D6 polymorphisms may affect the clinical efficacy and safety of fluvoxamine. Individuals with reduced levels of CYP2D6 activity, known as CYP2D6 poor metabolisers, may experience an increased risk of fluvoxamine adverse effects.
CYP2D6 allele frequencies vary among individuals of different populations and ethnic backgrounds. For example, CYP2D6*10 is common in Asians and CYP2D6*17 is common in people of Sub-Saharan African ancestry, while these alleles have considerably lower prevalence in other ethnic groups such as Caucasians of European ancestry. Thus, the alleles that should be tested may considerably vary for a given population. Approx 7% of the normal population may also have a genetic code which leads to low levels of CYP2D6 enzyme activity.
CYP2D6 ultrarapid metabolisers (carriers of duplicate functional alleles e.g. *1/*1xN, *1/*2xN, *2/*2xN)
No therapeutic recommendation due to lack of evidence.
CYP2D6 extensive metabolisers (carriers of 2 normal function alleles, or 2 decreased function alleles, or 1 normal function and 1 no function allele, or 1 normal function and 1 decreased function allele e.g. *1/*1, */*2, *1/*4, *1/*5, *1/*9, *1/*41, *2/*2, *2/*41, *41/*41)
Patients who are extensive metabolisers may have normal fluvoxamine metabolism. CPIC recommends initiation of treatment with the recommended starting dose. No dosage adjustment needed.
CYP2D6 intermediate metabolisers (carriers of 1 decreased function and 1 no function allele e.g. *4/*10, *4/*41, *5/*9)
Patients who are intermediate metabolisers may have reduced fluvoxamine metabolism as compared with extensive metabolisers, resulting to increased plasma fluvoxamine concentrations thus increasing the risk of adverse effects (e.g. insomnia, headache, sexual or gastrointestinal dysfunction). However, CPIC recommends initiation of treatment with the recommended starting dose and no dosage adjustment needed.
CYP2D6 poor metabolisers (carriers of only non-functional alleles e.g.*3/*4, *4/*4, *5/*5, *5/*6)
Patients who are poor metabolisers may have greatly reduced fluvoxamine metabolism as compared with extensive metabolisers, resulting to increased plasma fluvoxamine concentrations thus increasing the risk of adverse effects (e.g. insomnia, headache, sexual or gastrointestinal dysfunction). CPIC recommends a 25-50% dose reduction of recommended starting dose and titrate according to response, or use an alternative drug not metabolised by CYP2D6.
Renal Impairment
Initiate at lower dose and monitor closely.
Hepatic Impairment
Initiate at lower dose and monitor closely.
Administration
May be taken with or without food.
Contraindications
Unstable seizure disorder. Lactation. Concomitant admin or within 14 days of discontinuing MAOIs or fluvoxamine treatment. Concomitant use with alosetron, pimozide, thioridazine, tizanidine, cisapride, ramelteon, terfenadine, astemizole, linezolid, methylene blue IV.
Special Precautions
Patient with bipolar disorder; history of convulsive disorder; CV disease (e.g. recent history of MI, unstable heart disease), diabetes mellitus, history of mania or hypomania, history of bleeding or other predisposing conditions (e.g. thrombocytopenia, coagulation disorders), raised intraocular pressure or at risk of acute narrow-angle glaucoma, volume depletion. Smokers. Concomitant electroconvulsive therapy. Avoid abrupt withdrawal. Renal and hepatic impairment. Children and elderly. Pregnancy. CYP2D6 poor metabolisers.
Adverse Reactions
Significant: Suicidal thinking and behaviour in children, adolescent and young adults, shift to mania or hypomania, akathisia or psychomotor restlessness, bleeding events (e.g. cutaneous or mucous bleeding), CNS depression, mild pupillary dilation, bone fractures, impaired glucose control (e.g. hyper- or hypoglycaemia, decreased glucose tolerance), sexual dysfunction, hyponatraemia, syndrome of inappropriate antidiuretic hormone secretion (SIADH), withdrawal symptoms. Cardiac disorders: Palpitations, tachycardia. Gastrointestinal disorders: Nausea, vomiting, abdominal pain, constipation, diarrhoea, dry mouth, dyspepsia. General disorders and admin site conditions: Asthenia, malaise, ataxia. Hepatobiliary disorders: Abnormal hepatic function. Metabolism and nutrition disorders: Anorexia. Musculoskeletal and connective tissue disorders: Arthralgia, myalgia. Nervous system disorders: Headache, dizziness, somnolence, tremor, extrapyramidal disorder, convulsion. Psychiatric disorders: Agitation, anxiety, nervousness, insomnia, hallucination, confusion, aggression. Renal and urinary disorders: Urinary incontinence or retention, enuresis, nocturia. Reproductive system and breast disorders: Delayed ejaculation, galactorrhoea. Skin and subcutaneous tissue disorders: Hyperhidrosis, sweating, photosensitivity. Vascular disorders: Orthostatic hypotension. Potentially Fatal: Serotonin syndrome or neuroleptic malignant syndrome (NMS)-like events, haemorrhage (e.g. gastrointestinal or gynaecological haemorrhage).
PO: C, Z (Risk of postpartum haemorrhage, persistent pulmonary hypertension in infant and neonatal withdrawal/toxicity in late pregnancy use. Monitor closely.)
Patient Counseling Information
This drug may cause somnolence, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor weight and BMI; LFT at baseline and as clinically indicated. Closely monitor for clinical worsening, suicidality, changes in behaviour at treatment initiation and during dosage adjustments; anxiety, social functioning, mania, panic attacks, or other unusual behavioural changes. Monitor for signs and symptoms of serotonin syndrome and akathisia.
Overdosage
Symptoms: Nausea, vomiting, diarrhoea, somnolence, dizziness, tachycardia, bradycardia, hypotension, liver function disturbances, convulsion, and coma. Management: Symptomatic and supportive treatment. Ensure adequate airway, oxygenation and ventilation. Empty stomach as soon as possible after ingestion. Consider repeated activated charcoal administration, accompanied by an osmotic laxative if necessary.
Drug Interactions
Increased risk of bleeding with aspirin, NSAIDs, warfarin, ticlopidine, other anticoagulants, atypical antipsychotics and phenothiazines. May increase plasma concentrations of narrow therapeutic index drugs (e.g. theophylline, tacrine, methadone, mexiletine, phenytoin, carbamazepine, ciclosporin), TCAs (e.g. amitriptyline, clomipramine, imipramine), neuroleptics (e.g. clozapine, olanzapine, quetiapine), oxidatively metabolised benzodiazepines (e.g. triazolam, midazolam, alprazolam, diazepam), ropinirole, propranolol, warfarin. Increased risk of hyponatraemia with diuretics. Potentially Fatal: Increased risk of serotonin syndrome with triptans, fentanyl, lithium, tramadol, tryptophan, MAOIs, linezolid, IV methylene blue. May increase serum concentration of pimozide, tizanidine. May increase plasma concentration and risk of QTc prolongation/Torsade de Pointes of terfenadine, astemizole, cisapride, thioridazine.
Food Interaction
Increased risk of serotonin syndrome with St. John’s wort. Increased risk of psychomotor impairment with alcohol. May increase plasma levels of caffeine.
Action
Description: Mechanism of Action: Fluvoxamine, an aralkylketone derivative, selectively inhibits serotonin re-uptake in CNS neuron with minimal or no effect on norepinephrine or dopamine re-uptake. Onset: Depression: 4-8 weeks. Obsessive-compulsive disorder: 8-12 weeks. Pharmacokinetics: Absorption: Readily and completely absorbed from the gastrointestinal tract. Bioavailability: 53% (immediate-release); 84% (extended-release). Time to peak plasma concentration: 3-8 hours. Distribution: Widely distributed into the body. Crosses placenta and enters breastmilk. Volume of distribution: Approx 25 L/kg. Plasma protein binding: Approx 80%, mainly to albumin. Metabolism: Extensively metabolised in the liver via oxidative demethylation and deamination primarily by CYP2D6 isoenzyme to inactive metabolites. Excretion: Mainly via urine (approx 85% as metabolites; approx 2% as unchanged drug). Elimination half-life: Approx 14-16 hours.
Chemical Structure
Fluvoxamine Source: National Center for Biotechnology Information. PubChem Database. Fluvoxamine, CID=5324346, https://pubchem.ncbi.nlm.nih.gov/compound/Fluvoxamine (accessed on Jan. 21, 2020)
N06AB08 - fluvoxamine ; Belongs to the class of selective serotonin reuptake inhibitors. Used in the management of depression.
References
Hicks JK, Bishop JR, Sangkuhl K et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clinical Pharmacology and Therapeutics. 2015 Aug;98(2):127-134. doi: 10.1002/cpt.147. Accessed 20/09/2019. PMID: 25974703Hicks JK, Bishop JR, Sangkuhl K et al. Supplement to: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of SSRIs. CPIC Guidelines. Accessed 20/09/2019Annotation of CPIC Guideline for Fluvoxamine and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 20/09/2019.Annotation of FDA Label for Fluvoxamine and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 20/09/2019.Anon. Fluvoxamine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 20/09/2019.Buckingham R (ed). Fluvoxamine Maleate. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 20/09/2019.Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 20/09/2019.Fluvoxamine Maleate Capsule, Extended Release (Actavis Pharma, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 20/09/2019.Joint Formulary Committee. Fluvoxamine Maleate. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 20/09/2019.
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