high risk

• High Risk Drugs
• Pre-Registration Training
• This guide summarises the high risk drugs outlined in the GPhC framework. Please note that the information provided in this guide is not exhaustive. Additional notes can be added where required.
• ProPharmace Antibiotics Guide and the ProPharmace Diabetes Treatment Guide are available for further information on antibiotics, insulins and oral antidiabetic drugs respectively.
• High risk drugs


  Medicines that can cause significant harm to the patient; they may cause serious side-effects especially when administered incorrectly or when a dose is calculated incorrectly. High risk drugs may also have a narrow therapeutic range; which means there is little difference between sub-therapeutic, therapeutic and toxic doses.
• Therapeutic Drug Monitoring


  Aims to individualise drug therapy and avoid both sub-therapeutic and toxic plasma drug concentrations. Whole blood or serum drug concentrations are used for determining patient compliance and/or for assessing whether or not adequate concentrations are being achieved for the desired therapeutic outcomes or that potentially toxic concentrations are being reached.
• Therapeutic Range


  The concentration below which therapeutic effect is unlikely and above which toxic effect is more likely. Some patients respond to levels below or above a therapeutic range. Some patients may get toxic effects within the so-called therapeutic ranges. It is important to treat the patient and not the plasma concentration.
• Steady state


  Four to five half-lives after initiation of therapy or a change in dosage. Half-life is the time taken for concentration/amount of drug in body to be reduced by one-half. Target (optimum) concentration based on 'steady state' samples taken at specific times after the dose.
• Trough samples


  Taken at the end of a dosing interval (immediately before next dose)
• Peak samples


  Taken at a specific time after the dose is administered
• Loading dose


  Higher initial dose to rapidly achieve therapeutic response. Drugs with long half-lives will take longer to reach steady state, therefore require a loading dose to rapidly achieve target concentration for acute therapeutic response.
• Maintenance dose


  Subsequent dose(s) after loading dose to maintain therapeutic response.
• Amiodarone


  • Long half-life of about 50 days, loading doses may be required
• Therapeutic Range for Carbamazepine: 4 to 12mg/L (20 to 50 micromol/litre)
• Carbamazepine undergoes hepatic metabolism and is a major route of elimination
• Chemotherapy


  • Extravasation of IV drugs, nausea and vomiting, bone marrow suppression (except vincristine and bleomycin), other side effects including oral mucositis, diarrhoea, fatigue, organ toxicities, hyperuricaemia, urothelial toxicity
• Chemotherapy can be administered systemically (oral, IV, SC, IM) with aim of maximal therapeutic cytotoxic effect whilst avoiding extreme toxicity to normal healthy tissues or regionally (intrathecal, intraarterial) which is aimed at delivering cytotoxics directly into cavity in which tumour is located or blood vessel supplying tumour therefore minimizing side effects
• Therapeutic Range for Ciclosporin depends on clinical situation and indication for treatment, loading doses may be required
• Monitoring for CICLOSPORIN


  • Full blood count
  • Liver function
  • Serum electrolytes (K+, Mg2+)
  • Blood lipids
  • Renal function (including creatinine, urea)
  • Blood pressure
  • Dermatological and physical examination
• Warning signs for CICLOSPORIN

  • Neurotoxicity e.g. tremor, headache, encephalopathy (e.g. confusion, convulsions)
  • Blood disorders (signs of infection such as fever, sore throat, mouth ulcers, also unexplained bruising or bleeding) e.g. leucopenia, thrombocytopenia
  • Liver toxicity e.g. jaundice, nausea, vomiting, abdominal discomfort, dark urine
  • Nephrotoxicity e.g. elevated serum creatinine concentrations
  • Other signs of toxicity - vomiting, drowsiness, tachycardia
  • Hypertension
  • Headache
  • Gingivial hyperplasia
• Actions required for CICLOSPORIN


  • Advise patient to report immediately to a doctor if any warning signs occur
  • Hypertension is a common side-effect of ciclosporin therapy. Advise patient to have their blood pressure monitored regularly
  • Warn patients that they must not receive immunisation with live vaccines
  • Brand-specific prescribing is recommended (if changing brand monitor closely for changes in ciclosporin level, serum creatinine and blood pressure)
  • Advise patient to avoid excessive exposure to UV light, including sunlight and to use a wide-spectrum sunscreen (may reduce risk of secondary skin malignancies). Patients with atopic dermatitis and psoriasis should avoid use of UVB or PUVA
  • Advise patient to avoid a high potassium diet and grapefruit juice. The oral solution formulations can be taken with orange or apple juices to improve taste
• Interactions with CICLOSPORIN


  • Increased plasma concentration with clarithromycin, diltiazem, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, miconazole, metoclopramide, verapamil, colchicine (with which concomitant use also increases risk of nephrotoxicity and myotoxicity) and tacrolimus (avoid)
  • Decreased plasma concentration with carbamazepine, orlistat, phenobarbital, phenytoin, rifampicin, St. John's Wort
  • Increased risk of hyperkalaemia when ciclosporin given with ACE inhibitors or angiotensin-II receptor antagonists, aldosterone antagonists
  • Increased risk of nephrotoxicity when ciclosporin given with NSAIDs and increased plasma concentration of diclofenac
  • Ciclosporin increases plasma concentration of digoxin (increased risk of toxicity)
  • Increased risk of myopathy when ciclosporin given with atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatin (avoid concomitant use)
• Monitoring for CORTICOSTEROIDS


  • Blood pressure
  • Blood lipids
  • Serum potassium
  • Body weight and height (in children and adolescents)
  • Bone mineral density
  • Blood glucose
  • Eye exam (for intraocular pressure, cataracts)
  • Signs of adrenal suppression
• Warning signs for CORTICOSTEROIDS

  • Paradoxical bronchospasm (constriction of the airways)
  • Symptoms of uncontrolled asthma e.g. cough, wheeze, tight chest
  • Frequent courses of antibiotics and/or oral corticosteroids
  • Adrenal suppression e.g. nausea, vomiting, weight loss, fatigue, headache, muscular weakness
  • Immunosupression e.g. chicken pox, measles, oral candidiasis, more serious infections e.g. TB, septicaemia, ocular fungal or viral infections
  • Psychiatric reactions e.g. suicidal thoughts, nightmares, depression, insomnia
• Actions required for CORTICOSTEROIDS


  • Advise patient to report immediately to a doctor if any warning signs occur
  • Give the patient a steroid treatment card if long-term treatment is required. Explain that they must not stop treatment abruptly after prolonged treatment (> 3 weeks)
  • Check the patient is taking oral steroids in the morning as a single dose
  • Ensure that patients rinse their mouth or clean their teeth after using inhaled corticosteroids
  • If the patient has not had chicken pox and measles in the past, advise them to avoid anyone with these infections
• Interactions with CORTICOSTEROIDS


  • Metabolism of corticosteroids accelerated by carbamazepine, phenobarbital, phenytoin and rifamycins
  • Corticosteroids may induce or enhance anticoagulant effect of coumarins
  • High dose corticosteroid can impair immune response to vaccines; avoid concomitant use with live vaccines
  • Corticosteroids can mask the gastrointestinal effects of NSAIDs (including aspirin); avoid concomitant use if possible and consider gastroprotection
  • Hypokalaemia can be severe when given with other drugs that lower serum potassium e.g. loop and thiazide diuretics
  • Effects if antihypertensive and oral hypoglycaemic drugs are antagonized by glucocorticoids
• Therapeutic Range for DIGOXIN

  0.8 to 2 mcg/L (wide interindividual variations)
• Loading doses may be required for DIGOXIN
• Monitoring for DIGOXIN


  • Serum electrolytes (K+, Mg2+, Ca2+)
  • Renal function
  • Heart rate (maintained at greater than 60 beats per minute)
• Warning signs for DIGOXIN

  • Cardiac e.g. arrhythmias, heart block
  • Neurological e.g. weakness, lethargy, dizziness, headache, mental confusion, pyschosis
  • Gastrointestinal e.g. anorexia, nausea, vomiting, diarrhoea, abdominal pain
  • Visual e.g. blurred and/or yellow vision
• Actions required for DIGOXIN

  • Advise patient to report immediately to a doctor if any warning signs occur
• Dosage forms have different bioavailabilities for DIGOXIN (change of dose required to maintain same plasma-digoxin concentration)
• Bioavailability of DIGOXIN dosage forms

  • Intravenous: 100%
  • Tablet: 50-90%
  • Elixir: 75%
• Interactions with DIGOXIN


  • Increased plasma concentration with alprazolamamiodarone, ciclosporin, diltiazem, itraconazole, lercanidipine, macrolides, mirabegron, nicardipine, nifedipine, quinine, spironolactone and verapamil
  • Reduced plasma concentrations with St. John's Wort
  • Concomitant administration of acetazolamide, amphotericin, loop diuretics or thiazides and related diuretics can cause hypokalaemia that increases the risk of cardiac toxicity and digoxin toxicity
  • Drugs that impair renal function can affect the plasma digoxin concentration e.g. NSAIDs, ACE inhibitors
• Major Route of Elimination for DIGOXIN is Renal excretion
• Therapeutic Range for GENTAMICIN AND AMIKACIN


  For multiple daily dose regimens, one-hour (peak) serum concentration should be 5 to 10mg/L (3 to 5 mg/L for endocarditis), pre-dose (trough) concentration should be< 2mg/L (< 1mg/L for endocarditis); For once-daily dose regimens, consult local guidelines
• Loading doses may be required for GENTAMICIN AND AMIKACIN
• Monitoring for GENTAMICIN AND AMIKACIN

  • Renal function (nephrotoxicity)
  • Auditory and vestibular function (ototoxicity which is irreversible)
  • Serum-aminoglycoside concentration must be determined in the elderly, those with renal impairment, if high doses given, obesity and in cystic fibrosis
• Warning signs for GENTAMICIN AND AMIKACIN

  • Hearing impairment or hearing disturbance
• Actions required for GENTAMICIN AND AMIKACIN


  • Advise patient to report immediately to a doctor if any of the warning signs occur
  • Ensure patient is hydrated and drinking adequate amounts of fluid to prevent dehydration before starting treatment