High Risk Drugs Flashcards

Question

Side effects of carbamazepine?

Answer 1

Dizziness; drowsiness; dry mouth; eosinophilia; fatigue; fluid imbalance; gastrointestinal discomfort; headache; hyponatraemia; leucopenia; movement disorders; nausea; oedema; skin reactions; thrombocytopenia; vision disorders; vomiting; weight increased Some side-effects (such as headache, ataxia, drowsiness, nausea, vomiting, blurring of vision, dizziness and allergic skin reactions) are dose-related, and may be dose-limiting. * These side-effects are more common at the start of treatment and in the elderly. * Switching to a modified-release preparation of carbamazepine may help to reduce the incidence of central nervous system adverse effects, such as sedation. **Hyponatraemia** occurs in 20% of people taking carbamazepine. It is usually mild but in rare cases can lead to water intoxication accompanied by lethargy, vomiting, headache, and confusion. * Consider hyponatraemia if the person develops dizziness, drowsiness, confusion, nausea, muscle cramps, or seizures. * If hyponatraemia is suspected, reduce the dose or stop carbamazepine and manage according to severity of symptoms, duration, and state of hydration. **Allergic skin reactions** (including urticaria, which may be severe) are also common: * Withdraw carbamazepine if the skin reaction worsens, or is accompanied by other symptoms. * Cross-sensitivity has been reported with other antiepileptic drugs (including oxcarbazepine, phenytoin, primidone, and phenobarbital).

Answer 2

* The use of carbamazepine is not recommended in combination with monoamine oxidase inhibitors (MAOIs), or for 2 weeks after stopping an MAOI. * Avoid giving carbamazepine with diuretics — increased risk of hyponatraemia. * The plasma concentration of carbamazepine may be increased (with an increased risk of toxicity) by the concomitant use of certain drugs, including: * Acetazolamide. * Antidepressants — fluoxetine, fluvoxamine, paroxetine, trazodone. * Azole antifungals. * Antivirals — protease inhibitors for HIV treatment (for example ritonavir). * Cimetidine. * Ciprofloxacin. * Clarithromycin. * Danazol. * Dextropropoxyphene. * Diltiazem. * Erythromycin. * Isoniazid. * Loratadine. * Olanzapine. * Omeprazole * Verapamil. * Vigabatrin. * Carbamazepine accelerates the metabolism of certain drugs, including (but not limited to): * Azole antifungals — resulting in reduced levels of voriconazole and itraconazole. * Ciclosporin — resulting in reduced levels of ciclosporin. * Clozapine — resulting in reduced plasma concentration of clozapine; also avoid concomitant use of drugs with potential for causing agranulocytosis. * Corticosteroids (systemic) — resulting in their reduced effect. * Direct acting oral anti-coagulants (DOACs; rivaroxaban, dabigatran, apixaban, and edoxaban) may lead to reduced plasma concentrations of DOACs, which carries the risk of thrombosis. Closer monitoring is recommended. * Doxycycline — resulting in reduced effect. * Oestrogens and progestogens — resulting in reduced effect of oral contraceptives. * Thyroid hormones — requirements for thyroid hormones in hypothyroidism may be increased. * Tricyclic antidepressants — resulting in their reduced effect. * Simvastatin — consider increasing dose of simvastatin; statins metabolized by the same route as simvastatin may also have their levels reduced. * Warfarin — resulting in reduced anticoagulant effect. * Other interactions include: * Grapefruit juice — may increase plasma concentrations. * Lithuim — may result in enhanced neurotoxicity despite lithium plasma concentrations being within the therapeutic range. * Paracetamol — long term co-administration may result in hepatotoxicity. * Primidone, progabide, quetiapine, valproic acid, valnoctamide, and valpromide — may result in raised plasma levels of the active metabolite carbamazepine-10,11-epoxide, increasing the risk of adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia). The dosage of carbemazepine should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with these substances.

Answer 3

**Pregnancy:** * An increased risk of major congenital malformations has been seen with carbamazepine, see Pregnancy in Epilepsy for further details. Monitoring in pregnancy: Plasma-drug concentration should be monitored and may be maintained on the lower side of the therapeutic range provided seizure control is maintained

Answer 4

**Breast feeding:** * Amount probably to small to be harmful * Monitor infant for possible ADR

Answer 5

* Use with caution

Answer 6

Hepatic Impairment: Use with caution and close monitoring

Answer 7

**Pre-treatment Screening:** * Test for HLA-B\*1502 allele in individuals of Han Chinese or Thai origin (avoid unless no alternative—risk of Stevens-Johnson syndrome [[KS1]](#_msocom_1) in presence of HLA-B\*1502 allele). * * * [[KS1]](#_msoanchor_1)tevens-Johnson syndrome (SJS) is **a rare, serious disorder of the skin and mucous membranes**. It's usually a reaction to medication that starts with flu-like symptoms, followed by a painful rash that spreads and blisters. Then the top layer of affected skin dies, sheds and begins to heal after several days

Answer 8

* **Therapeutic drug monitoring For carbamazepine** Plasma concentration for optimum response 4–12 mg/litre (20–50 micromol/litre) measured after 1–2 weeks. * **Monitoring of patient parametersFor carbamazepine** Manufacturer recommends blood counts and hepatic (LFTs) and renal function tests (but evidence of practical value uncertain). Suicidal ideation has been reported in patients with antiepileptic drugs – make patients aware of this and to seek medical advice if needed.

Answer 9

When stopping treatment with carbamazepine for bipolar disorder, reduce the dose gradually over a period of at least 4 weeks. - this is to reduce risk of seizure

Answer 10

Manufacturer advises Tegretol® Prolonged Release tablets can be halved but should not be chewed.

Answer 11

In children: Expert sources advise oral liquid has been used rectally—should be retained for at least 2 hours (but may have laxative effect).

Answer 12

Carbamazepine is category one – the patient should be maintained on the same brand (if for epilepsy). Different formulations of oral preparations may vary in bioavailability. Patients being treated for epilepsy should be maintained on a specific manufacturer's product.

Answer 13

Blood, hepatic, or skin disorders

Answer 14

* Patients or their carers should be told how to recognise signs of blood, liver, or skin disorders, and advised to seek immediate medical attention if symptoms such as fever, rash, mouth ulcers, bruising, or bleeding develop. * Stick to same brand!! * That suicidal thoughts can occur as wuick as 1 week from starting - seek help if needed

Answer 15

* Blurred, double vision, nystagmus adverse effects * High doses can elicit diplopia, blurred vision, nystagmus or ataxia. Severe toxicity may induce seizures and progress to coma

Answer 16

* Tonic-Clonic Seizures * Focal Seizure * Prevention and treatment of seizures during or following neurosurgery or severe head injury * Status epilepticus[[KS1]](#_msocom_1) * Acute symptomatic seizures associated with head trauma or neurosurgery * * * [[KS1]](#_msoanchor_1)**A seizure that lasts longer than 5 minutes, or having more than 1 seizure within a 5 minutes period, without returning to a normal level of consciousness between episodes** is called status epilepticus. This is a medical emergency that may lead to permanent brain damage or death.

Answer 17

Category 1 - Different formulations of oral preparations may vary in bioavailability. Patients being treated for epilepsy should be maintained on a specific manufacturer's product

Answer 18

Preparations containing phenytoin sodium are not bioequivalent to those containing phenytoin base (such as Epanutin Infatabs® and Epanutin® suspension); 100 mg of phenytoin sodium is approximately equivalent in therapeutic effect to 92 mg phenytoin base. The dose is the same for all phenytoin products when initiating therapy. However, if switching between these products the difference in phenytoin content may be clinically significant. Care is needed when making changes between formulations and plasma-phenytoin concentration monitoring is recommended

Answer 19

* **General contraindications:** Acute porphyrias * **With IV use:** Second- and third-degree heart block; sino-atrial block; sinus bradycardia; Stokes-Adams syndrome

Answer 20

Intramuscular phenytoin should not be used (absorption is slow and erratic).

Answer 21

**General cautions:** Enteral feeding (interrupt feeding for 2 hours before and after dose; more frequent monitoring may be necessary); may exacerbate absence and myoclonic seizures **With intravenous use:** Heart failure; hypotension; injection solutions alkaline (irritant to tissues); respiratory depression; resuscitation facilities must be available

Answer 22

MHRA advises consider **vitamin D supplementation** in patients who are immobilised for long periods or who have inadequate sun exposure or dietary intake of calcium

Answer 23

Phenytoin is usually well tolerated. **Frequency not known:** * **With oral use:** Electrolyte imbalance; pneumonitis; vitamin D deficiency * **Rash:-** discontinue. If mild re-introduce cautiously but discontinue immediately of recurrence. * **Bradycardia and hypotension:-** With IV use – reduce rate of administration if either occurs

Answer 24

* Symptoms of phenytoin toxicity include nystagmus[[KS1]](#_msocom_1) , diplopia[[KS2]](#_msocom_2) , slurred speech, ataxia, confusion, and hyperglycaemia. * * * [[KS1]](#_msoanchor_1)Uncontrolled eye movement [[KS2]](#_msoanchor_2)Double vision

Answer 25

Yes - Rash is a common adverse effect of antiepileptic drug (AED) use. Cross-sensitivity of rash has been reported between various AEDs, but is most commonly encountered in patients treated with aromatic AEDs such as phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and lamotrigine.

Answer 26

Manufacturer advises caution (increased risk of accumulation and toxicity due to decreased protein binding in hepatic impairment, hypoalbuminaemia, or hyperbilirubinaemia). Phenytoin is also metabolised by CYP450s such as CYP 2C9 **Dose adjustments** * With oral use: Manufacturer advises consider dose reduction. * With intravenous use: Manufacturer advises consider maintenance dose reduction Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound concentration of phenytoin may be elevated in patients with hyperbilirubinemia. Unbound phenytoin concentrations may be more useful in these patient populations (see section 4.4 Special warnings and precautions for use-General).

Answer 27

* HLAB\* 1502 allele in individuals of Han Chinese or Thai origin—avoid unless essential (increased risk of Stevens- Johnson syndrome).

Answer 28

**In adults** * The usual total plasma-phenytoin concentration for optimum response is 10–20 mg/litre (or 40–80 micromol/ litre). In pregnancy, the elderly, and certain disease states where protein binding may be reduced, careful interpretation of total plasma-phenytoin concentration is necessary; it may be more appropriate to measure free plasma-phenytoin concentration. * Dosage should be individualised as there may be wide interpatient variability in phenytoin serum levels with equivalent dosage. Phenytoin should be introduced in small dosages with gradual increments until control is achieved or until toxic effects appear. In some cases serum level determinations may be necessary for optimal dosage adjustments - the clinically effective level is usually 10-20mg/l (40-80 micromoles/l) although some cases of tonic-clonic seizures may be controlled with lower serum levels of phenytoin. With recommended dosage a period of seven to ten days may be required to achieve steady state serum levels with Phenytoin and changes in dosage should not be carried out at intervals shorter than seven to ten days. Maintenance of treatment should be the lowest dose of anticonvulsant consistent with control of seizures. **In children** * Therapeutic plasma-phenytoin concentrations reduced in first 3 months of life because of reduced protein binding. * Trough plasma concentration for optimum response: neonate–3 months, 6–15 mg/litre (25–60 micromol/ litre); child 3 months–18 years, 10–20 mg/litre (40–80 micromol/litre).

Answer 29

**Blood counts** * Manufacturer recommends blood counts (but evidence of practical value uncertain). **With intravenous use** * Monitor ECG and blood pressure.

Answer 30

**Blood or skin disorders:** Patients or their carers should be told how to recognise signs of blood or skin disorders, and advised to seek immediate medical attention if symptoms such as fever, rash, mouth ulcers, bruising, or bleeding develop. Leucopenia that is severe, progressive, or associated with clinical symptoms requires withdrawal (if necessary under cover of a suitable alternative). **Sucicide:** Increased suicide risk - advise to monitor and seek help if needed **Brand:** Stick to same brand.

Answer 31

**Transplantation Indications:** * Solid organ transplant * Bone marrow transplant Immunosupressant so used to prevent transplant rejection **Non-transplantation Indications:** * Severe keratitis in dry eye disease that has not responded to treatment with tear substitutes (initiated by a specialist)\* * Ulcerative colitis refractory to corticosteroid treatment * Severe acute ulcerative colitis refractory to corticosteroid treatment * Unlicensed * Nephrotic syndrome * Neoral can be used to induce and maintain remissions. It can also be used to maintain steroid-induced remission, allowing withdrawal of steroids. * Rheumatoid arthritis\* * Treatment of severe, active rheumatoid arthritis * Psoriasis\* * Treatment of severe psoriasis in patients in whom conventional therapy is inappropriate or ineffective. * Atopic dermatitis\* * Short-term treatment of severe or very severe atopic dermatitis when systemic therapy is required. \*Administered on expert advice

Answer 32

Manufacture advises **_increase_** dose by **_50%_** or switch to IV with concurrent use of **_octreotide_**

Answer 33

Important Patients should be stabilised on a particular brand of oral ciclosporin because switching between formulations without close monitoring may lead to clinically important changes in blood-ciclosporin concentration. Ciclosporin must be prescribed and dispensed by brand name. This is because switching between formulations without close monitoring may lead to clinically important changes in blood-ciclosporin concentrations. If it is necessary to switch a patient to a different brand of ciclosporin, the patient should be monitored closely for changes in blood-ciclosporin concentration, serum creatinine, blood pressure, and transplant function (for transplant indications).

Answer 34

**When used by eye** Active or suspected ocular or peri-ocular infection; ocular or peri-ocular malignancies or premalignant conditions **With systemic use** Malignancy (inP non-transplant indications); uncontrolled hypertension (in non-transplant indications); uncontrolled infections (in non-transplant indications)

Answer 35

Elderly—monitor renal function; hyperuricaemia; in atopic dermatitis, active herpes simplex infections—allow infection to clear before starting (if they occur during treatment withdraw if severe); in atopic dermatitis, Staphylococcus aureus skin infections—not absolute contra-indication providing controlled (but avoid erythromycin unless no other alternative); in psoriasis treat, patients with malignant or pre-malignant conditions of skin only after appropriate treatment (and if no other option); in uveitis, Behcet's syndrome (monitor neurological status); lymphoproliferative disorders (discontinue treatment); malignancy

Answer 36

The principal adverse reactions observed in clinical trials and associated with the administration of ciclosporin include renal dysfunction, tremor, hirsutism, hypertension, diarrhoea, anorexia, nausea and vomiting. Many side effects associated with ciclosporin therapy are dose-dependent and responsive to dose reduction. **Common or very common:** Appetite decreased; diarrhoea; electrolyte imbalance; fatigue; fever; flushing; gastrointestinal discomfort; gingival hyperplasia; hair changes; headaches; hepatic disorders; hyperglycaemia; hyperlipidaemia; hypertension; hyperuricaemia; leucopenia; muscle complaints; nausea; paraesthesia; peptic ulcer; renal impairment (renal structural changes on long-term administration); seizure; skin reactions; tremor; vomiting; Hepatotoxicity **Infections:** Patients receiving immunosuppressant therapies are at increased risk of infections (viral, bacterial, fungal and parasitic) **Neoplasms benign, malignant and unspecified (including cysts and polyps):** Patients receiving immunosuppressant therapies are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The frequency of malignancies increases with the intensity and duration of therapy.

Answer 37

![]() Interactions: * Interacts with enzyme inducers and inhibitors. * Risk digoxin toxicity * Risk of myopathy with statins * Risk of nephrotoxicity with NSAIDS * Risk of hyperkalemia with K sparing diuretics/ACEI/ARB’s * Caution should be observed when co-administering ciclosporin with drugs that substantially increase or decrease ciclosporin plasma concentrations, through inhibition or induction of CYP3A4 and/or P-glycoprotein. Ciclosporin is also an inhibitor of CYP3A4. * Renal toxicity should be monitored when initiating ciclosporin use together with active substances that increase ciclosporin levels or with substances that exhibit nephrotoxic synergy * Concomitant use of ciclosporin and **tacrolimus** should be avoided * Ciclosporin increases the exposure to HMG-CoA reductase inhibitors (statins). When concurrently administered with ciclosporin, the dosage of the statins should be reduced and concomitant use of certain statins should be avoided according to their label recommendations. **Statin** therapy needs to be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis * Following concomitant administration of ciclosporin and lercanidipine, the AUC of **lercanidipine** was increased three-fold and the AUC of ciclosporin was increased 21%. Therefore the simultaneous combination of ciclosporin and lercanidipine should be avoided.

Answer 38

Crosses placenta; manufacturer advises avoid unless potential benefit outweighs risk

Answer 39

Avoid - present in milk

Answer 40

Ciclosporin is extensively metabolised by the liver. An approximate 2- to 3-fold increase in ciclosporin exposure may be observed in patients with hepatic impairment. Manufacturer advises caution in severe impairment (risk of increased exposure). Manufacturer advises consider dose reduction in severe impairment to maintain blood-ciclosporin concentration in target range—monitor until concentration stable.

Answer 41

Ciclosporin undergoes minimal renal elimination and its pharmacokinetics are not extensively affected by renal impairment. However, due to its nephrotoxic potential, careful monitoring of renal function is recommended In non-transplant indications, manufacturer advises establishing baseline renal function before initiation of treatment; if baseline function is impaired in non-transplant indications, except nephrotic syndrome—avoid. In nephrotic syndrome, manufacturer advises initial dose should not exceed 2.5 mg/kg daily in patients with baseline renal impairment

Answer 42

During treatment for non-transplant indications, manufacturer recommends if eGFR decreases by more than 25% below baseline on more than one measurement, reduce dose by 25–50%. If the eGFR decrease from baseline exceeds 35%, further dose reduction should be considered (even if within normal range); discontinue if reduction not successful within 1 month.

Answer 43

![]() **TDM** Monitor whole blood ciclosporin concentration (trough level dependent on indication—consult local treatment protocol for details) **Patient Parameters** Monitor liver function Monitor kidney function: * dose dependent increase in serum creatinine and urea during first few weeks may necessitate dose reduction in transplant patients (exclude rejection if kidney transplant) or discontinuation in non-transplant patients. * eGFR should be measured at least twice before starting treatment (for non-transplant indications) Monitor serum K+ levels: * Increased risk of hyperkalaemia, especially in patients with renal dysfunction * Caution is also required when ciclosporin is co-administered with potassium-sparing drugs (e.g. potassium-sparing diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) or potassium-containing medicinal products as well as in patients on a potassium rich diet. Control of potassium levels in these situations is advisable Monitor serum magnesium: * Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesaemia. If considered necessary, magnesium supplementation should be given. Blood Lipids: * Measure blood lipids before treatment and after the first month of treatment. * Ciclosporin can induce a reversible slight increase in blood lipids * If increased lipids – restrict dietary fat and, if appropirate, a dose reduction should be considered Hypertension: * Regular monitoring of BP required * discontinue if hypertension develops that cannot be controlled by antihypertensives. * Preference should be given to an antihypertensive agent that does not interfere with the pharmacokinetics of ciclosporin, e.g. isradipine Dermatological and physical examination, including blood pressure and renal function measurements required at least twice before starting treatment for psoriasis or atopic dermatitis. In psoriasis and atopic dermatitis monitor serum creatinine every 2 weeks for first 3 months then every month. Investigate lymphadenopathy that persists despite improvement in atopic dermatitis. In long-term management of nephrotic syndrome, perform renal biopsies at yearly intervals. In rheumatoid arthritis measure serum creatinine at least twice before treatment. During treatment, monitor serum creatinine every 2 weeks for first 3 months, then every month for a further 3 months, then every 4–8 weeks depending on the stability of the disease, concomitant medication, and concomitant diseases (or more frequently if dose increased or concomitant NSAIDs introduced or increased). Monitor hepatic function if concomitant NSAIDs given.

Answer 44

* Patients and carers should be counselled on the administration of different formulations of ciclosporin. * Manufacturer advises avoid excessive exposure to UV light, including sunlight. Also use high factor sun creams. In psoriasis and atopic dermatitis, avoid use of UVB or PUVA. This is due to cancer risk – increased risk of lymphomas and maligancies of the skin. * Live-attenuated vaccines:- During treatment with ciclosporin, vaccination may be less effective. The use of live attenuated vaccines should be avoided (for at least 6 months after stopping). * Immunosuppression: For patients who have not had chicken pox and are in contact with anyone with the virus follow guidance from Public Health England June 2019 https://www.gov.uk/government/publications/varicella-zosterimmunoglobulin Prescribing:

Answer 45

1. Potent immunosuppressant with common a/e of Nephrotoxicity 1. Monitoring: blood, skin, liver, potassium renal function, B.P, lipids. 1. Side effects and counselling * Formulation. Can you switch brands? * Sunlight * Signs & symptoms of bone marrow suppression * Easy bruising. Bleeding: nose bleeds, gums, or mouth. Tiny red spots on the skin (petechiae) Blood in the urine. Dark or black bowel movements. * Live vaccines 1. Interactions? * Interacts with enzyme inducers and inhibitors. * Risk digoxin toxicity * Risk of myopathy with statins * Risk of nephrotoxicity with NSAIDS * Risk of hyperkalemia with K sparing diuretics/ACEI/ARB’s

Answer 46

* Moderate to severe atopic eczema * Prophylaxis of graft rejection * Allograft rejection resistant to conventional immunosupressive therapy * Rejection therapy

Answer 47

* Adoport * Advagraf * Daliport * Envarus MR tablets * Modigraf * Prograf cap or infusion

Answer 48

For Prograf®: intravenous and oral doses are not interchangeable due to differences in bioavailability. Follow correct dosing recommendations for the dosage form when switching formulations

Answer 49

Inadvertent switching between oral tacrolimus products has been associated with reports of toxicity and graft rejection. To ensure maintenance of therapeutic response when a patient is stabilised on a particular brand, oral tacrolimus products should be prescribed and dispensed by brand name only. * Adoport® and Prograf® are immediate-release capsules that are taken twice daily, once in the morning and once in the evening; * Modigraf ® granules are used to prepare an immediate-release oral suspension which is taken twice daily, once in the morning and once in the evening; * Advagraf ® and Dailiport® are prolonged-release capsules that are taken once daily in the morning. Switching between tacrolimus brands requires careful supervision and therapeutic monitoring by an appropriate specialist. Important: Envarsus® is not interchangeable with other oral tacrolimus containing products; the MHRA has advised (June 2012) that oral tacrolimus products should be prescribed and dispensed by brand only.

Answer 50

**With topical use** Application to malignant or potentially malignant skin lesions; application under occlusion; avoid contact with eyes; avoid contact with mucous membranes; congenital epidermal barrier defects; generalised erythroderma; immunodeficiency; infection at treatment site

Answer 51

**General cautions** * UV light (avoid excessive exposure to sunlight and sunlamps) **Specific cautions** **With systemic use:** * Increased risk of infections; increased susceptibility to lymphoproliferative disorders; malignancies; neurotoxicity; risk factors for cardiomyopathies; risk factors for QT-interval prolongation

Answer 52

Patients may experience side effects: myalgia, tremor, fatigue, headache, infections, paraesthesia or nausea. Rare: pericardial effusion, respiratory distress syndrome, posterior reversible encephalopathy syndrome, dehydration, thrombotic thrombocytopenic purpura, blindness,**QT-prolongation**, hirsuitism and Stevens Johnston Syndrome. Nephrotoxicity, Neurotoxicity, cardiomyopathy, PREs ,(little hepatatoxicity), hyperkalameia, QT prolongation, hyperglycaemia (insulin resistance/glucose intolerance) **Cardiomyopathy** Cardiomyopathy has been reported to occur primarily in children with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Patients should be monitored by echocardiography for hypertrophic changes—consider dose reduction or discontinuation if these occur

Answer 53

Tacrolimus is metabolised by CYP3A4 * Risk of nephrotoxicity with NSAIDs and aminoglycosides * Risk of hyperkalamiea with K+ sparing diuretics/ ACEi/ ARBs * Interacts with enzyme inducers and inhibitors * QT prolongatino drugs * GRAPEFRUIT JUICE should be avoided * ST. JOHN’S WORT should not be taken * ORAL CONTRACEPTIVES are less effective * IBUPROFEN and NSAIDs should not be used - nephrotoxic * NIFEDIPINE and DILTIAZEM should be avoided (CYP3A4 inhibitor) * POTASSIUM SPARING DIURETICS should be avoided - hyperkalaemia * Macrolide antibiotics increase Tacrolimus (Advagraf ®) concentration * Avoid concomitant use of live vaccines As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existing hyperkalaemia, high potassium intake, or potassium-sparing diuretics (e.g., amiloride, triamterene, or spironolactone) should be avoided (see section 4.4). Care should be taken when tacrolimus is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Close monitoring of serum potassium is recommended.

Answer 54

Macrolides

Answer 55

Systemic use: Specialist sources indicate avoid unless benefit outweighs potential risk—crosses the placenta and risk of premature delivery, intra-uterine growth restriction, hyperkalaemia and renal toxicity. Maternal risk of hyperglycaemia, hypertension, pre-eclampsia and renal impairment With topical use: Specialist sources indicate that use can be considered if benefit outweighs potential risk—minimal systemic absorption; limited information available.

Answer 56

Specialist sources indicate present in milk (following systemic administration) but amount probably too small to be harmful—monitor exclusively breastfed infants, including blood concentrations, if there are concerns regarding toxicity.

Answer 57

With systemic use: Manufacturer advises caution in severe impairment. With topical use: Manufacturer advises caution in hepatic failure

Answer 58

With systemic use: * Manufacturer advises consider dose reduction in severe impairment. * Pharmacokinetics are unaffceted by renal function so no dose adjustemnt should be required – however, owing to the nephrotoxic potential of tacrolimus careful monitoring of renal function is reccomended

Answer 59

With systemic use: After initial dosing, and for maintenance treatment, tacrolimus doses should be adjusted according to whole-blood tacrolimus trough concentration (especially during episodes of diarrhoea). Patients of black African or African–Caribbean family origin may require higher doses. Consult local treatment protocols for further details of therapeutic drug monitoring.

Answer 60

With systemic use: Monitor blood pressure, ECG (for hypertrophic changes—risk of cardiomyopathy), fasting blood-glucose concentration, haematological and coagulation parameters, plasma protein, electrolytes, neurological (including visual) status, hepatic and renal function. Monitor for posterior reversible encephalopathy syndrome (PRES).

Answer 61

* Advise patients to avoid excessive exposure to UV light including sunlight and to report symptoms of eye disorders for prompt evaluation by an ophthalmologist. * Avoid Live vaccines * Stick to same brand

Answer 62

Blood trough levels of tacrolimus should be monitored during the post-transplantation period. When dosed orally, blood trough levels should be drawn approximately 12 hours post-dosing, just prior to the next dose. The frequency of blood level monitoring should be based on clinical needs. As Prograf is a medicinal product with low clearance, adjustments to the dosage regimen may take several days before changes in blood levels are apparent. Blood trough levels should be monitored approximately twice weekly during the early post-transplant period and then periodically during maintenance therapy. Blood trough levels of tacrolimus should also be monitored following dose adjustment, changes in the immunosuppressive regimen, or following co-administration of substances which may alter tacrolimus whole blood concentrations (see section 4.5). Clinical study analysis suggests that the majority of patients can be successfully managed if tacrolimus blood trough levels are maintained below 20 ng/ml. It is necessary to consider the clinical condition of the patient when interpreting whole blood levels. In clinical practice, whole blood trough levels have generally been in the range 5 - 20 ng/ml in liver transplant recipients and 10 - 20 ng/ml in kidney and heart transplant patients in the early post-transplant period. Subsequently, during maintenance therapy, blood concentrations have generally been in the range of 5 - 15 ng/ml in liver, kidney and heart transplant recipients.

Answer 63

1. Potent immunosuppressant: similar mode of action Ciclosporin, neurotoxicity greater * Cardiomyopathy * Nephrotoxicity * Disturbance of glucose metabolism – signs to look out for? 1. Increased thirst, dry mouth, needing to pee frequently, blurred vision, tirdness, frequent infections e.g. thrush, cystitis and skin infections. * Liver toxicity * Blood disorders 1. Can you switch brands? 1. Interactions? * Interacts with enzyme inducers and inhibitors. * Risk of nephrotoxicity with NSAIDS and aminoglycosides. * Risk of hyperkalemia with K sparing diuretics/ACEI/ARB’s

Answer 64

Tacrolimus is a calcineurin inhibitor * Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase). * Calcineurin inhibitors are medicines which inhibit the action of calcineurin. Calcineurin is an enzyme that activates T-cells of the immune system. * These are immunosupressant drugs

Answer 65

Chronic Asthma, severe asthma, reversible airway obstruction

Answer 66

200 mg every 12 hours, adjusted according to response to 400 mg every 12 hours, may be appropriate to give larger evening or morning dose to achieve optimum therapeutic effect when symptoms most severe; in patients whose night or daytime symptoms persist despite other therapy, who are not currently receiving theophylline, total daily requirement may be added as single evening or morning dose.

Answer 67

Uniphyllin Continus

Answer 68

The rate of absorption from modified-release preparations can vary between brands. If a prescription for a modified-release oral theophylline preparation does not specify a brand name, the pharmacist should contact the prescriber and agree the brand to be dispensed. Additionally, it is essential that a patient discharged from hospital should be maintained on the brand on which that patient was stabilised as an in-patient.

Answer 69

Cardiac arrhythmias or other cardiac disease (may exacerbate cardiac arrythmias); elderly (increased plasma-theophylline concentration) (in adults); epilepsy (exacerbate frequency/duration or seizures); fever; hypertension; peptic ulcer (theophylline may act as an GI irritant and increase gastric secretion); risk of hypokalaemia; thyroid disorder (Due to potential increased theophylline clearance, dose increase and monitoring of serum theophylline concentrations may be required in patients with hyperthyroidism). Due to potential decreased theophylline clearance, dose reduction and monitoring of serum theophylline concentrations may be required in elderly patients and patients with: * cardiac disease * hepatic disease * exacerbations of lung disease * hypothyroidism * fever * viral infections.

Answer 70

**Frequency not known** Anxiety; arrhythmias; diarrhoea; dizziness; gastrointestinal discomfort; gastrooesophageal reflux disease; headache; hyperuricaemia; nausea; palpitations; seizure; skin reactions; sleep disorders; tremor; urinary disorders; vomiting **Side-effects, further information** Potentially serious hypokalaemia may result from beta2-agonist therapy. Particular caution is required in severe asthma, because this effect may be potentiated by concomitant treatment with theophylline and its derivatives, corticosteroids, and diuretics, and by hypoxia. Plasma-potassium concentration should therefore be monitored in severe asthma.

Answer 71

Theophylline in overdose can cause vomiting (which may be severe and intractable), agitation, restlessness, dilated pupils, sinus tachycardia, and hyperglycaemia. More serious effects are haematemesis, convulsions, and supraventricular and ventricular arrhythmias. Severe hypokalaemia may develop rapidly.

Answer 72

* Smoking and alcohol consumption can also increase clearance of theophylline. * Factors such as viral infections, liver disease and heart failure also reduce theophylline clearance * Hypokalaemia resulting from beta2 agonist therapy, steroids, diuretics and hypoxia may be potentiated by xanthines. Particular care is advised in patients suffering from severe asthma who require hospitalisation. It is recommended that serum potassium concentrations are monitored in such situations. * Care should be taken in its concomitant use with β-adrenergic agonists, glucagon and other xanthine drugs, as these will potentiate the effects of theophylline. * The following increase clearance of theophylline and it may therefore be necessary to increase dosage to ensure a therapeutic effect: aminoglutethimide, carbamazepine, isoprenaline, phenytoin, rifampicin, ritonavir, sulphinpyrazone, barbiturates and hypericum perforatum (St John's Wort). * The following reduce clearance and a reduced dosage may therefore be necessary to avoid side-effects: aciclovir, allopurinol, carbimazole, cimetidine, clarithromycin, diltiazem, disulfiram, erythromycin, fluconazole, interferon, isoniazid, methotrexate, mexiletine, nizatidine, pentoxifylline, propafenone, propranolol, thiabendazole, verapamil and oral contraceptives (see section 4.9). * Theophylline has been shown to interact with some quinolone antibiotics including ciprofloxacin and enoxacin which may result in elevated plasma theophylline levels. * increase urinary lithium clearance. ![]()

Answer 73

Neonatal irritability and apnoea have been reported. Theophylline can be taken as normal during pregnancy as it is particularly important that asthma should be well controlled during pregnancy.

Answer 74

Present in milk—irritability in infant reported; modified-release preparations preferable. Theophylline can be taken as normal during breast-feeding.

Answer 75

Manufacturer advises caution (risk of increased exposure). Manufacturer advises consider dose reduction.

Answer 76

In most individuals, a plasma-theophylline concentration of 10–20 mg/litre (55–110 micromol/litre) is required for satisfactory bronchodilation, although a lower plasma-theophylline concentration of 5–15 mg/litre may be effective. Adverse effects can occur within the range 10–20 mg/litre and both the frequency and severity increase at concentrations above 20 mg/litre. Plasma-theophylline concentration is measured 5 days after starting oral treatment and at least 3 days after any dose adjustment. A blood sample should usually be taken 4–6 hours after an oral dose of a modified-release preparation (sampling times may vary—consult local guidelines).

Answer 77

* Metabolised in liver. * Increased levels in heart failure, hepatic impairment and viral infection * Decreased levels in smokers and alcohol * Dose adjustment with smoking status? * Can different brands be given? * Monitoring: plasma concentration? * Caution: CVD, Elderly, Fever, risk of hypokalemia, hypertension, peptic ulcer * Main s/e? * Common interactions: consider hypokalemia b2 agonists, increased risk convulsions quinolones, lithium concentration

Answer 78

* Severe Crohn’s Disease (IM) - unlicensed * Maintance of remission of severe Crohn’s * Moderate – Severe RA * Severe RA * Neoplastic diseases * Severe psoriasis

Answer 79

* Doses are given once weekly * RA dose is initially 7.5mg once weekly, adjusted according to response to max 20mg/week

Answer 80

Active infection; ascites; immunodeficiency syndromes; significant pleural effusion University Notes: * Pregnancy/breast feeding * Significant renal and hepatic impairment * Blood dycrasis * Severe acute/chronic infections

Answer 81

Photosensitivity—psoriasis lesions aggravated by UV radiation (skin ulceration reported); dehydration (increased risk of toxicity); diarrhoea; extreme caution in blood disorders (avoid if severe); peptic ulceration (avoid in active disease); risk of accumulation in pleural effusion or ascites—drain before treatment; ulcerative colitis; ulcerative stomatitis. Elderly (due to reduced hepatic/renal function – reduce dose should be considered and close monitoring for early signs or toxicity). Blood count Bone marrow suppression can occur abruptly; factors likely to increase toxicity include advanced age, renal impairment, and concomitant use with another anti-folate drug (e.g. trimethoprim). Manufacturer advises a clinically significant drop in white cell count or platelet count calls for immediate withdrawal of methotrexate and introduction of supportive therapy. Gastro-intestinal toxicity Manufacturer advises withdraw treatment if stomatitis or diarrhoea develops—may be first sign of gastro-intestinal toxicity. Liver toxicity Liver cirrhosis reported. Manufacturer advises treatment should not be started or should be discontinued if any abnormality of liver function or liver biopsy is present or develops during therapy. Abnormalities can return to normal within 2 weeks after which treatment may be recommenced if judged appropriate. Persistent increases in liver transaminases may necessitate dose reduction or discontinuation. Pulmonary toxicity Pulmonary toxicity may be a special problem in rheumatoid arthritis. Manufacturer advises patients to seek medical attention if dyspnoea, cough or fever develops; monitor for symptoms at each visit—discontinue if pneumonitis suspected.

Answer 82

**Common:** **With oral use** Anaemia; appetite decreased; diarrhoea; drowsiness; fatigue; gastrointestinal discomfort; headache; increased risk of infection; leucopenia; nausea; oral disorders; respiratory disorders; skin reactions; throat ulcer; thrombocytopenia; vomiting **Univeristy:** University: * Renal toxicity * Hepatic toxicity * Pulmonary toxicity * Blood Dyscarsis * Infections

Answer 83

A. Folic Acid B. Give folic acid to reduce side-effects. Folic acid decreases mucosal and gastrointestinal side-effects of methotrexate and may prevent hepatotoxicity; there is no evidence of a reduction in haematological side-effects. C. At least 72h after MXT dose

Answer 84

Folinic Acid

Answer 85

NSAIDs - * Increased & prolonged MXT concentation * Increased GI effects * Increased haematological toxicity * Increased nephrotoxicity * NSAIDs should not be administered concurrently with high dose MXT – however if aspiirn, ibuprofen or indometacin commenced monitor MXT dosage and treatment closely Folate Antagonists - * E.g. trimethoprim and Co-trimoxazole * Increased risk of haematological toxicity Alcohol - * Avoid * Hepatoxocity Nephrotoxic, Hepatotoxic and Myelotoxic Drugs * Increases risk of ADRs * E.g. other haematoxic DMARDs (e.g. leflunomide) is not adivisable Live Vaccines * Immunosuppressant so could cause serious infection or illness Antibacterials * Neomycin (and possibily tetracyclines and chloramphenicol) - reduced MXT absorption * Ciprofloxacin & Penicillins – MXT excretion reduced (increased toxicity risk) * Doxycycline, sulphonamides, tetracyclines – increased risk of MXT toxicity * Penicillin

Answer 86

Manufacturer advises effective contraception during and for at least 6 months after treatment in men and women.

Answer 87

Avoid (teratogenic; fertility may be reduced during therapy but this may be reversible)

Answer 88

Discontinue – present in breast milk

Answer 89

* When used for malignancy, avoid in severe hepatic impairment—consult local treatment protocol for details. * Avoid with hepatic impairment in non-malignant conditions—dose-related toxicity.

Answer 90

* Risk of nephrotoxicity at high doses. * Use with caution; avoid in severe impairment. * Reduce dose (consult product literature).

Answer 91

* Exclude pregnancy before treatment. * Patients should have full blood count and renal and liver function tests before starting treatment. * A chest X-ray is recommended prior to initiation

Answer 92

In view of reports of blood dyscrasias (including fatalities) and liver cirrhosis with low-dose methotrexate patients should: * have full blood count and renal and liver function tests repeated every 1–2 weeks until therapy stabilised, thereafter patients should be monitored every 2–3 months. * be advised to report all symptoms and signs suggestive of infection, especially sore throat More frequent check-ups are necessary when: * Dose increased * Increased risk of methotrexate toxicity (e.g. dehydration, impaired renal function, additonal or increased dose of medicines such as NSAIDs, administered concomitantly.

Answer 93

Note that the dose is a weekly dose. To avoid error with low-dose methotrexate, it is recommended that: * the patient or their carer is carefully advised of the dose and frequency and the reason for taking methotrexate and any other prescribed medication (e.g. folic acid); * only one strength of methotrexate tablet (usually 2.5 mg) is prescribed and dispensed; * the prescription and the dispensing label clearly show the dose and frequency of methotrexate administration

Answer 94

* Patients and their carers should be warned to report immediately the onset of any feature of blood disorders (e.g. sore throat, bruising, and mouth ulcers), liver toxicity (e.g. nausea, vomiting, abdominal discomfort, jaundice and dark urine), and respiratory effects (e.g. shortness of breath). * If any of these symptom's treatment should be stopped and medical advice sought * Advised to take once a week * Advised to take folic acid at least 72 hours after methotrexate * Advised to attend regular blood tests * Contraception advice should be given and patients advised that contracpetion should be continued for at least 6 months after stopping methotrexate * Avoid live vaccines * Patients should be advised to avoid self-medication with over-the-counter aspirin or ibuprofen. Counsel on use of NSAIDs. * Inform patients of potential fatal risk of accidental overdose if methotrexate is used more frequently than once a week. They should seek medical attention immediately if overdose is suspected. * Supply treatment booklet and alert card to patient. Patients should be encouraged to write the day of the week for dosing in their patient alert card and carry it with them.

Answer 95

* If you forget to take a dose, take it as soon as you remember the next day or the day after. * If your dose is more than 2 days late, contact your doctor or the clinic for advice about what to do. * Never take 2 doses together to make up for a missed dose.

Answer 96

Aminoglycoside

Answer 97

Aminoglycosides have bactericidal activity for some Gram-positive and most aerobic and facultative anaerobic Gram-negative bacteria. As aminoglycoside uptake into bacteria is oxygen dependent, they are therefore not active against anaerobes * aerobic - requires O2 * Facultative anaerobes - bacteria that can grow in both the presence or absence of oxygen

Answer 98

Once inside the bacterial cell, they bind to the 30S subunit of the ribosome causing misreading of mRNA, resulting in interruption of normal bacterial protein synthesis. Bactericidial

Answer 99

Gentamicin is the most frequently used of the aminoglycosides and is indicated for the treatment of **gram negative infections** and in **surgical prophlyaxis**. Some examples include: urinary tract infections, sepsis, intra-abdominal infections, endocarditis, pelvic inflammatory disease and complicated skin, bone and soft tissue infections. It is often used for more serious Gram-negative infections, or in combination with a broad spectrum beta lactam antibiotic to provide coverage against Gram-positive bacteria. Gram-negative bacteria can be difficult to treat because of the complex nature of their cell wall. Beta lactam antibiotics active against the cell wall (e.g. piperacillin/tazobactam) can be taken simultaneously to facilitate aminoglycoside penetration into the cell, increasing efficacy and resilience. Other indications listed in the BNF are as follows: * Bacterial eye infections * Bacterial otitis externa infection * Diabetic foot infection (moderate or severe), Leg ulcer infection (in combo with other drugs) * Septicaemia,Meningitis and other CNS infections,Biliary-tract infection, Endocarditis, Pneumonia in hospital patients, Adjunct in listerial meningitis, Prostatitis * CNS infections * Surgical prophylaxis

Answer 100

To avoid excessive dosage in obese patients, use ideal weight for height to calculate parenteral dose and monitor serum-gentamicin concentration closely.

Answer 101

Myasthenia gravis (aminoglycosides may impair neuromuscular transmission)

Answer 102

Auditory disorder; care must be taken with dosage (the main side-effects of the aminoglycosides are dose-related); conditions characterised by muscular weakness (aminoglycosides may impair neuromuscular transmission); if possible, dehydration should be corrected before starting an aminoglycoside; vestibular disorder; whenever possible, parenteral treatment should not exceed 7 days

Answer 103

**Ototoxicity** and **nephrotoxicity** are important side-effects to consider with aminoglycoside therapy. Nephrotoxicity occurs most commonly in patients with renal impairment, who may require reduced doses; monitoring is particularly important in the elderly. Severe subcutaneous adverse reactions such as Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with gentamicin treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. Treatment should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of skin hypersensitivity. **Other side-effects:** **Common or very common** Aphonia; appetite decreased; bronchospasm; chest discomfort; cough; deafness; diarrhoea; dizziness; dysphonia; fever; haemoptysis; headache; increased risk of infection; nausea; oropharyngeal pain; renal impairment; skin reactions; taste altered; tinnitus; vomiting **Rare or very rare** Anaemia; azotaemia; eosinophilia; hearing loss (sometimes irreversible); hypomagnesaemia; paraesthesia **Frequency not known** Confusion; lethargy; leucopenia; muscle weakness; nephrotoxicity; peripheral neuropathy; thrombocytopenia; vertigo

Answer 104

**Ototoxic and nephrotoxic drugs should be avoided.** Potent diuretics such as etacrynic acid and furosemide are expected to enhance the risk of ototoxicity whilst amphotericin B, cisplatin and ciclosporin are potential enhancers of nephrotoxicity. Any potential nephrotoxicity of cephalosporins, and in particular cephaloridine, may also be increased in the presence of gentamicin. Consequently, if this combination is used monitoring of kidney function is advised. Avoid co-administration with neurotoxic or nephrotoxic agents, e.g. neuromuscular blockers (increased risk toxicity), nonsteroidal anti-inflammatory drugs, ACE Inhibitors; potent diuretics; other aminoglycosides

Answer 105

**Pregnancy For all aminoglycosides (by injection)** There is a risk of auditory or vestibular nerve damage in the infant when aminoglycosides are used in the second and third trimesters of pregnancy. The risk is greatest with streptomycin. The risk is probably very small with gentamicin and tobramycin, but their use should be avoided unless essential. **Monitoring in pregnancy** If given during pregnancy, serum-aminoglycoside concentration monitoring is essential.

Answer 106

Gentamicin is excreted in human breast milk and was detected in low concentrations in the serum of breast-fed infants, except in cases where the mucous membrane of the infant's stomach and intestines is severely eroded. In cases of suspected severe mucosal erosion, if the infant is breast-fed during gentamicin treatment, it is recommended to monitor the serum concentration of gentamicin in the infant (see section 4.2). Animal and human data suggest that if the serum gentamicin concentration in the infant exceeds 1 µg/ml either breast-feeding or the gentamicin therapy may need to be discontinued, under medical supervision. The following effects of gentamicin on the infant's normal gastrointestinal flora are possible and it is recommended to monitor the infant for possible effects such as diarrhoea, candidiasis and bloody stools

Answer 107

**For all aminoglycosides (by injection)** Aminoglycosides are primarily renally excreted and accumulation can occur in renal impairment (increased risk of ototoxicity and nephrotoxicity)—serum-aminoglycoside concentrations must be frequently monitored in patients with renal impairment. **Dose adjustments** Reduce dose and/or increase the dose interval according to impairment (consult product literature).

Answer 108

**For all aminoglycosides (by injection)** **Therapeutic drug monitoringFor all aminoglycosides (by injection)** **Serum concentrations** Serum concentration monitoring avoids both excessive and subtherapeutic concentrations thus preventing toxicity and ensuring efficacy. Serum-aminoglycoside concentrations should be measured in all patients receiving parenteral aminoglycosides and must be determined in obesity, if high doses are being given and in cystic fibrosis. **In adults** Serum aminoglycoside concentrations must be determined in the elderly. In patients with normal renal function, aminoglycoside concentrations should be measured after 3 or 4 doses of a multiple daily dose regimen and after a dose change. For multiple daily dose regimens, blood samples should be taken approximately 1 hour after intramuscular or intravenous administration (‘peak’ concentration) and also just before the next dose (‘trough’ concentration). If the pre-dose (‘trough’) concentration is high, the interval between doses must be increased. If the post-dose (‘peak’) concentration is high, the dose must be decreased. For once daily dose regimens, consult local guidelines on serum concentration monitoring. **Monitoring of patient parameters For all aminoglycosides (by injection)** Renal function should be assessed before starting an aminoglycoside and during treatment. Auditory and vestibular function should also be monitored during treatment. **Monitoring requirements For gentamicin** **Therapeutic drug monitoring For gentamicin** **With intramuscular use or intravenous use in adults** For multiple daily dose regimen, one-hour (‘peak’) serum concentration should be 5–10 mg/litre; pre-dose (‘trough’) concentration should be less than 2 mg/litre. For multiple daily dose regimen in endocarditis, one-hour (‘peak’) serum concentration should be 3–5 mg/litre; pre-dose (‘trough’) concentration should be less than 1 mg/litre. Serum-gentamicin concentration should be measured after 3 or 4 doses, then at least every 3 days and after a dose change (more frequently in renal impairment). **With intravenous use in adults** For once-daily dose regimen, consult local guidelines on monitoring serum-gentamicin concentration.

Answer 109

**Renal Toxicity** * Monitor creatinine daily. Seek advice if renal function is unstable (e.g. a change in creatinine of \>15-20%). * Signs of renal toxicity include an increase in creatinine or decrease in urine output / oliguria. * Consider an alternative agent if creatinine is rising or the patient becomes oliguric. **Ototoxicity** * Ototoxicity secondary to gentamicin is independent of drug concentration. It is suggested by any of the following: new tinnitus, dizziness, poor balance, hearing loss or oscillating vision. * Toxicity is associated with prolonged aminoglycoside use (usually \>10 days but may be \>3 days) and is secondary to drug accumulation within the inner ear. * Stop treatment if ototoxicity is suspected and refer to a microbiology / infection specialist for advice on future therapy * If gentamicin continues for \>7 days, suggest referring to audiology for assessment.

Answer 110

Glycopeptide

Answer 111

Gram positive infections, in particular MRSA.

Answer 112

Vancomycin is a tricyclic glycopeptide antibiotic that inhibits the synthesis of the cell wall in sensitive bacteria by binding with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units. The drug is slowly bactericidal for dividing microorganisms. In addition, it impairs the permeability of the bacterial cell membrane and RNA synthesis.

Answer 113

**BNF:** * C.diff * Diabetic foot infection (moderate or severe), leg ulcer infection * Cellulitis * Complicated skin and soft tissue infections,Bone infections,Joint infections,Community-acquired pneumonia,Hospital-acquired pneumonia [including ventilator-associated pneumonia],Infective endocarditis,Acute bacterial meningitis,Bacteraemia [occurring in association with or suspected to be associated with the licensed indications] * Surgical prophylaxis (when high risk of MRSA) **EMC:** ![]()

Answer 114

Oral - little systemic absorption

Answer 115

Oral - little systemic absorption

Answer 116

125 mg every 6 hours for 10 days; increased if necessary to 500 mg every 6 hours for 10 days, increased dose if life-threatening or refractory infection.

Answer 117

**Intravenous administration** The initial dose should be based on total body weight. Subsequent dose adjustments should be based on serum concentrations to achieve targeted therapeutic concentrations. Renal function must be taken into consideration for subsequent doses and interval of administration. **Patients 12 and over:** The recommended dose is 15 to 20 mg/kg of body weight every 8 to 12 h (not to exceed 2 g per dose). In seriously ill patients, a loading dose of 25–30 mg/kg of body weight can be used to facilitate rapid attainment of target trough serum vancomycin concentration.

Answer 118

**With IV** * Previous hearing loss

Answer 119

**With oral use** Systemic absorption may be enhanced in patients with inflammatory disorders of the intestinal mucosa or with Clostridioides difficile-induced pseudomembranous colitis (increased risk of adverse reactions)

Answer 120

**Side-effects, further information** * Vancomycin is associated with a higher incidence of nephrotoxicity than teicoplanin. * Important side-effects: **Ototoxicity, nephrotoxicity, Red-man Syndrome** (slow administration required). **General side-effects:** **Frequency not known** Agranulocytosis; dizziness; drug fever; eosinophilia; hypersensitivity; nausea; nephritis tubulointerstitial; neutropenia (more common after 1 week or cumulative dose of 25g); renal failure; severe cutaneous adverse reactions (SCARs); skin reactions; thrombocytopenia; tinnitus (discontinue); vasculitis; vertigo **Specific side-effects:** **Common or very common** **With intravenous use** Vancomycin infusion reaction **Frequency not known** **With intravenous use** Back pain; bradycardia; cardiac arrest (on rapid intravenous injection); cardiogenic shock (on rapid intravenous injection); chest pain; dyspnoea; hearing loss; hypotension; muscle complaints; pseudomembranous enterocolitis; wheezing

Answer 121

Caution if teicoplanin sensitivity.

Answer 122

* Manufacturer advises use only if potential benefit outweighs risk. * Plasma-vancomycin concentration monitoring essential to reduce risk of fetal toxicity.

Answer 123

Present in milk—significant absorption following oral administration unlikely.

Answer 124

Manufacturer advises serial monitoring of renal function. **With intravenous use:** Manufacturer advises use with caution—increased risk of toxic effects with prolonged high blood concentration. **Dose adjustments** **With oral use:** Manufacturer advises dose adjustment is unlikely to be required unless substantial oral absorption occurs in inflammatory disorders of the intestinal mucosa or with Clostridioides difficile-induced pseudomembranous colitis, see Monitoring. **With intravenous use:** Manufacturer advises initial dose must not be reduced—consult product literature. In patients with mild or moderate renal failure, the starting dose must not be reduced. In patients with severe renal failure, it is preferable to prolong the interval of administration rather than administer lower daily doses. Appropriate consideration should be given to the concomitant administration of medicinal products that may reduce vancomycin clearance and/or potentiate its undesirable effects

Answer 125

**With intravenous use** Manufacturer advises initial doses should be based on body-weight; subsequent dose adjustments should be based on serum-vancomycin concentrations to achieve targeted therapeutic concentrations. All patients require serum-vancomycin measurement (on the second day of treatment, immediately before the next dose if renal function normal, earlier if renal impairment—consult product literature). Frequency of monitoring depends on the clinical situation and response to treatment; regular monitoring indicated in high-dose therapy and longer-term use, particularly in patients with impaired renal function, impaired hearing, or concurrent use of nephrotoxic or ototoxic drugs. Manufacturer advises pre-dose (‘trough’) concentration should normally be 10–20 mg/litre depending on the site of infection and the susceptibility of the pathogen; trough concentration of 15–20 mg/litre is usually recommended to cover susceptible pathogens with MIC greater than or equal to 1 mg/litre—consult product literature. Manufacturer advises monitoring serum-vancomycin concentration in inflammatory intestinal disorders.

Answer 126

**With intravenous use** Manufacturer advises periodic testing of auditory function. Manufacturer advises monitor blood counts, urinalysis, hepatic and renal function periodically in all patients; monitor leucocyte count regularly in patients receiving long-term vancomycin or if given concurrently with other drugs that may cause neutropenia or agranulocytosis. **With oral use** Manufacturer advises serial tests of auditory function may be helpful to minimise the risk of ototoxicity in patients with an underlying hearing loss, or who are receiving concomitant therapy with other ototoxic drugs. **With intravenous use in adults** Manufacturer advises monitor vestibular and auditory function during and after treatment in the elderly; avoid concurrent or sequential use of other ototoxic drugs.

Answer 127

Cardiac glycosides

Answer 128

* AF * HF (if in sinus rhythm)

Answer 129

Digoxin induces an increase in intracellular sodium that will drive an influx of calcium in the heart and cause an increase in contractility

Answer 130

* Prescribe a loading dose of 250 micrograms to 750 micrograms a day for 7 days, followed by a maintenance dose. A clinical response is usually seen within 1 week. * The usual maintenance dose is 125 micrograms to 250 micrograms a day; this should be adjusted according to renal function, initial loading dose, and the heart rate response. * A more rapid response may be achieved by prescribing 750 micrograms to 1500 micrograms in divided doses over 24 hours. However, previous expert reviewers of this CKS topic suggest that usually no more than 1000 micrograms (1 mg) is needed in 24 hours. If a more rapid clinical response is required, consider referral to secondary care.

Answer 131

* **Seek specialist advice for people who are elderly and who have renal impairment. The loading dose of digoxin will need to be reduced.**

Answer 132

* **0.7 nanograms/mL - 2.0 nanograms/mL**

Answer 133

* Take blood samples at least 6 hours after the previous dose, but ideally 8–12 hours afterwards. * Monitor digoxin levels several days after the last dose change. * **Routine monitoring of serum digoxin is not recommended** because there is no evidence from randomized controlled trials to indicate that regular monitoring confers better outcomes.

Answer 134

* Check the person's **pulse rate** and **heart rate** no later than **1 week after initiation** of treatment, and **after any change** in dose. * **In addition, check blood chemistry** (electrolytes, urea, and creatinine) at least annually (more frequently in elderly people and people with renal impairment). * These tests will often be done routinely, as renal function is likely to be monitored owing to the use of nephrotoxic drugs (such as diuretics and drugs affecting the renin-angiotensin system).

Answer 135

* Digoxin toxicity can occur even when the serum digoxin concentration is within the therapeutic range (between 0.7 nanograms/mL and 2.0 nanograms/mL) * The likelihood of toxicity depends on the serum concentration of digoxin. * Levels less than 1.5 nanograms/mL in the absence of hypokalaemia indicate that digoxin toxicity is unlikely. * Levels greater than 3.0 nanograms/mL indicate that digoxin toxicity is likely. * With levels between 1.5 nanograms/mL and 3.0 nanograms/mL, digoxin toxicity should be considered a possibility.

Answer 136

* Confusion, nausea, anorexia, or disturbance of colour vision

Answer 137

* Some supraventricular arrhythmias (such as Wolff–Parkinson–White syndrome). * Arrhythmias caused by previous use of digoxin or another cardiac glycoside. * Heart conduction problems (such as intermittent complete heart block or atrioventricular heart block). * Ventricular tachycardia or ventricular fibrillation. * Hypertrophic obstructive cardiomyopathy, unless there is concomitant atrial fibrillation and heart failure (but use with caution in this case)

Answer 138

Hypercalcaemia (risk of digitalis toxicity); hypokalaemia (risk of digitalis toxicity); hypomagnesaemia (risk of digitalis toxicity); hypoxia (risk of digitalis toxicity); recent myocardial infarction; severe respiratory disease; sick sinus syndrome; thyroid disease * elderly - reduce doses * renal impairment - consider reduction

Answer 139

BNF. **Common or very common** Arrhythmias; cardiac conduction disorder; cerebral impairment; diarrhoea; dizziness; eosinophilia; nausea; skin reactions; vision disorders; vomiting **Uncommon** Depression **Rare or very rare** Appetite decreased; asthenia; confusion; gastrointestinal disorders; gynaecomastia; headache; malaise; psychosis; thrombocytopenia Has narrow TW - side effects normally due to this/ NICE: * **Cardiac adverse effects** are the most serious adverse effects of digoxin and are usually associated with overdose. They include various conduction and rhythm disturbances, such as: * Sinoatrial and atrioventricular block. * Premature ventricular contractions (resulting in bigeminy or trigeminy). * PR prolongation and ST-segment depression. * **Non-cardiac adverse effects** of digoxin include: * Nausea, vomiting, and (less commonly) diarrhoea. Nausea, in particular, is indicative of overdose. * Visual abnormalities (blurred or yellow vision). * Central nervous system effects, such as weakness, dizziness, confusion, apathy, malaise, headache, depression, and psychosis. * Thrombocytopenia and agranulocytosis (rare). * Gynaecomastia in men following prolonged administration (digoxin has oestrogenic activity). * **The adverse effects of digoxin are frequently due to its narrow therapeutic window.** If significant adverse effects occur, [monitor](https://cks.nice.org.uk/topics/atrial-fibrillation/prescribing-information/digoxin/#monitoring) serum levels of digoxin

Answer 140

When switching from intravenous to oral route may need to increase dose by 20–33% to maintain the same plasma-digoxin concentration.

Answer 141

Manufacturer advises reduce dose by half with concurrent use of amiodarone, dronedarone and quinine.

Answer 142

* **Antidepressants** * Avoid tricyclic antidepressants with digoxin as they are possibly proarrhythmic in cardiac disease. Consider selective serotonin reuptake inhibitors (SSRIs) or mirtazapine instead. * Avoid venlafaxine with digoxin in people at risk of arrhythmias. Consider SSRIs or mirtazapine instead. * Avoid trazodone with digoxin because it increases digoxin plasma levels. Consider SSRIs or mirtazapine instead. * **Beta-blockers** * Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong atrioventricular (AV) conduction time, increasing the risk of AV block and bradycardia. Monitor pulse carefully. * An increase in plasma digoxin levels has been noted with carvedilol. Monitor for signs of digoxin toxicity (confusion, anorexia, nausea, and disturbance of colour vision) when starting, adjusting, or stopping carvedilol. * **Buproprion** — co-administration of buproprion with digoxin may decrease digoxin levels. Digoxin levels may rise on discontinuation of bupropion, people taking buproprion and digoxin should be monitored for possible digoxin toxicity when buproprion is discontinued. * **Diuretics, acetazolamide, and amphotericin** * Increased cardiac toxicity with digoxin if hypokalaemia occurs with these drugs. Monitor digoxin levels and adjust dose accordingly. * **St John's wort** * The plasma concentration of digoxin may be reduced by St John's wort. Advise people taking digoxin that they should not use St John's wort and that they should check with their pharmacist before using any other over-the-counter medications. * **Proton pump inhibitors** — the manufacturer's SPC advise the co-administration of proton pump inhibitors (particularly omeprazole) causes increasing plasma levels of digoxin. Similar effects have been reported with pantoprazole and rabeprazole to a lesser extent. the manufacturer advises caution in co-prescribing these drugs. [[ABPI, 2020b](https://cks.nice.org.uk/topics/atrial-fibrillation/references/)] * **Monitor for signs and symptoms of** [**digoxin toxicity**](https://cks.nice.org.uk/topics/atrial-fibrillation/prescribing-information/digoxin/#adverse-effects) **(and adjust doses accordingly) if digoxin is given with the following drugs, which may increase plasma concentration of digoxin:** * Amiodarone. * Antimicrobials (itraconazole, macrolide antibiotics, tetracycline, and trimethoprim). * Calcium-channel blockers (diltiazem, verapamil, and possibly nifedipine). There is also an increased risk of AV block and bradycardia with verapamil. * Chloroquine and hydroxychloroquine. * Spironolactone.

Answer 143

* **Antidepressants** * Avoid tricyclic antidepressants with digoxin as they are possibly proarrhythmic in cardiac disease. Consider selective serotonin reuptake inhibitors (SSRIs) or mirtazapine instead. * Avoid venlafaxine with digoxin in people at risk of arrhythmias. Consider SSRIs or mirtazapine instead. * Avoid trazodone with digoxin because it increases digoxin plasma levels. Consider SSRIs or mirtazapine instead. * **Beta-blockers** * Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong atrioventricular (AV) conduction time, increasing the risk of AV block and bradycardia. Monitor pulse carefully. * An increase in plasma digoxin levels has been noted with carvedilol. Monitor for signs of digoxin toxicity (confusion, anorexia, nausea, and disturbance of colour vision) when starting, adjusting, or stopping carvedilol. * **Buproprion** — co-administration of buproprion with digoxin may decrease digoxin levels. Digoxin levels may rise on discontinuation of bupropion, people taking buproprion and digoxin should be monitored for possible digoxin toxicity when buproprion is discontinued. * **Diuretics, acetazolamide, and amphotericin** * Increased cardiac toxicity with digoxin if hypokalaemia occurs with these drugs. Monitor digoxin levels and adjust dose accordingly. * **St John's wort** * The plasma concentration of digoxin may be reduced by St John's wort. Advise people taking digoxin that they should not use St John's wort and that they should check with their pharmacist before using any other over-the-counter medications. * **Proton pump inhibitors** — the manufacturer's SPC advise the co-administration of proton pump inhibitors (particularly omeprazole) causes increasing plasma levels of digoxin. Similar effects have been reported with pantoprazole and rabeprazole to a lesser extent. the manufacturer advises caution in co-prescribing these drugs. [[ABPI, 2020b](https://cks.nice.org.uk/topics/atrial-fibrillation/references/)] * **Monitor for signs and symptoms of** [**digoxin toxicity**](https://cks.nice.org.uk/topics/atrial-fibrillation/prescribing-information/digoxin/#adverse-effects) **(and adjust doses accordingly) if digoxin is given with the following drugs, which may increase plasma concentration of digoxin:** * Amiodarone. * Antimicrobials (itraconazole, macrolide antibiotics, tetracycline, and trimethoprim). * Calcium-channel blockers (diltiazem, verapamil, and possibly nifedipine). There is also an increased risk of AV block and bradycardia with verapamil. * Chloroquine and hydroxychloroquine. * Spironolactone.