High Risk Drugs Flashcards
What are some examples of drugs with a narrow therapeutic index?
- Lithium
- Carbamazepine
- Phenytoin
- Ciclosporin
- Tacrolimus
- Theophylline
What are the indications for lithium
- Treatment and prophylaxis of mania,
- Treatment and prophylaxis of bipolar disorder,
- Treatment and prophylaxis of recurrent depression,
- Treatment and prophylaxis of aggressive or self-harming behaviour
What is the dosing of lithium?
What is the dosing of lithium in the elderly?
Differing brands have different starting doses for treatment and prophylactic lithium. All starting doses are divided throughout the day. The dose is adjusted based on serum-lithium concentration and once stable once daily administration is preferred.
Should lithium be prescribed by brand?
If so, why?
No – stick to same brand!! Different brands are absorbed differently in the stomach
What are examples of lithium brands?
Camcolit® IR or MR tablets, Liskonum® tablets, Priadel® tablets
What is the serum lithium target?
How is lithium monitoring carried out - think short term and long term
Lithium salts have a narrow therapeutic/toxic ratio and should therefore not be prescribed unless facilities for monitoring serum-lithium concentrations are available.
Samples should be taken 12 hours after the dose (take dose at night so bloods can be taken in morning i.e if take 10pm at night bloods should be done at 10am) to achieve a serum-lithium concentration of 0.4–1 mmol/litre (lower end of the range for maintenance therapy and elderly patients).
- ?16 - 65:- 0.4 - 1 mmol/L
- >65y:- 04 - 0.8mmol/L
A target serum-lithium concentration of 0.8–1 mmol/litre is recommended for acute episodes of mania, and for patients who have previously relapsed or have sub-syndromal symptoms. It is important to determine the optimum range for each individual patient.
Routine serum-lithium monitoring should be performed weekly after initiation and after each dose change until concentrations are stable, then every 3 months for the first year, and every 6 months thereafter. Patients who are 65 years and older, taking drugs that interact with lithium, at risk of impaired renal or thyroid function, raised calcium levels or other complications, have poor symptom control or poor adherence, or whose last serum-lithium concentration was 0.8 mmol/litre or higher, should be monitored every 3 months. Additional serum-lithium measurements should be made if a patient develops significant intercurrent disease or if there is a significant change in a patient’s sodium or fluid intake.
What events/conditions would trigger additional lithium monitoring?
Additional serum-lithium measurements should be made if a patient develops significant intercurrent disease or if there is a significant change in a patient’s sodium or fluid intake.
Other than lithium concentration monitoring, what other monitoring should be carried out for lithium?
A. Before initation
B. After initation
A. Manufacturer advises to assess renal, cardiac, and thyroid function before treatment initiation. An ECG is recommended in patients with cardiovascular disease or risk factors for it. Body-weight or BMI, serum electrolytes, and a full blood count should also be measured before treatment initiation.
B. Monitor body-weight or BMI, serum electrolytes, eGFR, and thyroid function every 6 months during treatment, and more often if there is evidence of impaired renal or thyroid function, or raised calcium levels. Manufacturer also advises to monitor cardiac function regularly.
What are contraindications to using lithium?
Addison’s disease; cardiac disease associated with rhythm disorder; cardiac insufficiency; dehydration; family history of Brugada syndrome; low sodium diets; personal history of Brugada syndrome; untreated hypothyroidism
What are cautions to using lithium?
Avoid abrupt withdrawal; cardiac disease; concurrent ECT (may lower seizure threshold); diuretic treatment (risk of toxicity); elderly (reduce dose); epilepsy (may lower seizure threshold); myasthenia gravis; psoriasis (risk of exacerbation); QT interval prolongation; review dose as necessary in diarrhoea; review dose as necessary in intercurrent infection (especially if sweating profusely); review dose as necessary in vomiting; surgery
What side effects may patients typically experience when using lithium (especially during initation stage)?
Side effects are usually related to serum lithium concentrations and are less common in patients with plasma lithium concentrations below 1 mmol/L. Initaly therapy may result in fine tremor of the hands, polyuria and thirst.
upset stomach – particularly at the start of treatment; fine shake (‘tremor’) of your hands; metallic taste in your mouth; weight gain; swelling of your ankles; feeling more thirsty than usual and passing a lot of urine.
- Rare or very rare – nephropathy
- Frequency not known – QT interval prolongation
What are signs of lithium toxicity?
What is used to reverse lithium toxicity?
- Toxic effects may be expected at serum lithium concentrations of ~1.5mmol/L, although they are possible at lower concentrations.
- The onset of toxicity symptoms may be delayed up to 24 hours. They include nausea, diarrhoea, polyuria, drowsiness, increased confusion, restlessness, hypernatremia, coma, convulsions, cardia dysthymias and renal failure.
- There is NO antidote to lithium poisoning
How should lithium be stopped and why?
While there is no clear evidence of withdrawal or rebound psychosis, abrupt discontinuation of lithium increases the risk of relapse. If lithium is to be discontinued, the dose should be reduced gradually over a period of at least 4 weeks (preferably over a period of up to 3 months). Patients and their carers should be warned of the risk of relapse if lithium is discontinued abruptly. If lithium is stopped or is to be discontinued abruptly, consider changing therapy to an atypical antipsychotic or valproate.
What advice should be given to patients started on lithium?
1. Dehydration
- Getting deyhdrated can make the lithium level in your blood high too high
- Maintain adequate fluid intake
- If you have sickness or diarrhoea for a day or two see your doctor to have lithium levels taken
2. Sodium Diet
- Avoid dietary changes which reduce or increase sodium intake
- Low sodium diet - Rapid reduction of sodium intake may cause raised lithium levels.
- Don’t go on a low sodium diet - talk to doctor first
3. Interactions
- Carry lithium card with patient
- Check medicines prescribed or at CP buying OTC
4. Signs of Lithium Toxicity
- Patients should be advised to report signs and symptoms of lithium toxicity, hypothyroidism, renal dysfunction (including polyuria and polydipsia), and benign intracranial hypertension (persistent headache and visual disturbance).
5. A lithium treatment pack
- should be given to patients on initiation of treatment with lithium. The pack consists of a patient information booklet, lithium alert card, and a record book for tracking serum-lithium concentration.
6. Regular Blood Tests
- That regular blood tests are important and the results should be recorded in their lithium record booklet.
7. NSAIDs
- Not to take over-the-counter nonsteroidal anti-inflammatory drugs.
8. Missed Doses
- That if a dose is missed they should take it as soon as possible; but if yesterday’s dose was missed then they should not double today’s dose.
9. Abrupt withdrawal
- Not to stop taking lithium abruptly, and that non-compliance may lead to a relapse.
What are common drug interactions with lithium?
- Diuretics — thiazide diuretics can cause a rapid increase in serum lithium levels (7–10 days) by reducing clearance of lithium. The increase in lithium levels varies from 25–400% Loop diuretics also cause lithium retention but are less likely to result in lithium toxicity.
- Nonsteroidal anti-inflammatory drugs (NSAIDs) — may increase serum lithium levels. The increase in lithium varies from 40–50%. The mechanism of this interaction is thought to be related to the effects of NSAIDs on fluid balance. This is particularly important if NSAIDs are added to a long-standing prescription of lithium.
- Haloperidol — severe neurotoxicity has been reported with this combination, however successful and uneventful use of this combination has also been reported.
- Carbamazepine in combination with lithium has been reported to cause neurotoxic reactions . However successful and uneventful use of this combination has also been reported.
- Antidepressants with a serotonergic action (such as selective serotonin reuptake inhibitors, tricyclic antidepressants, venlafaxine, duloxetine) have rarely been linked to an increased incidence of central nervous system toxicity when used with lithium.
- ACE inhibitors decrease the excretion of lithium. They can also precipitate renal failure. If these two drugs are prescribed together, extra care is required in monitoring both serum creatinine and lithium levels.
- Drugs that prolong the QT-interval — potential for additive effects when co-administered.
- Drugs that cause hypokalaemia — potentially increased risk of torsade de points when co-administered.
What are Long-term adverse effects of lithium?
Long-term use of lithium has been associated with thyroid disorders and mild cognitive and memory impairment. Long-term treatment should therefore be undertaken only with careful assessment of risk and benefit, and with monitoring of thyroid function every 6 months (more often if there is evidence of deterioration).
The need for continued therapy should be assessed regularly and patients should be maintained on lithium after 3–5 years only if benefit persists
Some examples of long-term use (NICE) include:
- Hypothyroidism: there is a small risk that people taking lithium at therapeutic doses may develop clinical goitre, hypothyroidism, or both; the risk appears to be greatest in the first 2 years of treatment. Although this may occur, it should not be a reason for stopping lithium treatment. Levothyroxine replacement is usually indicated. Thyroxine function tests usually return to normal when lithium is discontinued.
- Hyperthyroidism: lithium-associated thyrotoxicosis is rare and occurs mainly after long-term use. It should not constitute an absolute contraindication to lithium treatment. Specialist advice should be sought regarding management.
- Hyperparathyroidism: lithium use has been associated with hypercalcaemia accompanied by elevations in circulating parathyroid hormone (PTH). The coexistence of hypercalcaemia and elevated PTH levels suggests primary hyperparathyroidism. However, significantly greater serum levels of calcium are probably required to inhibit PTH secretion during lithium therapy. The presence of mild hypercalcaemia with elevated PTH is consistent with lithium-induced hyperparathyroidism. Parathyroid surgery is not indicated in this situation, and withdrawal of lithium will result in prompt normalization of serum calcium and PTH levels.
- Nephrotoxicity: a small reduction in glomerular filtration rate is seen in 20% of people taking lithium. In the vast majority of these people this effect is benign. A very small number of people taking lithium may develop interstitial nephritis. Lithium can also cause a reduction in urinary concentrating capacity (nephrogenic diabetes insipidus, with symptoms of thirst and polyuria) which is reversible in the short-to-medium term, but may be irreversible after long-term treatment (greater than 15 years).
- Renal tumours: cases of microcysts, oncocytomas, and collecting duct renal carcinoma have been reported in people with severe renal impairment who received lithium for more than 10 years.
- Rhabdomyolysis: muscle weakness and rhabdomyolysis have been reported in people taking lithium.
What happens to the dose in surgery and eldelry for lithium?
- Bariatric surgery - lower maintenance dosage of Lithium may be required for patients, who have undergone a bariatric surgery because of decreased glomerular filtration following marked weight loss. Also, drug levels should be monitored closely in connection with bariatric surgery due to the risk of lithium toxicity.
- Starting doses in elderly should be lower and maintain stable concentration preferably between
Can lithium be used in pregnancy?
Can lithium be used in breast-feeding?
- Avoid if possible, particularly in the first trimester (risk of teratogenicity, including cardiac abnormalities).
- Dose requirements increased during the second and third trimesters (but on delivery return abruptly to normal)
- Close monitoring of serum-lithium concentration advised in pregnancy (risk of toxicity in neonate).
- Breast feeding
- Present in milk and risk of toxicity in infant—avoid.
- Can lithium be used in renal impairment?
- Can lithium be used in hepatic impairment?
- Caution in mild to moderate impairment; avoid in severe impairment
- Does not say
What Indications is Carbamaepine used for?
Carbamazepine is a drug of choice for simple and complex focal seizures and is a first-line treatment option for generalised tonic-clonic seizures. It can be used as adjunctive treatment for focal seizures when monotherapy has been ineffective. It is essential to initiate carbamazepine therapy at a low dose and build this up slowly. Carbamazepine may exacerbate tonic, atonic, myoclonic and absence seizures and is therefore not recommended if these seizures are present.
Indications:
- Focal and secondary generalised tonic-clonic seizures
- Primary generalised tonic-clonic seizure [KS1]
- Trigeminal neuralgia[KS2]
- Prophylaxis of bipolar disorder unresponsive to lithium
- Adjunct in acute alcohol withdrawal (unlicensed)
- Diabetic neuropathy (unlicensed)
[KS1]Usual maintance dose between 0.8g-1.2g daily in divided doses but can be increased up to 1.6g-2g daily in divided doses.
[KS2]Trigeminal neuralgia is sudden, severe facial pain. It’s often described as a sharp shooting pain or like having an electric shock in the jaw, teeth or gums. It usually happens in short, unpredictable attacks that can last from a few seconds to about 2 minutes. The attacks stop as suddenly as they start.
~95% pf cases caused by pressure on trigeminal nerve
What are common brand names of carbamazepine
- Tegretol MR
- Carbagen SR
Contraindications to using Carbamazepine
Contraindications:
- Acute porphyrias[KS1] ; AV conduction abnormalities (unless paced); history of bone-marrow depression
- *
[KS1]Acute porphyrias include forms of the disease that typically cause nervous system symptoms, which appear quickly and can be severe. Symptoms may last days to weeks and usually improve slowly after the attack. Acute intermittent porphyria is the common form of acute porphyria
What are cautions for using Carbamazepine?
Cautions:
- Cardiac disease; history of haematological reactions to other drugs; may exacerbate absence and myoclonic seizures; skin reactions; susceptibility to angle-closure glaucoma[KS1] , risk of suciside
Blood, hepatic, or skin disorders
Carbamazepine should be withdrawn immediately in cases of aggravated liver dysfunction or acute liver disease. Leucopenia that is severe, progressive, or associated with clinical symptoms requires withdrawal (if necessary under cover of a suitable alternative).
[KS1]Glaucoma is a common eye condition where the optic nerve, which connects the eye to the brain, becomes damaged. It’s usually caused by fluid building up in the front part of the eye, which increases pressure inside the eye. Glaucoma can lead to loss of vision if it’s not diagnosed and treated early.
Glaucoma is a common eye condition where the optic nerve, which connects the eye to the brain, becomes damaged.
Symptoms of glaucoma can include blurred vision or seeing rainbow-coloured circles around bright lights. Both eyes are usually affected.
What drug should be considered in patients on carbamazepine?
Cautions, further information
Consider vitamin D supplementation in patients who are immobilised for long periods or who have inadequate sun exposure or dietary intake of calcium.
.
Side effects of carbamazepine?
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).
What interactions are possible with carbamazepine?
- 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.
Can Carbamaxepine be used in pregnancy?
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
Can Carbamazepine be used in breastfeeding?
Breast feeding:
- Amount probably to small to be harmful
- Monitor infant for possible ADR
Can Carbamazepine be used in renal impairment?
- Use with caution
Can Carbamazepine be used in hepatic impairment?
Hepatic Impairment:
Use with caution and close monitoring
What genetic testing is reccomended in which patient group before comensing Carbamazepine and why?
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] in presence of HLA-B*1502 allele).
- *
[KS1]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
What monitoring should occur with Carbamazepine?
What are target levels for carbamazepine?
- 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.
How should carbamazepine be stopped?
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
True or False?
- Tegretol MR (Carbamazepine) can be halfed?
- Can be chewed?
Manufacturer advises Tegretol® Prolonged Release tablets can be halved but should not be chewed.
True or false?
In children oral liquid carbamazepine can be used rectally?
In children: Expert sources advise oral liquid has been used rectally—should be retained for at least 2 hours (but may have laxative effect).
Can you switch brands with carbamazepine?
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.
What are serious ADRs for carbamazepine?
Blood, hepatic, or skin disorders
What advice should be given to patients on carbamazepine?
- 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
What are signs of very high doses of carbamazepine?
- 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
What indications can phenytoin be used for?
- Tonic-Clonic Seizures
- Focal Seizure
- Prevention and treatment of seizures during or following neurosurgery or severe head injury
- Status epilepticus[KS1]
- Acute symptomatic seizures associated with head trauma or neurosurgery
[KS1]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.
Can Phenytoin brand be switched?
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
What are the dose equivalents for phenytoin sodium and phenytoin base?
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
What are contraindications to using phenytoin?
- General contraindications: Acute porphyrias
- With IV use: Second- and third-degree heart block; sino-atrial block; sinus bradycardia; Stokes-Adams syndrome
What route of administration should not be used with phenytoin and why?
Intramuscular phenytoin should not be used (absorption is slow and erratic).
What are cautions to using phenytoin?
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
What medicine should be considered in patients taking phenytoin and why?
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
What are side effects of Phenytoin use?
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
What are symptoms of phenytoin overdose?
True or false
Phenytoin is associated with allergy and cross-sensivity?
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.
Can Phenytoin be used in hepatic or renal impairment?
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).
What pre-treatment screening should in which patient groups before starting phenytoin?
- HLAB* 1502 allele in individuals of Han Chinese or Thai origin—avoid unless essential (increased risk of Stevens- Johnson syndrome).
What TDM should be carried out for phenytoin?
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).
Other than TDM monitoring, what other monitoring should be carried out?
Blood counts
- Manufacturer recommends blood counts (but evidence of practical value uncertain).
With intravenous use
- Monitor ECG and blood pressure.
What advice should be given to patients starting on phenytoin?
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.
Phenytoin Interactions?
What indications can ciclosporin be used for?
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
In relation to Ciclosporin:-
Manufacture advises to A dose by B % or switch to IV with concurrent use of C :
A. Increase/decrease
B. X%
C .Drug
Manufacture advises increase dose by 50% or switch to IV with concurrent use of octreotide
Can you switch brands with Ciclosporin?
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).
What are contraindications to using ciclosporin?
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)
What are cautions to using ciclosporin?
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
What are side effects to using Ciclosporin?
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.
What are possible interactions with Ciclopsorin
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.
Can Ciclosporin be used in pregnancy?
Crosses placenta; manufacturer advises avoid unless potential benefit outweighs risk
Can Ciclosporin be used in breastfeeding?
Avoid - present in milk
Can Ciclosporin be used in hepatic impairment?
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.
Can Ciclosporin be used in renal impairment?
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
What dose change should occur in renal impairment in patients using ciclosporin?
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.
What Monitoring is required for patients on ciclosporin?
- Pre-treatment
- After starting?
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.
What patient counselling should occur for patients on ciclosporin?
- 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:
Points to consider Ciclopsorin
- Potent immunosuppressant with common a/e of Nephrotoxicity
- Monitoring: blood, skin, liver, potassium renal function, B.P, lipids.
- 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 - 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
