• The reported therapeutic range for 12-hour trough (C0) levels from whole blood which appear to minimize side effects and rejection episodes is between 100 to 400 ng/mL as measured by the RIA method based on the specific monoclonal antibody (Compendium of Pharmaceuticals and Specialties (CPS 2003)

• Therapeutic trough plasma concentrations are 50 to 300 ng/mL (RIA). (Poisondex)

• Nephrotoxicity has been associated with trough plasma (RIA) levels greater than 250 ng/mL, and hepatotoxicity with levels greater than 1000 ng/mL. (Poisondex)

There appears to be overlap between therapeutic concentrations and those associated with serious adverse effects.

• Digoxin and other digitalis glycosides may cause potentially fatal arrhythmias (CPS 2003)

• Serum digoxin levels ranging from 0.8 to 2.0 ng/mL are generally seen in adequately digitalized patients. Levels greater than 2.0 ng/mL are often associated with toxicity. (CPS 2003)

• Digoxin and the other cardiac glycosides commonly produce adverse effects because the margin between the therapeutic and toxic doses is small; plasma concentrations of digoxin in excess of 2 ng/mL are considered to be an indication that the patient is at special risk although there is considerable inter-individual variation. There have been many fatalities, particularly due to cardiac toxicity. (Martindale: The Extra Pharmacopoeia)

• The probabilities of occurrence of digoxin-induced arrhythmias at 1.7 ng/mL, 2.5 ng/mL and 3.3 ng/mL are 10%, 50% and 90% respectively (Goodman and Gilman's Pharmacological Basis of Therapeutics)

• Therapeutic plasma concentrations of flecainide range from 0.2 to 1.0 mcg/mL (CPS 2003)

• Flecainide can cause new or worsened arrhythmias, potentially including tachycardia that is resistant to conversion to sinus rhythm with potentially fatal consequences.

• Frequency of occurrence of ventricular arrhythmias appears to be related to dose and to the underlying cardiac disease.

• In most patients flecainide slows cardiac conduction sufficiently to produce dose-related increases in the duration of the PR, QRS and QT intervals on the ECG. There have been a few cases of torsades de point-type arrhythmia associated with flecainide-induced QT prolongation and bradycardia.

• For some patients, treatment with flecainide must be started in a hospital.

• It is recommended that plasma flecainide levels be monitored. Attempts should be made to keep trough plasma levels to below 0.7 to 1.0 mcg/mL The probability of adverse experiences, especially cardiac, may increase with higher trough plasma levels especially when these exceed 0.7 mcg/mL. (CPS 2003)

Lithium toxicity is closely related to serum lithium levels and can occur at levels close to the therapeutic range. (CPS 2003)

For manic patients, the dosage should be adjusted to obtain serum concentrations between 0.8 and 1.2 mmol/L (CPS 2003)

Lithium toxicity is closely related to the concentration of lithium in the blood and is usually associated with serum concentrations in excess of 2 mmol/L. (CPS 2003)

In all patients with lithium intoxication, the primary problem is neurologic toxicity that may progress from fine tremor to hyperreflexia, fasiculations, muscular irritability, choreoathesis, clonus, agitation, altered mental status, lethargy, seizures and coma. (CPS 2003)

Symptoms of toxicity, at serum-lithium concentrations above 2 mmol per litre, include hyperreflexia and hyperextension of limbs, syncope, toxic psychosis, seizures, polyuria, renal failure, electrolyte imbalance, dehydration, circulatory failure, coma, and occasionally death. (Martindale: The Extra Pharmacopoeia)

Reports of adverse effects on the heart associated with lithium have included bradycardia due to sinus node dysfunction, which has persisted after stopping lithium, premature ventricular contractions, atrioventricular block, and T-wave depression. (Martindale: The Extra Pharmacopoeia)

• Severe cardiotoxic reactions and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. (CPS 2003)

• Hematological adverse effects include thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. Some reactions have been fatal. (CPS 2003)

• Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome, and toxic epidermal necrolysis. (Physicians Desk Reference (PDR))

• The most common manifestations encountered with phenytoin therapy are referable to the central nervous system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased co-ordination and mental confusion (PDR)

• Therapeutic phenytoin levels range from 40 to 80 μmol/L. Mild to moderate neurologic toxicity is associated with levels of 80 to 160 μmol/L. At levels above 160 μmol/L, severe neurologic toxicity may occur. (CPS 2003)

• In epilepsy, dosage should be individualized to achieve maximal benefit, including serum level monitoring (optimal control of seizures without clinical signs of toxicity occurs most often with serum levels between 10 to 20 micrograms/milliliter). (Product Info Kapseals^®) Dilantin^®), 2002).

• Blood levels should be monitored in patients with hepatic impairment; during concurrent administration of inhibitors and inducers of CYP3A4 and P-glycoprotein; and if the cyclosporine dosage is markedly changed or discontinued. (CPS 2003)

• There is a significant association between trough values less than 5 ng/mL and the severity and occurrence of acute rejection episodes. There is a correlation of the occurrence of hypertriglyceridemia, thrombocytopenia, and leukopenia, but not hypercholesterolemia, with trough concentrations above 15 ng/mL. (Kahan et al. Clin Transplantation 2000;14:97-109)

• May cause neurotoxicity and nephrotoxicity and the likelihood increases with higher blood levels.

• Monitoring of tacrolimus blood levels in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management. (CPS 2003)

• In kidney transplant patients a significant correlation was found between tacrolimus levels and the incidence of both toxicity and rejection (Kershner et al. Transplantation 1996;62(7):(920-6)

• The accepted therapeutic plasma concentration range has traditionally been 55 to 110 μmol/L (10-20 μg/mL) in children and adults. (CPS 2003)

• Optimum therapeutic serum concentrations are generally considered to range from 10 to 20 micrograms per mL (55 to 110 micromol per litre) (Martindale: The Extra Pharmacopoeia)

• Atrial and ventricular arrhythmias may occur with serum theophylline concentrations greater than 110 μmol/L, or at therapeutic concentrations in patients with heart disease. Focal or generalized seizures may occur at high serum concentrations, or at therapeutic serum concentrations in predisposed individuals. (CPS 2003)

• Theophylline has a narrow therapeutic index; therefore, cautious dosage determination is essential. Symptoms of toxicity may even occur when serum concentrations are within the upper end of the therapeutic range (85 to 110 μmol/L), particularly during initiation of therapy (CPS 2003)

• May cause fatal or nonfatal hemorrhage from any tissue or organ. (CPS 2003)

• Warfarin is a narrow therapeutic range (index) drug (CPS 2003)

• Effective concentration reported to be 2.2 ± 0.4 μg/mL. (Goodman and Gilman's The Pharmacological Basis of Therapeutics)

• Although a relationship between milligram/kilogram ingested and amount of hypocoagulability has not yet been established (Poisondex), the narrow effective concentration range and the seriousness of potential adverse effects, suggest that this drug should be considered a critical dose drug.