Dose reduction

During the maintenance phase dose reductions are aimed. However, in most cases a dual or triple combination therapy is still necessary. The use of drugs with different mechanisms of immunosuppressive action allows the application of lower doses additionally resulting in decreased toxicity. 

Luzius Dettli was not only the first who described the linear function for the dependence of diug elimination on glomerular filtration rate. He was also the first who proposed the fundamental dose adjustment recommendation, the proportional dose reduction rule. Two alternatives are given to either reduce the single dose (D) or extend the interval (Tau). 

Clinical experience suggests that alprazolam can be particularly difficult to taper when lower doses are reached (e.g., tapering from 1 to 0 mg) (Ciraulo et al. 1990). One possible explanation for this is suggested by data from an animal model showing that alprazolam at doses of 0.02—0.05 mg/kg increases benzodiazepine receptor number above baseline (Miller et al. 1987). When difficulty is encountered in tapering the last 1—2 mg of alprazolam, the rate of dose reduction can be decreased to 0.25 mg/week, and/or adjunctive medication may... 

Dosing recommendations for milrinone include a loading dose of 50 mcg/kg, followed by an infusion beginning at 0.5 mcg/kg per minute (range 0.23 mcg/kg per minute for patients with renal failure up to 0.75 mcg/kg per minute). A loading dose is not necessary if immediate hemodynamic effects are not required or if patients have low systolic blood pressures (less than 90 mm Hg). Decreases in blood pressure during an infusion may necessitate dose reductions as well. 

Desirudin is a SC administered DTI approved for VTE prevention after hip replacement surgery but is not yet commercially available in the United States. Desirudin has an elimination half-life of 2 to 3 hours and is typically dosed every 12 hours. It is primarily eliminated through the kidneys, so dose reduction is needed in patients with renal impairment. The aPTT should be used to measure desirudin s anticoagulant activity.29,38,41... 

Both of these agents have been associated with rare reports of Churg-Strauss syndrome. This syndrome may result from the corticosteroid dose reduction, as it has also been reported when systemic corticosteroids have been reduced or withdrawn in conjunction with the initiation of high-potency inhaled corticosteroids.35... 

Once remission is achieved, evaluate the patient s drug regimen to determine if dose reductions or changes in frequency of administration are required. Reinforce the need for adherence to drug therapy in order to maximize effectiveness. 

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

The therapeutic dose of acamprosate is 666 mg orally three times daily, and it is supplied as a 333 mg tablet. It can be started at the full dose in most patients without titration. It differs from disulfiram and naltrexone in that it is excreted by the kidneys without liver metabolism. Consequently, it is contraindicated in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/minute), and dose reduction is necessary when the creatinine clearance is between 30 and 50 mL/minute. The most common side effects are gastrointestinal and include nausea and diarrhea. Rates of suicidal thoughts were also increased in patients treated for 1 year with acamprosate (2.4%) versus placebo (0.8%). If necessary the total daily dose maybe decreased by 1 to 3 tablets (333-999 mg) per day to alleviate side effects. 

Children treated with GH replacement therapy rarely experience significant adverse effects, whereas adults are more susceptible to dose-related adverse effects. Treatment with GH may mask underlying hypothyroidism. GH-induced symptoms, such as edema, arthralgia, myalgia, and carpal tunnel syndrome, are common and necessitate dose reductions in up to 40% of adults. Benign increases in intracranial pressure may occur with GH therapy and generally are reversible with discontinuation of treatment. Often, GH therapy can be restarted with smaller doses without symptom recurrence. 

If the prolactin level is well controlled with dopamine agonist therapy for 2 to 3 years, gradually taper therapy to the lowest effective dose. Check prolactin levels after each dose reduction.46... 

Evaluate toxicity as treatment progresses. Is the toxicity severe enough to warrant dose reduction or pharmacologic treatment Record graded toxicities according to the NCI CTC V3.0 criteria. 

Fever, rigors, chills, malaise headaches, myalgia Nausea, emesis Neutropenia Hepatic enzyme elevation Cutaneous—alopecia, transient, mild rashlike reaction Acetaminophen (APAP). NSAID if APAP is not effective. Meperidine for severe chills and rigors. Bedtime administration. 5-HT3 antagonist, prochlorperazine, metoclopramide, fluids Weekly complete blood count reduce dose by 30-50% Liver function tests (LFTs) weekly withhold treatment until LFTs normalize restart at 30-50% dose reduction reversible on dose reduction or cessation. Interferon is contraindicated in patients with psoriasis because exacerbation of psoriasis has been noted during IFN therapy. 

TMPT activity in human erythrocytes is transmitted as an autosomic codominant trait [15] and is trimodally distributed, with 89-94% of the individuals having high, 6-11% intermediate, and 0.3% low activity [7, 15-17] (Figure 14.2). The measurement of TPMT activity in erythrocytes closely reflects the ability of bone marrow to inactivate 6-MP. TPMT activity is inversely related to erythrocyte 6-TGN levels [7, 13, 18, 19], and children with low TPMT activity and very high 6-TGN levels experienced profound myelotoxicity [20, 21]. Moreover, TPMT phenotype in erythrocyte reflects that in leukemic blasts [22]. Patients with intermediate TPMT activity had a 5-fold greater cumulative incidence of dose reductions than subjects with high activity [13], and TPMT activity has been inversely related to the time of treatment withdrawal due to cytopenia [21]. 

This corresponds to a dose reduction in the house of more than a factor of 2. It also shows that more than half of the household radon is caused by the radon from water. The 0.76 pCi/1 is the radon caused by soil gas and building materials. These results are summarized in Table IV. 

It is possible to remove radon decay products from indoor air by filtration. The effects of air cleaning on dose levels are described by Jonassen (1987). However, there are major uncertainties in the effectiveness of air cleaning to remove the decay products because the particles are also removed. When the particles are removed, the "unattached fraction increases and although there are fewer decay products, they are more effective in depositing their dose of radiation to the lung tissue. Thus, there will. be much lower dose reduction than there is radioactivity reduction. It, therefore, may be more protective of health to control the radon rather than its decay products. 

Methotrexate—25% dose reduction for creatinine 1.5-2 and 50% reduction for creatinine > 2 do not give if patient has an effusion ( reservoir effect )... 

Because most adrenal crises occur because of glucocorticoid dose reductions or lack of stress-related dose adjustments, patients receiving corticosteroid-replacement therapy should add 5 to 10 mg hydrocortisone (or equivalent) to their normal daily regimen shortly before strenuous activities such as exercise. During times of severe physical stress (e.g., febrile illnesses, after accidents), patients should be instructed to double their daily dose until recovery. 

Dose reduction recommended in those with creatinine clearance less than 30 mL/min. 

Lithium clearance increases by 50% to 100% during pregnancy. Serum levels should be monitored monthly during pregnancy and weekly the week before delivery. At delivery, a dose reduction to prepregnancy doses and adequate hydration are recommended. 

Physical dependence A state of adaptation that is manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. 

Dechallenge. Action taken with the suspect drug (stopped, continued, dose reduction). 

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