Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Protein Restriction in Chronic Renal Failure Harold I. Feldman To cite this article: Harold I. Feldman (1991) Protein Restriction in Chronic Renal Failure, Hospital Practice, 26:6, 220-225, DOI: 10.1080/21548331.1991.11704199 To link to this article: http://dx.doi.org/10.1080/21548331.1991.11704199
Published online: 17 May 2016.
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View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [The University Of Melbourne Libraries]
Date: 22 June 2016, At: 09:13
Management Update
Protein Restriction in Chronic Renal Failure
Downloaded by [The University Of Melbourne Libraries] at 09:13 22 June 2016
HAROLD I. FELDMAN
University of Pennsylvania
Medicare's End-Stage Renal Disease Program has undergone remarkable growth since 1973, when federal legislation mandated the provision offunds for dialysis and transplantation services to the vast majority of Americans with ESRD. By the end of 1988, nearly 150,000 patients were receiving Medicare benefits for renal replacement therapies, representing an annual rate of growth exceeding 12% over the preceding decade. Yet in spite ofthe technologic advances permitting the broad application of these therapies, the survival and quality of life of patients with end-stage renal disease remains disappointingly poor. The overall five-year crude mortality among patients who began renal replacement therapy in 1984 was 41%. Even higher death rates were recorded in the elderly. In view of these unfavorable statistics, the extensive morbidity and dysfunction associated with end-stage renal disease, and the growing cost of caring for patients receiving dialysis and transplantation, the identification of strategies to prevent renal disease has become increasingly urgent. Unfortunately, few apDr. Feldman is Assistant Professor of Medicine, University of Pennsylvania School of Medicine.
220
Hospital Practice June 15, 1991
proaches have come to the forefront that meaningfully and consistently prevent or delay endstage disease in individuals with progressive renal disorders. Among the most promising strategies identified thus far is the reduction of dietary protein.
Possible Mechanisms The apparently inexorable progression characteristic of many kidney diseases seems in part to be related to changes in hemodynamics within the still-functioning parenchymachanges that can be exacerbated by large quantities of dietary protein. Early work in animal models has demonstrated that dietary protein reduction leads to measurable falls in intrarenal pressure and thereby prolongs the survival of rats subjected to partial renal ablation. Similar benefits attributable to dietary manipulation have been observed in animal models of glomerulonephritis and systemic lupus erythematosus. Other mechanisms through which dietary protein reduction may improve renal survival have also been postulated. These include the suppression of immune mechanisms (including complement activation) involved in the primary disease process, the reduction of the work of ex-
creting ammonia and phosphorus, and the reduction of serum lipid concentrations. The obvious limitations of animal data have prompted a host of controlled and uncontrolled observations in the clinical setting, all representing attempts torelate dietary protein intake to the progression of renal disease in humans. Several issues affecting these clinical studies deserve mention. First, protein reduction has been examined by several approaches that specify differing quantities of protein, with or without supplemental essential amino acids or their ketoanalogues. As will be seen, study diets containing at least 0.6 gm!kg per day of protein have usually been prescribed without amino acid supplementation, whereas diets containing 0.3 to 0.4 gm/kg per day of protein have usually included amino acid ketoanalogues. Second, many studies have not included a control group of patients with unmodified diets. While the improvement on renal function tests observed in many of these uncontrolled studies may have been due to the diet, the effect of concomitant medical treatment cannot always be ruled out, nor can the possibility of misleading renal function findings. The rate of decline of (continues)
Downloaded by [The University Of Melbourne Libraries] at 09:13 22 June 2016
Low PRoTEIN
(continued)
the inverse of the serum creatinine level, used as a measure of the glomerular filtration rate in many of these studies, may fall after dietary intervention not because the GFR has stabilized but simply because the amount of ingested creatinine (found in cooked meat) has declined or because the patient's lean body mass has been reduced. Finally, aggregation of patients with diverse renal disorders into a single study may have obscured important relationships between diet and progression of renal dysfunction specific to particular types of kidney disease.
Available Evidence Several cohorts of patients with heterogeneous renal disease or diabetes have been placed on low-protein diets (0.6 gm/kg per day). In these groups, repeated measurement of serum creatinine has demonstrated an apparent reduction in the rate of decline of renal function. Diets containing 20 to 30 gm/day of protein supplemented by ketoanalogues of amino acids have also been administered in uncontrolled cohort studies of patients with various renal diseases. Again, the dietary intervention has been associated with preservation of renal function, as assessed by serum creatinine. The absence of adequate control groups greatly limits the interpretability of these studies, as does the use of serum creatinine as an index of renal function. To date, four randomized controlled clinical trials of protein restriction in chronic renal failure have also been performed. In the largest of these (Figure 1 }, Johan B. Rosman and colleagues in Switzerland, Ger(conttnues)
Figure 1. Four-year randomized controlled trial of dietary protein restriction for patients with chronic renal failure did not show universal benefit but did suggest that renal deterioration is slowed in some patients. Subjects with initial creatinine clearances of 31 to 60 ml/min ate either their usual diet or one with a protein content restricted to 0.6 gm/kg per day. For subjects with poorer initial clearance, the restriction was greater: 0.4 gm/kg per day. Creatinine clearance declined in parallel for the restricted-diet groups and their controls (top). However, a post-trial analysis found that patients with primary glomerular disease (bottom) had benefited. (Data of Rosman JB et al, 1989) Hospital Practice June 15, 1991
221
Once-a-day
Downloaded by [The University Of Melbourne Libraries] at 09:13 22 June 2016
HISMAnA[ (ASTEMIZOLE)r~g~~
Low
Before prescribing, please consult complete prescribing information of which the following is a brief summary. DESCRIPTION: HISMANAL® (astemizole) is a histamine H,-receptor antagonist available in scored white tablets for oral use. CONTRAINDICATIONS: HISMANAL is contraindicated in patients with known hypersensitivity to astemizole or any of the inactive ingredients. PRECAUTIONS: General: Caution should be given to potential anticholinergic (drying) effects in patients wrth lower airway diseases, including asthma. Caution should be used in patients with cirrhosis or other liver diseases (See Clinical Pharmacology section). HISMANAL does not appear to be dialyzable. Caution should also be used when treating patients with renal impairment. Information for Patients: Patients taking HISMANAL should receive the following information and instructions. Antihistamines are prescribed to reduce allergic symptoms. Patients should be questioned about pregnancy or lactation before starting HISMANAL therapy, since the drug should be used in pregnancy or lactation only if the potential benefit justifies the potential risk to fetus or baby (see Pregnancy subsection). Patients should be instructed 1) to take HISMANAL only as needed, 2) not to exceed the prescribed dose. and 3) to take HISMANAL on an empty stomach, e.g., at least 2 hours after a meal. No additional food should be taken for at least 1 hour post-dosing. Patients should also be instructed to store this medication in a tightly closed container in a cool, dry place, away from heat or direct sunlight, and away from children. Carcinogenesis, Mutagenesis, Impairment of Fertllltr: Carcinogenic potential has not been revealed in rats given 260x the recommended human dose of astemizole for 24 months, or in mice given 400x the recommended human dose for 18 months. Micronucleus, dominant lethal, sister chromatid exchange and Ames tests of astemizole have not revealed mutagenic activity. Impairment of fertility was not observed in male or female rats given 200x the recommended human dose. PregniRCJ: Pregnancr Catagorr C: Teratogenic effects were not observed in rats administered 200x the recommended human dose or in rabbits given 200x the recommended human dose. Maternal toxicity was seen in rabbits administered 200x the recommended human dose. Embryocidal effects accompanied by maternal toxicity were observed at 100x the recommended human dose in rats. Embryotoxicity or maternal toxicity was not observed in rats or rabbits administered 50x the recommended human dose. There are no adequate and well controlled studies in pregnant women. HISMANAL should be used during pregnancy only if the potential benefrt justifies the potential risk to the fetus. Metabolites may remain in the body for as long as 4 months after the end of dosing, calculated on the basis of 6 times the terminal half-life (See Clinical Pharmacology section). Nursing Mothers: It is not known whether this drug is excreted in human milk. Because certain drugs are known to be excreted in human milk, caution should be exercised when HISMANAL is administered to a nursing woman. HISMANAL is excreted in the milk of dogs. Pediatric Usa: Safety and efficacy in children under 12 years of age has not been demonstrated. ADVERSE REACTIONS: The reported incidences of adverse reactions listed in the following table are derived from controlled clinical studies in aduns. In these studies the usual maintenance dose of HISMANAL® (astemizole) was 10 mg once daily. Percent of Patients Reporting Controlled Studies*
ADVERSE EVENT Central Nervous System Drowsiness
Headache
Fatigue Appetite increase
Weight increase Nervousness Diuy
Hismanal
Placebo
Classical**
(N =1630) %
(N=1109) %
(N=304) %
7.1 6.7 4.2 3.9 3.6 2.1 2.0
6.4 9.2 1.6 1.4 0.7 1.2 1.8
22.0 3.3 11.8 0.0 1.0 0.3 1.0
2.5
2.9
1.3
Gastrointestinal System
Nausea
Diarrhea 1.8 2.0 0.7 Abdominal pain 1.4 1.2 0.7 Eye, Ear, Nose, and Throat Mouth dry 5.2 3.8 7.9 Pharyngitis 1.7 2.3 0.3 Conjunctivitis 1.2 1.2 0.7 Other Arthralgia 1.2 1.6 0.0 Durat1on of treatment 1n Controlled Stud1es ranged from 7 to 182 Days -*Classical Dru_gs: ~lemastine (N= 137); Chlorphemramme (N= 100); Pheniramine Maleate {N=47); d-Chlorphemramme {N = 20)
Adverse reaction information has been obtained from more than 7500 patients in all clinical trials. Weight gain has been reported in 3.6% of astemizole treated patients involved in controlled studies, with an average treatment duration of 53 days. In 46 of the 59 patients for whom actual weight gain data was available, the average weight gain was 3.2 kg. Less frequently occurring adverse experiences reported in clinical trials or spontaneously from marketing experience with HISMANAL include: angioedema, bronchospasm, depression, edema, epistaxis, myalgia, palpitation, photosensitivity, pruritus, and rash. Marketing experiences include isolated cases of convulsions. A causal relationship with HISMANAL has not been established. · OVERDOSAGE: In the event of overdosage, supportive measures including gastric lavage and emes1s should be employed. Cases of overdose have been reported from foreign marketing experrence. Anhough overdoses of up to 500 mg have been reported with no ill effects, cases of serious ventricular arrhythmias, including Torsades de pointes, following overdoses of greater than 200 mg have been reported. Patients should be carefully observed and EGG monitoring is recommended in cases of suspected overdose. An appropriate antiarrhythmic treatment may be needed. HISMANAL does not appear to be dialyzable. Care should be taken not to exceed dosing recommended in the DOSAGE AND ADMINISTRATION section. Oral LD 50 values for HISMANAL were 2052 mg/kg in mice and 3154 mg/kg in rats. In neonatal rats, the oral LD 50 was 905 mg/kg in males and 1235 mg/kg in females. NDC 50458-510-01 (10 X 10 blister) NDC 50458-510-10 (100 tablets) Store tablets at room temperature (59"-86"F) (15"-30"C). Protect from moisture. References: 1. Kn1ghl A Aslemllole-a new. non-sedatmg ant1h1stamine for haylever J Ototaryngol 198514(2)85-88 2. Howarlh PH. Holgate ST Comparalive tnal ol two non-sedaiiVe H1 ant1h1stammes. terfenadme and astemllole. for hay fever Thorax. 1984;39668-672
~D jt\~M~~~~~ I!' 40 Kingsbridge Road Piscataway, NJ 08855-3998
May 1991
December 1988 U.S. Patent 4,219,559 JPI-HS-103-2 1P41N98A-M
PROTEIN
(continued)
many, and the Netherlands studied 248 patients with various renal diagnoses. Half of the subjects were randomized to a diet including 0.4 or 0.6 gm/kg per day of protein. Mter two years of follow-up, renal function was found to be better in the low-protein group than in the subjects who had continued to consume their usual diet. The difference was statistically significant. A four-year analysis, however. failed to confirm the difference, except in a post-trial subgroup analysis of men and of patients with glomerulonephritis. J _Bergstrom and colleagues at the Karolinska Institute in Stockholm presented the results of a randomized clinical trial comparing usual diet to one containing 0.4 gm/kg per day of protein supplemented by 0.1 gm/kgper day of essential amino acids. They studied 57 patients with severe renal failure, all of whom had exhibited progression of renal dysfunction during a 12- or 24-month antecedent observation period. Only 28 patients completed the trial (which was as long as the preceding observation period had been). Evolution of renal function was documented by repeat measurements of the urinary clearance of EDTA labeled with radioactive chromium. The 51 Cr-EDTA clearance correlates well with the true GFR and is not directly affected by dietary protein intake. No effect of the dietary intervention was observed. However. lowering of blood pressure was found to be associated with a slower decline of renal function in both study groups. The failure of this trial to detect differences between the two groups may have been related to the small (continues)
224
Downloaded by [The University Of Melbourne Libraries] at 09:13 22 June 2016
Low
PROTEIN
(continued)
number of subjects and also, perhaps, to their advanced renal dysfunction by the time of enrollment. In 1989, Benno U. Ihle and colleagues at the Royal Melbourne Hospital reported the results of an Australian clinical trial of a diet incorporating 0.4 gm!kg per day of protein, as opposed to a usual diet, in 64 patients with initial serum creatinine levels between 4 and 11 rngtdl. Mter 18 months of follow-up, a significantly greater proportion of control patients had progressed to end-stage renal disease (27%, compared with 6% of the patients consuming a low-protein diet). This finding was mirrored by a drop in mean GFR (as measured by 51 Cr-EDTA clearance) that was significantly greater in the usual-diet group than in the restricted-diet subjects. Unfortunately, a number of problems-the short duration offallow-up, the advanced nature of renal dysfunction in study subjects, and imbalance in the underlying diagnoses between the two study groups-make it difficult to generalize these results to patients with mild or moderate renal insufficiency treated with dietary modification for many years. Finally, Kathleen Zeller and colleagues at the University of Texas Southwestern Medical Center at Dallas have recently reported a clinical trial involving 35 patients with insulin-dependent diabetes mellitus who were randomized to a diet containing 0.6 gm!kgper day of protein or to the usual diet (with the proviso that the usual diet include at least 1 gm!kgper day of protein). Although the actual protein intake by the restricted-diet group was 0. 72 gm/kg per day (as calculated from urinary excre-
tion of urea nitrogen), the investigators found a significant decline in the rate of reduction of GFR (as assessed by iothalamate clearance). This study had several limitations. In the control group, follow-up of a disproportionate number of patients was ended during the first year, owing to the development of end-stage renal disease. The disproportion raises important doubts about the comparability of the baseline renal function in the two study groups. Then, too, the investigators based their analysis on the slope of the decline of GFR, which in turn requires the assumption that the fall of GFR over time is linear. The brief follow-up of many of the study's patients made this assumption untestable.
Conclusions Despite the limitations of individual studies, evidence has accumulated indicating that protein restriction may reduce the rate of decline of renal function in patients with chronic renal insufficiency. Moreover, no evidence has surfaced thus far to suggest that protein restriction in the range of 0.6 gm/kg per day leads to malnutrition or other significant adverse outcomes. Al-
though numerous questions remain to be answered by future research, the institution of protein restriction in the range of 0. 6 gm/kg per day-with careful follow-up of nutritional status-appears to be a reasonable therapeutic approach for patients with mild to moderate renal insufficiency. We must, however, understand better the long-term efficacy of dietary protein reduction before we can embrace it as the standard of care. We must also learn how its efficacy is modified by the level of renal function and type of renal disease, and we must identify the risks, if any, that its institution entails. The Modification of Diet in Renal Disease Study, funded by the National Institutes of Health, promises better answers to those questions. It is a large, multicenter clinical trial of the efficacy of low- and very low protein diets in preventing the progression of renal failure. If we are able to demonstrate convincingly a sustained beneficial effect of dietary intervention, we will need to address the great challenge of devising strategies through which our patients can comply with dietary modification and sustain it for many years in the setting outside the artificial study environment. D
References Rosman JB et al: Protein-restricted diets in chronic renal failure: A four year follow-up shows limited indications. Kidney Int 36(suppl 27) :S96, 1989 Bergstrom J et al: Stockholm clinical study on progression of chronic renal failure: An interim report. Kidney Int 36(suppl 27) :SilO, 1989 Ihle BU et al: The effect of protein restriction on the progression of renal insufficiency. N Eng! J Med 321: 1773, 1989 Zeller K et al: Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Eng! J Med 324:78, 1991 Klahr S: The Modification of Diet In Renal Disease Study. N Eng! J Med 320:864, 1989
Hospital Practice June 15, 1991
225
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Protein Restriction in Chronic Renal Failure Harold I. Feldman To cite this article: Harold I. Feldman (1991) Protein Restriction in Chronic Renal Failure, Hospital Practice, 26:6, 220-225, DOI: 10.1080/21548331.1991.11704199 To link to this article: http://dx.doi.org/10.1080/21548331.1991.11704199
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [The University Of Melbourne Libraries]
Date: 22 June 2016, At: 09:13
Management Update
Protein Restriction in Chronic Renal Failure
Downloaded by [The University Of Melbourne Libraries] at 09:13 22 June 2016
HAROLD I. FELDMAN
University of Pennsylvania
Medicare's End-Stage Renal Disease Program has undergone remarkable growth since 1973, when federal legislation mandated the provision offunds for dialysis and transplantation services to the vast majority of Americans with ESRD. By the end of 1988, nearly 150,000 patients were receiving Medicare benefits for renal replacement therapies, representing an annual rate of growth exceeding 12% over the preceding decade. Yet in spite ofthe technologic advances permitting the broad application of these therapies, the survival and quality of life of patients with end-stage renal disease remains disappointingly poor. The overall five-year crude mortality among patients who began renal replacement therapy in 1984 was 41%. Even higher death rates were recorded in the elderly. In view of these unfavorable statistics, the extensive morbidity and dysfunction associated with end-stage renal disease, and the growing cost of caring for patients receiving dialysis and transplantation, the identification of strategies to prevent renal disease has become increasingly urgent. Unfortunately, few apDr. Feldman is Assistant Professor of Medicine, University of Pennsylvania School of Medicine.
220
Hospital Practice June 15, 1991
proaches have come to the forefront that meaningfully and consistently prevent or delay endstage disease in individuals with progressive renal disorders. Among the most promising strategies identified thus far is the reduction of dietary protein.
Possible Mechanisms The apparently inexorable progression characteristic of many kidney diseases seems in part to be related to changes in hemodynamics within the still-functioning parenchymachanges that can be exacerbated by large quantities of dietary protein. Early work in animal models has demonstrated that dietary protein reduction leads to measurable falls in intrarenal pressure and thereby prolongs the survival of rats subjected to partial renal ablation. Similar benefits attributable to dietary manipulation have been observed in animal models of glomerulonephritis and systemic lupus erythematosus. Other mechanisms through which dietary protein reduction may improve renal survival have also been postulated. These include the suppression of immune mechanisms (including complement activation) involved in the primary disease process, the reduction of the work of ex-
creting ammonia and phosphorus, and the reduction of serum lipid concentrations. The obvious limitations of animal data have prompted a host of controlled and uncontrolled observations in the clinical setting, all representing attempts torelate dietary protein intake to the progression of renal disease in humans. Several issues affecting these clinical studies deserve mention. First, protein reduction has been examined by several approaches that specify differing quantities of protein, with or without supplemental essential amino acids or their ketoanalogues. As will be seen, study diets containing at least 0.6 gm!kg per day of protein have usually been prescribed without amino acid supplementation, whereas diets containing 0.3 to 0.4 gm/kg per day of protein have usually included amino acid ketoanalogues. Second, many studies have not included a control group of patients with unmodified diets. While the improvement on renal function tests observed in many of these uncontrolled studies may have been due to the diet, the effect of concomitant medical treatment cannot always be ruled out, nor can the possibility of misleading renal function findings. The rate of decline of (continues)
Downloaded by [The University Of Melbourne Libraries] at 09:13 22 June 2016
Low PRoTEIN
(continued)
the inverse of the serum creatinine level, used as a measure of the glomerular filtration rate in many of these studies, may fall after dietary intervention not because the GFR has stabilized but simply because the amount of ingested creatinine (found in cooked meat) has declined or because the patient's lean body mass has been reduced. Finally, aggregation of patients with diverse renal disorders into a single study may have obscured important relationships between diet and progression of renal dysfunction specific to particular types of kidney disease.
Available Evidence Several cohorts of patients with heterogeneous renal disease or diabetes have been placed on low-protein diets (0.6 gm/kg per day). In these groups, repeated measurement of serum creatinine has demonstrated an apparent reduction in the rate of decline of renal function. Diets containing 20 to 30 gm/day of protein supplemented by ketoanalogues of amino acids have also been administered in uncontrolled cohort studies of patients with various renal diseases. Again, the dietary intervention has been associated with preservation of renal function, as assessed by serum creatinine. The absence of adequate control groups greatly limits the interpretability of these studies, as does the use of serum creatinine as an index of renal function. To date, four randomized controlled clinical trials of protein restriction in chronic renal failure have also been performed. In the largest of these (Figure 1 }, Johan B. Rosman and colleagues in Switzerland, Ger(conttnues)
Figure 1. Four-year randomized controlled trial of dietary protein restriction for patients with chronic renal failure did not show universal benefit but did suggest that renal deterioration is slowed in some patients. Subjects with initial creatinine clearances of 31 to 60 ml/min ate either their usual diet or one with a protein content restricted to 0.6 gm/kg per day. For subjects with poorer initial clearance, the restriction was greater: 0.4 gm/kg per day. Creatinine clearance declined in parallel for the restricted-diet groups and their controls (top). However, a post-trial analysis found that patients with primary glomerular disease (bottom) had benefited. (Data of Rosman JB et al, 1989) Hospital Practice June 15, 1991
221
Once-a-day
Downloaded by [The University Of Melbourne Libraries] at 09:13 22 June 2016
HISMAnA[ (ASTEMIZOLE)r~g~~
Low
Before prescribing, please consult complete prescribing information of which the following is a brief summary. DESCRIPTION: HISMANAL® (astemizole) is a histamine H,-receptor antagonist available in scored white tablets for oral use. CONTRAINDICATIONS: HISMANAL is contraindicated in patients with known hypersensitivity to astemizole or any of the inactive ingredients. PRECAUTIONS: General: Caution should be given to potential anticholinergic (drying) effects in patients wrth lower airway diseases, including asthma. Caution should be used in patients with cirrhosis or other liver diseases (See Clinical Pharmacology section). HISMANAL does not appear to be dialyzable. Caution should also be used when treating patients with renal impairment. Information for Patients: Patients taking HISMANAL should receive the following information and instructions. Antihistamines are prescribed to reduce allergic symptoms. Patients should be questioned about pregnancy or lactation before starting HISMANAL therapy, since the drug should be used in pregnancy or lactation only if the potential benefit justifies the potential risk to fetus or baby (see Pregnancy subsection). Patients should be instructed 1) to take HISMANAL only as needed, 2) not to exceed the prescribed dose. and 3) to take HISMANAL on an empty stomach, e.g., at least 2 hours after a meal. No additional food should be taken for at least 1 hour post-dosing. Patients should also be instructed to store this medication in a tightly closed container in a cool, dry place, away from heat or direct sunlight, and away from children. Carcinogenesis, Mutagenesis, Impairment of Fertllltr: Carcinogenic potential has not been revealed in rats given 260x the recommended human dose of astemizole for 24 months, or in mice given 400x the recommended human dose for 18 months. Micronucleus, dominant lethal, sister chromatid exchange and Ames tests of astemizole have not revealed mutagenic activity. Impairment of fertility was not observed in male or female rats given 200x the recommended human dose. PregniRCJ: Pregnancr Catagorr C: Teratogenic effects were not observed in rats administered 200x the recommended human dose or in rabbits given 200x the recommended human dose. Maternal toxicity was seen in rabbits administered 200x the recommended human dose. Embryocidal effects accompanied by maternal toxicity were observed at 100x the recommended human dose in rats. Embryotoxicity or maternal toxicity was not observed in rats or rabbits administered 50x the recommended human dose. There are no adequate and well controlled studies in pregnant women. HISMANAL should be used during pregnancy only if the potential benefrt justifies the potential risk to the fetus. Metabolites may remain in the body for as long as 4 months after the end of dosing, calculated on the basis of 6 times the terminal half-life (See Clinical Pharmacology section). Nursing Mothers: It is not known whether this drug is excreted in human milk. Because certain drugs are known to be excreted in human milk, caution should be exercised when HISMANAL is administered to a nursing woman. HISMANAL is excreted in the milk of dogs. Pediatric Usa: Safety and efficacy in children under 12 years of age has not been demonstrated. ADVERSE REACTIONS: The reported incidences of adverse reactions listed in the following table are derived from controlled clinical studies in aduns. In these studies the usual maintenance dose of HISMANAL® (astemizole) was 10 mg once daily. Percent of Patients Reporting Controlled Studies*
ADVERSE EVENT Central Nervous System Drowsiness
Headache
Fatigue Appetite increase
Weight increase Nervousness Diuy
Hismanal
Placebo
Classical**
(N =1630) %
(N=1109) %
(N=304) %
7.1 6.7 4.2 3.9 3.6 2.1 2.0
6.4 9.2 1.6 1.4 0.7 1.2 1.8
22.0 3.3 11.8 0.0 1.0 0.3 1.0
2.5
2.9
1.3
Gastrointestinal System
Nausea
Diarrhea 1.8 2.0 0.7 Abdominal pain 1.4 1.2 0.7 Eye, Ear, Nose, and Throat Mouth dry 5.2 3.8 7.9 Pharyngitis 1.7 2.3 0.3 Conjunctivitis 1.2 1.2 0.7 Other Arthralgia 1.2 1.6 0.0 Durat1on of treatment 1n Controlled Stud1es ranged from 7 to 182 Days -*Classical Dru_gs: ~lemastine (N= 137); Chlorphemramme (N= 100); Pheniramine Maleate {N=47); d-Chlorphemramme {N = 20)
Adverse reaction information has been obtained from more than 7500 patients in all clinical trials. Weight gain has been reported in 3.6% of astemizole treated patients involved in controlled studies, with an average treatment duration of 53 days. In 46 of the 59 patients for whom actual weight gain data was available, the average weight gain was 3.2 kg. Less frequently occurring adverse experiences reported in clinical trials or spontaneously from marketing experience with HISMANAL include: angioedema, bronchospasm, depression, edema, epistaxis, myalgia, palpitation, photosensitivity, pruritus, and rash. Marketing experiences include isolated cases of convulsions. A causal relationship with HISMANAL has not been established. · OVERDOSAGE: In the event of overdosage, supportive measures including gastric lavage and emes1s should be employed. Cases of overdose have been reported from foreign marketing experrence. Anhough overdoses of up to 500 mg have been reported with no ill effects, cases of serious ventricular arrhythmias, including Torsades de pointes, following overdoses of greater than 200 mg have been reported. Patients should be carefully observed and EGG monitoring is recommended in cases of suspected overdose. An appropriate antiarrhythmic treatment may be needed. HISMANAL does not appear to be dialyzable. Care should be taken not to exceed dosing recommended in the DOSAGE AND ADMINISTRATION section. Oral LD 50 values for HISMANAL were 2052 mg/kg in mice and 3154 mg/kg in rats. In neonatal rats, the oral LD 50 was 905 mg/kg in males and 1235 mg/kg in females. NDC 50458-510-01 (10 X 10 blister) NDC 50458-510-10 (100 tablets) Store tablets at room temperature (59"-86"F) (15"-30"C). Protect from moisture. References: 1. Kn1ghl A Aslemllole-a new. non-sedatmg ant1h1stamine for haylever J Ototaryngol 198514(2)85-88 2. Howarlh PH. Holgate ST Comparalive tnal ol two non-sedaiiVe H1 ant1h1stammes. terfenadme and astemllole. for hay fever Thorax. 1984;39668-672
~D jt\~M~~~~~ I!' 40 Kingsbridge Road Piscataway, NJ 08855-3998
May 1991
December 1988 U.S. Patent 4,219,559 JPI-HS-103-2 1P41N98A-M
PROTEIN
(continued)
many, and the Netherlands studied 248 patients with various renal diagnoses. Half of the subjects were randomized to a diet including 0.4 or 0.6 gm/kg per day of protein. Mter two years of follow-up, renal function was found to be better in the low-protein group than in the subjects who had continued to consume their usual diet. The difference was statistically significant. A four-year analysis, however. failed to confirm the difference, except in a post-trial subgroup analysis of men and of patients with glomerulonephritis. J _Bergstrom and colleagues at the Karolinska Institute in Stockholm presented the results of a randomized clinical trial comparing usual diet to one containing 0.4 gm/kg per day of protein supplemented by 0.1 gm/kgper day of essential amino acids. They studied 57 patients with severe renal failure, all of whom had exhibited progression of renal dysfunction during a 12- or 24-month antecedent observation period. Only 28 patients completed the trial (which was as long as the preceding observation period had been). Evolution of renal function was documented by repeat measurements of the urinary clearance of EDTA labeled with radioactive chromium. The 51 Cr-EDTA clearance correlates well with the true GFR and is not directly affected by dietary protein intake. No effect of the dietary intervention was observed. However. lowering of blood pressure was found to be associated with a slower decline of renal function in both study groups. The failure of this trial to detect differences between the two groups may have been related to the small (continues)
224
Downloaded by [The University Of Melbourne Libraries] at 09:13 22 June 2016
Low
PROTEIN
(continued)
number of subjects and also, perhaps, to their advanced renal dysfunction by the time of enrollment. In 1989, Benno U. Ihle and colleagues at the Royal Melbourne Hospital reported the results of an Australian clinical trial of a diet incorporating 0.4 gm!kg per day of protein, as opposed to a usual diet, in 64 patients with initial serum creatinine levels between 4 and 11 rngtdl. Mter 18 months of follow-up, a significantly greater proportion of control patients had progressed to end-stage renal disease (27%, compared with 6% of the patients consuming a low-protein diet). This finding was mirrored by a drop in mean GFR (as measured by 51 Cr-EDTA clearance) that was significantly greater in the usual-diet group than in the restricted-diet subjects. Unfortunately, a number of problems-the short duration offallow-up, the advanced nature of renal dysfunction in study subjects, and imbalance in the underlying diagnoses between the two study groups-make it difficult to generalize these results to patients with mild or moderate renal insufficiency treated with dietary modification for many years. Finally, Kathleen Zeller and colleagues at the University of Texas Southwestern Medical Center at Dallas have recently reported a clinical trial involving 35 patients with insulin-dependent diabetes mellitus who were randomized to a diet containing 0.6 gm!kgper day of protein or to the usual diet (with the proviso that the usual diet include at least 1 gm!kgper day of protein). Although the actual protein intake by the restricted-diet group was 0. 72 gm/kg per day (as calculated from urinary excre-
tion of urea nitrogen), the investigators found a significant decline in the rate of reduction of GFR (as assessed by iothalamate clearance). This study had several limitations. In the control group, follow-up of a disproportionate number of patients was ended during the first year, owing to the development of end-stage renal disease. The disproportion raises important doubts about the comparability of the baseline renal function in the two study groups. Then, too, the investigators based their analysis on the slope of the decline of GFR, which in turn requires the assumption that the fall of GFR over time is linear. The brief follow-up of many of the study's patients made this assumption untestable.
Conclusions Despite the limitations of individual studies, evidence has accumulated indicating that protein restriction may reduce the rate of decline of renal function in patients with chronic renal insufficiency. Moreover, no evidence has surfaced thus far to suggest that protein restriction in the range of 0.6 gm/kg per day leads to malnutrition or other significant adverse outcomes. Al-
though numerous questions remain to be answered by future research, the institution of protein restriction in the range of 0. 6 gm/kg per day-with careful follow-up of nutritional status-appears to be a reasonable therapeutic approach for patients with mild to moderate renal insufficiency. We must, however, understand better the long-term efficacy of dietary protein reduction before we can embrace it as the standard of care. We must also learn how its efficacy is modified by the level of renal function and type of renal disease, and we must identify the risks, if any, that its institution entails. The Modification of Diet in Renal Disease Study, funded by the National Institutes of Health, promises better answers to those questions. It is a large, multicenter clinical trial of the efficacy of low- and very low protein diets in preventing the progression of renal failure. If we are able to demonstrate convincingly a sustained beneficial effect of dietary intervention, we will need to address the great challenge of devising strategies through which our patients can comply with dietary modification and sustain it for many years in the setting outside the artificial study environment. D
References Rosman JB et al: Protein-restricted diets in chronic renal failure: A four year follow-up shows limited indications. Kidney Int 36(suppl 27) :S96, 1989 Bergstrom J et al: Stockholm clinical study on progression of chronic renal failure: An interim report. Kidney Int 36(suppl 27) :SilO, 1989 Ihle BU et al: The effect of protein restriction on the progression of renal insufficiency. N Eng! J Med 321: 1773, 1989 Zeller K et al: Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Eng! J Med 324:78, 1991 Klahr S: The Modification of Diet In Renal Disease Study. N Eng! J Med 320:864, 1989
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