Intranasal beclomethasone dipropionate for perennial allergic rhinitis M.T. LIN, MD; C. COLLINS-WILLIAMS, MD, FRCP[C]
There have been several favourable reports from Europe of the efficacy of nasal inhalation of beclomethasone dipropionate in the treatment of hay fever,1'2 perennial allergic rhinitis in children3 and adults,4'5 and nasal polyps in adults.6 It has the advantage of not causing adrenal suppression.1'4'7 We conducted a double-blind crossover trial of therapy with beclomethasone dipropionate, using Beconase inhalers (Glaxo [Canada] Ltd., Toronto). Patients and methods
Patients A total of 34 children and young adults were studied - 24 males and 10 females. All suffered from chronic perennial allergic rhinitis and we excluded only those considered too young to take part in the trial. The ages ranged from 6 to 20 years (average, 12.8 years). The duration of rhinitis averaged 8 years. Methods The patients continued their usual medication under observation for 3 weeks before starting the 6-week trial. They then received placebo or used a Beconase inhaler for 3 weeks, and whichever they had not used for the other 3 weeks. The dosage of Beconase was 50 p.g qid for each nostril (daily total, 400 pg). Throughout the 9-week study period patients kept daily scores for nasal blockage, rhinorrhea and sneezing; they scored 0 for no symptoms, 1 for mild symptoms, 2 for moderate symptoms and 3 for severe symptoms. They also recorded the amount of antihistamines or other nasal medications used. Many of the patients were From the department of pediatrics (allergy division), The Hospital for Sick Children, Toronto and the department of pediatrics, University of Toronto Reprint requests to: Dr. M.T. Lin, Department of pediatrics (allergy division), The Hospital for Sick Children, 555 University Ave., Toronto, Ont. MSG 1X8
taking antihistamines but none were taking steroids orally. Objective indices included eosinophil counts of nasal mucus, the appearance of the nasal mucosa and pharynx, and nasal patency before and after each treatment period. Nasal smears for eosinophils were stained and were graded 0 to 4 according to Hansel's method.8 Nasal patency was assessed with a Wright peak-flow meter modified for connection to a transparent cushioned face-mask (Fig. 1). The patients blew into the meter three times through the mouth only and then three times
MUCH FIG. 1-Measurement of nasal resistance with modified Wright peak-flow meter.
through the nose only; the highest value of each of the three blows was recorded and the nasal blockage index9 (denoting nasal resistance) was calculated from the following equation: Blocking index = log . [ PEFR0-PEFR. ]
where PEFRO and PEFR. are oral and nasal peak expiratory flow rate, respectively. We discarded two of the objective indices for determining the therapeutic effect: eosinophil counts showed only minor variation and findings on clinical examination were difficult to assess accurately. Therefore, the effect of therapy was judged according to the symptom scores (including the amount of antihistamine consumed) and nasal patency, as follows: * Much improved: Increased nasal patency and decreased symptom scores. * Improved: Increased nasal patency or decreased symptom scores with some improvement in the other. 0 Slightly improved: No apparent increase in nasal patency or decrease
PATIENTS' CONDITION IMPROVED
+1ul
U
z
-0-
IU.'
NO CHANGE
IMPROVED
TITfl I
h
)
XI
z
z
-2-
)
0 C-
78LL 10
4
6 78 9101112
Liii
1234
NUMBER OF PATIENTS
U
12
Hiiii
123456
FIG. 2-Estimations of nasal resistance: initially (0); after 3 weeks' Beconase (beclomethasone dipropionate) therapy (A); and after 3 weeks of placebo therapy (X). CMA JOURNAL/APRIL 23, 1977/VOL. 116 895
Cu7®
brand of intrauterine copper
Indication - Intrauterine contraception. ContraIndications - Cu-7 is contraindicated in the presence of: Pregnancy or suspected pregnancy, abnormal uterine bleeding, bicornuate uterus, uterine hypoplasia, and otherabnormalities of the uterine cavity, uterine fibroids associated with menstrual disorders, active pelvic inflammatory disease, a history of pelvic inflammatory disease within the past three months or a history of repeated episodes of pelvic inflammatory disease, a history of postpartum endometritis or infected abortion within the previous three months, endometrial disease such as hyperplasia, polyps, malignancy or suspected uterine malignancy, dysplasia, suspected or proven carcinoma of the cervix, (papanicolaou smear Class Ill or IV), acute cervicitis, a history nf copper allergy, disorders of copper metabolism (Wilson's disease). Cu-7 should not be inserted within the two months immediately following delivery or abortion. Warnings - If perforation of the uterine wall is diagnosed or suspected during or at any time following insertion, the Cu-7 should be removed immediately. If penetration into the abdominal cavity occurs, laparotomy should be performed and the Cu-7 recovered. Local inflammatory reaction with abscess formation is a possibility ifs device is left in the abdomen. Persistent or excessive cramping or excessive bleeding may lecessitate the removal of the Cu-i. The Cu-i should be removed in cases of incomplete expulsion. Reinsertion of another Cu-i may be considered. In the extremely rare case of pregnancy in which the Cu-i has remained in utero, removal of the Cu-i may precipitate abortion. In dys p asia, suspected or proven carcinoma of the cervix (Papanicolaou smear C lass Ill or IV) the Cu-i should be removed. Precautions - Prior to insertion of Cu-i a thorough history and physical examination including a pelvic examination and Papanicolaou smear should be performed. It is advisable to insert Cu-i at the end of menstruation. Sterile technique should be adhered to during insertion of Cu-i. No undue force or pressure is required during proper insertion of Cu-i. Such force or pressure is unwarranted and may lead to complications. The hazard of uterus perforation can be reduced by sounding the uterus before insertion and by aligning the corpus and cervix by traction on a tenaculum. (The uterus should always be sounded prior to insertion.) If pelvic infection occurs which is unresponsive to treatment, consideration should be given to removal of the Cu-i. If treatment of persistent cervical erosion is not successful with conventional treatment, the Cu-i should be removed. The presence of metallic copper within the uterus should be taken into consideration prior to administration of short wave diathermy or ionizing radiation to the pelvic region. If any patient with a Cu-i suddenly develops overt clinical hepatitis or abnormal liver function tests, appropriate diagnostic procedures should be initiated. It is advisable to inform the patient that cramping, spotting or light bleeding may occur in the first several d.iys following insertion but if these symptoms continue or are severe she should contact her physician. The patient should be advised that should she become aware that the Cu-i has been expelled, she should contact her physician. The patient should be advised to periodically check the presence of the thread in the vagina. She should be cautioned, however, not to pull the thread. Should she be unable to locate the thread she should contact her physician. Should the physician be unable to locate the thread, the necessary diagnostic steps (uterine sounding, x-ray of the abdominal and pelvic cavity, installation of contrast material into the uterus if necessary) should be undertaken to localize the Cu-i. The patient should be advised to return to her physician at least yearly for Papanicolaou smear and follow-up examination. The Cu-i should be replaced every twenty-four months to ensure reliable contraception. Adverse Effects - Perforation of the uterus has occurred. Post insertion cramping, usually of no more than a few minutes duration may occur. However, a few women may experience this for several days and occasionally this cramping is more prolonged. Transient spotting, bleeding or prolongation of menstrual flow may occur in the first few cycles and occasionally these effects may persist longer. Uncommonly, pelvic infection has been reported. Complete or partial expulsion of the Cu-i occur in some patients particularly those with uteri measuring less than 6.5 cm by sounding. The following adverse reactions have been reported although their relation to the Cu-i has not been established. Amenorrhea or delayed menstruation, backache, cervical erosion, cystic masses in the pelvis, vaginitis, vaginal discharge, leg pain or soreness, weight loss or gain, nervousness, dyspareunia, cystitis. Packaging of the Cu-7- The Cu-i will be supplied as a single unit consisting of a labelled carton. Inside the carton will be a hermetically sealed (sterile) paperplastic bag. This bag contains a support card on which is mounted the Cu-i and the inserter. A package insert giving directions for use is contained within each carton. The entire package is disposable after the Cu-i is inserted.
Searle Pharmaceuticals Oakville, Ontario L6H 1M5
Table I-Effect of inhaled beclomethasone dipropionate (Beconase) in perennial allergic rhinitis, based on measurement of nasal patency plus symptom score Much improved 0 10 10
Therapy Placebo Beconase Total
Patients' condition; no. of patients Slightly improved Improved 0 6 4 12 4 18
No change 2 2
Table Il-Effect of Beconase on subjective indices in the 22 patients whose condition was improved or much improved
Therapeutic period Observation Placebo Beconase
Average daily total symptom score Sneezing Rhinorrhea Nasal obstruction Average Range Average Range Average Range 1.68 1.52 1.13
0.76-3.00 0.05-2.48 0-2.20
0.70 0.70 0.48
in symptom scores, but the patient preferred the active agent (felt better). * No change: No effect with placebo or Beconase. * Anomalous result: Increased nasal patency and decreased symptom scores with placebo only. Results The results of the trial are shown in Fig. 2 and Table I. In 26 of the 34 patients, Beconase increased nasal patency and relieved symptoms. The signs of improvement (Table II) were decreased nasal blockage, rhinorrhea and sneezing, usually becoming obvious on about the 5th to 7th day of treatment, decreased antihistamine intake and increased nasal patency. The nasal mucosa appeared to be less swollen with less mucus after the use of the Beconase inhaler, but the pallor remained unchanged. Initially, the nasal mucus grading was 3± for eosinophils in 33 cases and nasal smears showed fewer eosinophils in 7. Neither index changed significantly with treatment. Side effects of Beconase were negligible. Twelve patients noted increased sneezing and itching temporarily, but this occurred with the placebo also. One patient had transient, mild headache. Comment The use of transparent face-masks in measuring nasal patency ensured accuracy of the recorded values in this study since we could make certain that the patient's mouth was tightly closed when he blew through the nose only. We consider nasal patency a sensitive, objective index. In 26 patients all symptom scores improved after Beconase therapy, especially those for antihistamine intake
896 CMA JOURNAL/APRIL 23, 1977/VOL. 116
0-2.10 0-2.11 0-2.00
0.64 0.75 0.30
0-2.32 0-2.30 0-1.00
Antihistamine intake No. of doses Average Range 40 27 18
0-84 0-66 0-62
and sneezing, which decreased 55% and 53%, respectively. In two patients severe swelling of the turbinates was observed. Nasal patency in these two patients was zero throughout the trial and the failure of therapy presumably resulted from inability of the pressurized medication to reach the mucous membrane. In this circumstance, prior intranasal administration of a vasoconstrictor would probably produce better results than Beconase alone. This seems a logical addition to the treatment of patients with severe nasal obstruction; additional treatment was unacceptable in this trial but might have made the final results much better. Since Beconase took effect on approximately the 5th to 7th day of treatment we suggest that it should be used for at least this length of time before one decides it is not beneficial. References 1. MYGIND N: Local effect of intranasal beclomethasone dipropionate aerosol in hay fever. Br Med 14: 464, 1973 2. BROWN HM, STOREY G: Beclomethasone dipropionate aerosol in the treatment of seasonal asthma and hay fever. Clin Allergy 4: 331, 1974 3. SMITH JM, CLEGO RT, COOK N, et al: Intranasal beclomethasone dipropionate in allergic rhinitis. Br Med 1 2: 255, 1975 4. GiBSON GJ, MABERLY DJ, LAs 5, et al: Double-blind cross-over trial comparing intranasal beclomethasone dipropionate and placebo in perennial rhinitis. Br Med 1 4: 503, 1974 5. CHATTERJEE SS, NASSER WY, WILSON 0, et al: Intranasal beclomethasone dipropionate and intranasal sodium cromoglycate: a comparative trial Clin Allergy 4: 343, 1974 6. MYGIND N, PEDERSEN CB, PRYTZ S, et al: Treatment of nasal polyps with intranasal beclomethasone dipropionate aerosol. Clin Allergy 5: 159, 1975 7. HARRIS DM, MARTIN LE, HARRIsON C, et al: The effect of intranasal beclomethasone dipropionate on adrenal function. Clin Allergy 4: 291, 1974 8. HANSEL FK: Clinical Allergy, St. Louis, Mosby, 1953, p 403 9. TAYLOR G, PAm D, MAcNEIL AR, et al: Assessing degree of nasal patency by measuring peak expiratory flow rate through the nose. I Allergy Clin Immunol 52: 193, 1973
There have been several favourable reports from Europe of the efficacy of nasal inhalation of beclomethasone dipropionate in the treatment of hay fever,1'2 perennial allergic rhinitis in children3 and adults,4'5 and nasal polyps in adults.6 It has the advantage of not causing adrenal suppression.1'4'7 We conducted a double-blind crossover trial of therapy with beclomethasone dipropionate, using Beconase inhalers (Glaxo [Canada] Ltd., Toronto). Patients and methods
Patients A total of 34 children and young adults were studied - 24 males and 10 females. All suffered from chronic perennial allergic rhinitis and we excluded only those considered too young to take part in the trial. The ages ranged from 6 to 20 years (average, 12.8 years). The duration of rhinitis averaged 8 years. Methods The patients continued their usual medication under observation for 3 weeks before starting the 6-week trial. They then received placebo or used a Beconase inhaler for 3 weeks, and whichever they had not used for the other 3 weeks. The dosage of Beconase was 50 p.g qid for each nostril (daily total, 400 pg). Throughout the 9-week study period patients kept daily scores for nasal blockage, rhinorrhea and sneezing; they scored 0 for no symptoms, 1 for mild symptoms, 2 for moderate symptoms and 3 for severe symptoms. They also recorded the amount of antihistamines or other nasal medications used. Many of the patients were From the department of pediatrics (allergy division), The Hospital for Sick Children, Toronto and the department of pediatrics, University of Toronto Reprint requests to: Dr. M.T. Lin, Department of pediatrics (allergy division), The Hospital for Sick Children, 555 University Ave., Toronto, Ont. MSG 1X8
taking antihistamines but none were taking steroids orally. Objective indices included eosinophil counts of nasal mucus, the appearance of the nasal mucosa and pharynx, and nasal patency before and after each treatment period. Nasal smears for eosinophils were stained and were graded 0 to 4 according to Hansel's method.8 Nasal patency was assessed with a Wright peak-flow meter modified for connection to a transparent cushioned face-mask (Fig. 1). The patients blew into the meter three times through the mouth only and then three times
MUCH FIG. 1-Measurement of nasal resistance with modified Wright peak-flow meter.
through the nose only; the highest value of each of the three blows was recorded and the nasal blockage index9 (denoting nasal resistance) was calculated from the following equation: Blocking index = log . [ PEFR0-PEFR. ]
where PEFRO and PEFR. are oral and nasal peak expiratory flow rate, respectively. We discarded two of the objective indices for determining the therapeutic effect: eosinophil counts showed only minor variation and findings on clinical examination were difficult to assess accurately. Therefore, the effect of therapy was judged according to the symptom scores (including the amount of antihistamine consumed) and nasal patency, as follows: * Much improved: Increased nasal patency and decreased symptom scores. * Improved: Increased nasal patency or decreased symptom scores with some improvement in the other. 0 Slightly improved: No apparent increase in nasal patency or decrease
PATIENTS' CONDITION IMPROVED
+1ul
U
z
-0-
IU.'
NO CHANGE
IMPROVED
TITfl I
h
)
XI
z
z
-2-
)
0 C-
78LL 10
4
6 78 9101112
Liii
1234
NUMBER OF PATIENTS
U
12
Hiiii
123456
FIG. 2-Estimations of nasal resistance: initially (0); after 3 weeks' Beconase (beclomethasone dipropionate) therapy (A); and after 3 weeks of placebo therapy (X). CMA JOURNAL/APRIL 23, 1977/VOL. 116 895
Cu7®
brand of intrauterine copper
Indication - Intrauterine contraception. ContraIndications - Cu-7 is contraindicated in the presence of: Pregnancy or suspected pregnancy, abnormal uterine bleeding, bicornuate uterus, uterine hypoplasia, and otherabnormalities of the uterine cavity, uterine fibroids associated with menstrual disorders, active pelvic inflammatory disease, a history of pelvic inflammatory disease within the past three months or a history of repeated episodes of pelvic inflammatory disease, a history of postpartum endometritis or infected abortion within the previous three months, endometrial disease such as hyperplasia, polyps, malignancy or suspected uterine malignancy, dysplasia, suspected or proven carcinoma of the cervix, (papanicolaou smear Class Ill or IV), acute cervicitis, a history nf copper allergy, disorders of copper metabolism (Wilson's disease). Cu-7 should not be inserted within the two months immediately following delivery or abortion. Warnings - If perforation of the uterine wall is diagnosed or suspected during or at any time following insertion, the Cu-7 should be removed immediately. If penetration into the abdominal cavity occurs, laparotomy should be performed and the Cu-7 recovered. Local inflammatory reaction with abscess formation is a possibility ifs device is left in the abdomen. Persistent or excessive cramping or excessive bleeding may lecessitate the removal of the Cu-i. The Cu-i should be removed in cases of incomplete expulsion. Reinsertion of another Cu-i may be considered. In the extremely rare case of pregnancy in which the Cu-i has remained in utero, removal of the Cu-i may precipitate abortion. In dys p asia, suspected or proven carcinoma of the cervix (Papanicolaou smear C lass Ill or IV) the Cu-i should be removed. Precautions - Prior to insertion of Cu-i a thorough history and physical examination including a pelvic examination and Papanicolaou smear should be performed. It is advisable to insert Cu-i at the end of menstruation. Sterile technique should be adhered to during insertion of Cu-i. No undue force or pressure is required during proper insertion of Cu-i. Such force or pressure is unwarranted and may lead to complications. The hazard of uterus perforation can be reduced by sounding the uterus before insertion and by aligning the corpus and cervix by traction on a tenaculum. (The uterus should always be sounded prior to insertion.) If pelvic infection occurs which is unresponsive to treatment, consideration should be given to removal of the Cu-i. If treatment of persistent cervical erosion is not successful with conventional treatment, the Cu-i should be removed. The presence of metallic copper within the uterus should be taken into consideration prior to administration of short wave diathermy or ionizing radiation to the pelvic region. If any patient with a Cu-i suddenly develops overt clinical hepatitis or abnormal liver function tests, appropriate diagnostic procedures should be initiated. It is advisable to inform the patient that cramping, spotting or light bleeding may occur in the first several d.iys following insertion but if these symptoms continue or are severe she should contact her physician. The patient should be advised that should she become aware that the Cu-i has been expelled, she should contact her physician. The patient should be advised to periodically check the presence of the thread in the vagina. She should be cautioned, however, not to pull the thread. Should she be unable to locate the thread she should contact her physician. Should the physician be unable to locate the thread, the necessary diagnostic steps (uterine sounding, x-ray of the abdominal and pelvic cavity, installation of contrast material into the uterus if necessary) should be undertaken to localize the Cu-i. The patient should be advised to return to her physician at least yearly for Papanicolaou smear and follow-up examination. The Cu-i should be replaced every twenty-four months to ensure reliable contraception. Adverse Effects - Perforation of the uterus has occurred. Post insertion cramping, usually of no more than a few minutes duration may occur. However, a few women may experience this for several days and occasionally this cramping is more prolonged. Transient spotting, bleeding or prolongation of menstrual flow may occur in the first few cycles and occasionally these effects may persist longer. Uncommonly, pelvic infection has been reported. Complete or partial expulsion of the Cu-i occur in some patients particularly those with uteri measuring less than 6.5 cm by sounding. The following adverse reactions have been reported although their relation to the Cu-i has not been established. Amenorrhea or delayed menstruation, backache, cervical erosion, cystic masses in the pelvis, vaginitis, vaginal discharge, leg pain or soreness, weight loss or gain, nervousness, dyspareunia, cystitis. Packaging of the Cu-7- The Cu-i will be supplied as a single unit consisting of a labelled carton. Inside the carton will be a hermetically sealed (sterile) paperplastic bag. This bag contains a support card on which is mounted the Cu-i and the inserter. A package insert giving directions for use is contained within each carton. The entire package is disposable after the Cu-i is inserted.
Searle Pharmaceuticals Oakville, Ontario L6H 1M5
Table I-Effect of inhaled beclomethasone dipropionate (Beconase) in perennial allergic rhinitis, based on measurement of nasal patency plus symptom score Much improved 0 10 10
Therapy Placebo Beconase Total
Patients' condition; no. of patients Slightly improved Improved 0 6 4 12 4 18
No change 2 2
Table Il-Effect of Beconase on subjective indices in the 22 patients whose condition was improved or much improved
Therapeutic period Observation Placebo Beconase
Average daily total symptom score Sneezing Rhinorrhea Nasal obstruction Average Range Average Range Average Range 1.68 1.52 1.13
0.76-3.00 0.05-2.48 0-2.20
0.70 0.70 0.48
in symptom scores, but the patient preferred the active agent (felt better). * No change: No effect with placebo or Beconase. * Anomalous result: Increased nasal patency and decreased symptom scores with placebo only. Results The results of the trial are shown in Fig. 2 and Table I. In 26 of the 34 patients, Beconase increased nasal patency and relieved symptoms. The signs of improvement (Table II) were decreased nasal blockage, rhinorrhea and sneezing, usually becoming obvious on about the 5th to 7th day of treatment, decreased antihistamine intake and increased nasal patency. The nasal mucosa appeared to be less swollen with less mucus after the use of the Beconase inhaler, but the pallor remained unchanged. Initially, the nasal mucus grading was 3± for eosinophils in 33 cases and nasal smears showed fewer eosinophils in 7. Neither index changed significantly with treatment. Side effects of Beconase were negligible. Twelve patients noted increased sneezing and itching temporarily, but this occurred with the placebo also. One patient had transient, mild headache. Comment The use of transparent face-masks in measuring nasal patency ensured accuracy of the recorded values in this study since we could make certain that the patient's mouth was tightly closed when he blew through the nose only. We consider nasal patency a sensitive, objective index. In 26 patients all symptom scores improved after Beconase therapy, especially those for antihistamine intake
896 CMA JOURNAL/APRIL 23, 1977/VOL. 116
0-2.10 0-2.11 0-2.00
0.64 0.75 0.30
0-2.32 0-2.30 0-1.00
Antihistamine intake No. of doses Average Range 40 27 18
0-84 0-66 0-62
and sneezing, which decreased 55% and 53%, respectively. In two patients severe swelling of the turbinates was observed. Nasal patency in these two patients was zero throughout the trial and the failure of therapy presumably resulted from inability of the pressurized medication to reach the mucous membrane. In this circumstance, prior intranasal administration of a vasoconstrictor would probably produce better results than Beconase alone. This seems a logical addition to the treatment of patients with severe nasal obstruction; additional treatment was unacceptable in this trial but might have made the final results much better. Since Beconase took effect on approximately the 5th to 7th day of treatment we suggest that it should be used for at least this length of time before one decides it is not beneficial. References 1. MYGIND N: Local effect of intranasal beclomethasone dipropionate aerosol in hay fever. Br Med 14: 464, 1973 2. BROWN HM, STOREY G: Beclomethasone dipropionate aerosol in the treatment of seasonal asthma and hay fever. Clin Allergy 4: 331, 1974 3. SMITH JM, CLEGO RT, COOK N, et al: Intranasal beclomethasone dipropionate in allergic rhinitis. Br Med 1 2: 255, 1975 4. GiBSON GJ, MABERLY DJ, LAs 5, et al: Double-blind cross-over trial comparing intranasal beclomethasone dipropionate and placebo in perennial rhinitis. Br Med 1 4: 503, 1974 5. CHATTERJEE SS, NASSER WY, WILSON 0, et al: Intranasal beclomethasone dipropionate and intranasal sodium cromoglycate: a comparative trial Clin Allergy 4: 343, 1974 6. MYGIND N, PEDERSEN CB, PRYTZ S, et al: Treatment of nasal polyps with intranasal beclomethasone dipropionate aerosol. Clin Allergy 5: 159, 1975 7. HARRIS DM, MARTIN LE, HARRIsON C, et al: The effect of intranasal beclomethasone dipropionate on adrenal function. Clin Allergy 4: 291, 1974 8. HANSEL FK: Clinical Allergy, St. Louis, Mosby, 1953, p 403 9. TAYLOR G, PAm D, MAcNEIL AR, et al: Assessing degree of nasal patency by measuring peak expiratory flow rate through the nose. I Allergy Clin Immunol 52: 193, 1973
