Professional Drug Information > Nedocromil

Nedocromil (Inhalation-Local)

VA CLASSIFICATION
Primary: RE110
Secondary: RE190

Commonly used brand name(s): Tilade.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anti-inflammatory, nonsteroidal (inhalation)—

asthma prophylactic—

antiallergic (inhalation)—

Indications

Note: Bracketed information in the Indications section refers to indications that are not included in U.S. product labeling.

Accepted

Asthma, bronchial (prophylaxis) ^{67}—Nedocromil is indicated for prevention of airway inflammation and ^{37} bronchoconstriction in patients with bronchial asthma ^{32} who require daily therapy ^{56}. It may be used alone as primary therapy or with ^{{52} {53}} other asthma medications, such as bronchodilators and/or ^{{50} {55} {56}} corticosteroids. ^{32} In mild or moderate ^{63} asthma, nedocromil may be used instead of corticosteroids, inhaled or systemic. ^{{54} {67}}

[Bronchospasm (prophylaxis)]—Nedocromil is indicated for prevention of bronchospasm in patients with reversible obstructive airways disease. ^{{02} {38} {39} {40} {41} {51}} It may be used regularly ^{41} or occasionally ^{50} just ^{55} prior to an anticipated exposure to such provocation as inhaled allergens, ^{10} exercise, ^{12} cold air, ^{10} or atmospheric pollutants. ^{{02} {03} {15} {16} {21} {28} {36}}

Unaccepted
Nedocromil is not a bronchodilator and, therefore, is not indicated for the reversal or relief of acute bronchospasm, especially in status asthmaticus. ^{{02} {29} {32}}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Pyranoquinoline. ^{32}
Molecular weight—
    415.31 ^{{02} {32} {33}}

pKa—
    2 ^{{06} {10} {18}}

Mechanism of action/Effect:

Nedocromil inhibits activation and release of inflammatory mediators from a variety of cell types in the lumen and mucosa of the bronchial tree. ^{{02} {05} {36}} These mediators, which include the leukotrienes, histamine, and prostaglandins, are preformed or derived from arachidonic acid metabolism through the lipoxygenase and cyclo-oxygenase pathways. A range of human cells associated with asthma ^{32}, such as eosinophils, neutrophils, macrophages, monocytes, mast cells, and platelets, may be involved. ^{{04} {05} {13} {14} {17} {26} {27} {28} {29} {30} {34} {35} {36}} Nedocromil exhibits specific anti-inflammatory properties when administered directly ^{61} to the bronchial mucosa. ^{{02} {04} {28} {36}} It has demonstrated a significant inhibitory effect on allergen-induced early and late asthmatic reactions and on bronchial hyperresponsiveness. ^{{01} {10} {13} {18} {28} {36} {41}} Nedocromil may also affect sensory nerves in the lung. The mechanism of action of nedocromil may be due partly to inhibition of axon reflexes and release of sensory neuropeptides, such as substance P, neurokinin A, and calcitonin-gene–related peptides. The result is inhibition of bradykinin-induced bronchoconstriction. ^{05} Nedocromil does not posess any bronchodilator, antihistamine, or corticosteroid activity. ^{67} At recommended doses, inhaled nedocromil has no known systemic activity. ^{67}

Absorption:

The extent of absorption is about 7 to 9% of a single inhaled dose of 3.5 to 4 mg and 17% of multiple inhaled doses, with absorption largely from the respiratory tract. ^{{07} {55}}

Gastrointestinal tract—Although most of an inhaled dose of nedocromil is subsequently swallowed, only 2 to 3% of it is absorbed from the gastrointestinal tract. ^{{07} {55}}

Respiratory tract—5 to 6% of an inhaled dose of nedocromil is absorbed slowly ^{07} from the respiratory tract. ^{{02} {05} {06} {07} {28} {55}}

Distribution:

Distributed into plasma. With repeated dosing, nedocromil seems to exert a residual effect that allows for twice-a-day dosing for some patients. ^{{07} {62}}

Protein binding:

Approximately 89% is reversibly bound to plasma proteins when plasma concentrations range between 0.5 and 50 mcg/mL. ^{32}

Biotransformation:

Nedocromil is not metabolized. ^{{02} {05} {26} {32}}

Half-life:

Approximately 1.5 to 3.3 hours. ^{{07} {32} {36}}

Onset of action:

Nedocromil has been shown to prevent bronchospasm when administered up to 30 minutes before exposure to a chemical irritant, an allergen, or exercise. ^{{03} {05} {10} {28} {36} {41} {42}}

When nedocromil is used as maintenance therapy, clinical improvement in symptoms and lung function usually occurs within 2 to 4 weeks of the beginning of treatment. ^{{15} {28} {31} {32} {33} {36}} In some patients, improvement of symptoms can occur within a few days. ^{{15} {36} {41} {50}}

Time to peak concentration:

Following single-dose or multiple-dose inhalation—In asthmatic patients: 5 to 90 minutes. ^{{05} {32}}

Peak serum concentration

Following single-dose or multiple-dose inhalation—In asthmatic patients: 2.8 nanograms per mL. ^{{05} {07} {28} {32}}

Duration of action:

When a single dose is administered prior to an allergen challenge, nedocromil inhibits the late reactions of bronchoconstriction occurring 6 to 12 hours after provocation. ^{{10} {24} {41}}

Elimination:
    Rapidly excreted as unchanged drug, in the bile and urine. ^{{02} {07} {32}}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to fluorocarbons may be sensitive to the fluorocarbons, dichlorotetrafluoroethane and dichlorodifluoromethane, contained in this preparation. ^{{02} {40}}

Carcinogenicity/Mutagenicity

Various animal studies and in vitro studies using human cells showed no evidence of mutagenic or carcinogenic potential. ^{{02} {06} {32}}

Pregnancy/Reproduction
Fertility—
The results of fertility studies of nedocromil in rats and mice showed no effect on male or female fertility. ^{67}

Pregnancy—
Adequate and well controlled studies in humans have not been done.

In reproduction studies in rats and mice, small amounts of nedocromil crossed the placenta but did not cause teratogenic or embryotoxic effects. ^{{02} {06}}

FDA Pregnancy Category B. ^{32}

Breast-feeding

It is not known whether nedocromil is distributed into human breast milk ^{55}. However, problems in humans have not been documented. In animal studies, small amounts of nedocromil were distributed into milk but did not cause adverse effects. ^{{02} {32}}

Pediatrics

Appropriate studies have been performed in children 6 years of age and older, although data regarding use of nedocromil in treatment of childhood asthma remain limited to date. These studies have not demonstrated pediatrics-specific problems that would limit the usefulness of nedocromil in children. ^{{28} {36}} The types and frequency of side effects associated with nedocromil use in children were similar to those observed in adults. ^{67}

Nedocromil appeared to offset the increase of symptoms of asthma when used in pediatric patients who experience seasonal exacerbations of asthma. ^{67}


Geriatrics


No information is available on the relationship of age to the effects of nedocromil in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Nedocromil has not shown an increase in frequency of adverse reactions or lab abnormalities with concomittant use of other anti-asthma medications, such as inhaled or oral bronchodilators, or inhaled corticosteriods; however, no formal drug interaction studies have been conducted. ^{67}


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problem exists
Sensitivity to nedocromil


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Abdominal pain^{67}
    
bronchospasm, increased ^{32}{36}(increased wheezing, tightness in chest, or difficulty in breathing)—may be due to sensitivity to nedocromil or fluorocarbon propellants^{02}{32}

Incidence rare
    
Arthritis^{67} (pain, stiffness, or swelling of joints)
    
neutropenia or leukopenia (signs of infection, such as fever, sore throat, body aches, or chills)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
—(about 4 to 7%)    
Cough ^{32}{36}
    
headache ^{32}{36}
    
nausea or vomiting ^{32}{36}
    
rhinitis ^{36}{55}{62}(runny or stuffy nose)
    
throat irritation ^{{02}{12}{25}{32}{36}}

Incidence rare
    
Sensation of warmth^{67}
    
tremor^{67}



Those not indicating need for medical attention
Incidence more frequent
—(about 12% or more)    
Unpleasant taste after inhalation ^{{02}{32}{36}{62}}





Overdose

Clinical effects of overdose
Overdosage of necrodomil is unlikely to result in any clinical manifestations which would require more than the observation of the patient and discontinuation of the medication where appropriate. ^{67}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Nedocromil (Inhalation).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to nedocromil

Proper use of this medication
» Helps prevent, but does not relieve, acute attacks of asthma or bronchospasm

Reading patient instructions carefully before using

Using metered dose inhaler; checking periodically with doctor, nurse, or pharmacist for proper use of inhaler to prevent incorrect dosage

Priming inhaler with three actuations before using for the first time or if inhaler has not been used for more than seven days

Proper administration technique

» Proper dosing
Importance of not increasing or decreasing dose without physician's supervision

Proper administration technique if spacer device used

Proper cleaning procedure for inhaler
Missed dose: If used regularly, using as soon as possible; using any remaining doses for that day at regularly spaced intervals

» Proper storage
Importance of storing canister at room temperature before use for best results

Keeping out of the reach of children

For patients on scheduled dosing regimen
» Compliance with therapy; 2 to 4 weeks usually required for maximum therapeutic benefit after the beginning of nedocromil therapy

Precautions while using this medication
» Checking with physician if symptoms do not improve within 2 to 4 weeks; checking with physician immediately if condition becomes worse

» Importance of not discontinuing any concurrent antiasthmatic medication without physician's advice

Gargling or rinsing mouth after inhalation to relieve throat irritation and unpleasant taste


Side/adverse effects
Signs of potential side effects, especially abdominal pain, increased bronchospasm, arthritis, or neutropenia or leukopenia


General Dosing Information
In maintenance therapy, nedocromil must be used regularly, even during symptom-free periods, to achieve benefit. ^{32}

It is essential that patients be properly instructed in the use of the inhaler, and that the correct method be reinforced periodically. ^{32}

A decrease in severity of clinical symptoms or in the need for concomitant therapy is a sign of improvement that usually will be evident in the first 2 to 4 weeks of therapy if patient responds to nedocromil therapy. ^{{15} {28} {32} {36}}

After a patient becomes stabilized on nedocromil, the frequency of administration may be slowly decreased to a frequency that maintains freedom from exacerbations of asthma. ^{{20} {28} {32}} The frequency of administration is usually no less than twice a day. ^{64}

When nedocromil is added to an existing regimen of bronchodilators and/or inhaled or systemic corticosteroids, a reduction in dosage of the corticosteroid or bronchodilator may be achieved in some patients. ^{{08} {15} {25} {31} {32}} However, the reduction should be gradual and under close medical supervision to avoid an exacerbation of asthma ^{{25} {32}}, since nedocromil has a very limited capacity to effectively substitute for inhaled or systemic corticosteroids. ^{54}

Nedocromil therapy should be continued during acute exacerbations, unless the patient becomes intolerant to the use of inhaled dosage forms. ^{67}

When nedocromil is added to as-needed usage of beta ₂-adrenergic bronchodilators, symptom control and pulmonary function improve after approximately 2 weeks of therapy. ^{67}

Studies were conducted comparing both two-times-a-day and four-times-a-day nedocromil dosing regimens. The medication was found to be more effective when used four times a day; however, if good control of symptoms has been maintained on the four-times-daily regimen, a less frequent dosing schedule may be considered. ^{67}

Nedocromil inhaler requires priming with three actuations before the initial use and when the inhaler has not been used for more than 7 days. ^{69}

For treatment of adverse effects
Recommended treatment consists of the following:    • Discontinue nedocromil and substitute alternative therapy if bronchospasm occurs after administration of nedocromil. ^{67}



Inhalation Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

NEDOCROMIL INHALATION AEROSOL

Usual adult and adolescent dose
Asthma, bronchial (prophylaxis)
Oral inhalation, 3.5 or 4 mg (2 inhalations) four times a day at regular intervals. Dosage frequency may be reduced to three times a day and then two times a day when patient's asthma is under good control. ^{{02} {21} {28} {32} {36} {43}}

[Bronchospasm (prophylaxis)]
Oral inhalation, 4 mg (2 inhalations) as a single dose up to thirty minutes before exercise or exposure to any precipitating factor. ^{{02} {09} {11} {12} {19} {21} {36}}


Usual adult prescribing limits
14 mg or 16 mg of nedocromil per twenty-four-hour period (2 inhalations four times daily at evenly spaced intervals). ^{67}

Note: If the patient's asthma is well-controlled, as demonstrated by the absence of serious exacerbations and only occasional use of inhaled or oral beta ₂-adrenergic bronchodilators, a less frequent dosing schedule may be effective. ^{67}


Usual pediatric dose
Children up to 6 years of age: Safety and efficacy have not been established. ^{67}
Children 6 years of age and older: See Usual adult and adolescent dose .

Usual geriatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


1.75 mg per metered spray (Rx) [Tilade^{67}]

Note: Each 16.2 gm canister contains 210 gm of nedocromil and provides 104 actuations. Use of the inhaler should not exceed 104 actuations as the dose may be inaccurate for subsequent doses. ^{67}


Canada—


2 mg per metered spray (Rx) [Tilade^{68}]

Note: Each 17 mL canister contains 112 actuations. ^{68}
In Canada, metered dose inhalers are labeled according to the amount of nedocromil delivered at the valve; in the U.S., metered dose inhalers are labeled according to the amount of nedocromil delivered at the mouthpiece or actuator. Therefore, 2 mg of nedocromil delivered at the valve is equivalent to 1.75 mg delivered at the mouthpiece. ^{{36} {49}}


Packaging and storage:
Store between 2 and 30 °C (36 and 86 °F), unless otherwise specified by manufacturer. ^{67} Protect from freezing. ^{67}

Canister contents are under pressure, therefore the canister should not be punctured, incinerated, or placed near sources of heat. The product should not be exposed to temperatures above 49 °C (120 ° F). ^{67}

Auxiliary labeling:
   • For oral inhalation only.
   • Shake well before using.
   • Store away from heat and direct sunlight.
   • Do not use with other mouthpieces. ^{66}

Note: Include patient instructions when dispensing.
Demonstrate inhalation technique to patient when dispensing.


Additional information:
This product contains dichlorotetrafluoroethane and dichlorodifluoromethane, substances that harm public health and the environment by destroying ozone in the upper atmosphere. ^{32}

Revised: 06/14/1999

References

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2. Tilade product monograph (Fisons—Canada), Rev 1/16/91, Rec 3/20/91.
   

3. Dixon CMS, Ind PW. Inhaled sodium metabisulphite induced bronchoconstriction: inhibition by nedocromil sodium and sodium cromoglycate. Br J Clin Pharmacol 1990; 30: 371-6.
   

4. Rainey DK. Evidence for the anti-inflammatory activity of nedocromil sodium [editorial]. Clin Exp Allergy 1992; 22: 976-9.
   

5. Gonzalez JP, Brogden RN. Nedocromil sodium: a primary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of reversible obstructive airways disease. Adis Drug Information Services, Manchester Auckland 1987 Nov; 34: 560-77.
   

6. Ruggieri F, Patalano F. Nedocromil sodium: a review of clinical studies. Eur Respir J 1989; Suppl 6: 568-75.
   

7. Neale MG, Brown K, Foulds RA, et al. The pharmacokinetics of nedocromil sodium, a new drug for the treatment of reversible obstructive airways disease, in human volunteers and patients with reversible obstructive airway disease. Br J Clin Pharmacol 1987 Oct; 24: 493-501.
   

8. Williams HN. Multi-center clinical trial of nedocromil sodium in reversible obstructive airways disease in adults. Curr Med Res Opin 1989; 11: 417-26.
   

9. Nair N, Hopp RJ, Townley R. Effect of nedocromil on antigen-induced bronchoconstriction in asthmatic subjects. Ann Allergy 1989 April; 62: 329-31.
   

10. Aalbers R, Kauffman HF, Groen H, Koeter GH, Demonchy JGR. The effect of nedocromil on the early and late reaction and allergen-induced bronchial hyperresponsiveness. J Allergy Clin Immunol 1991 May; 993-1001.
    

11. Greif J, Fink G, Smorzik Y, Topilsky M, Bruderman I, Spitzer SA. Nedocromil sodium and placebo in the treatment of bronchial asthma. A multicenter, double-blind, parallel-group comparison. Chest 1989 Sept; 96(3): 583-8.
    

12. Morton AR, Ogle SL, Fitch KD. Effects of nedocromil sodium, cromolyn sodium, and a placebo in exercise-induced asthma. Ann Allergy 1992 Feb; 68: 143-8.
    

13. Richards R, Phillips GD, Holgate ST. Nedocromil sodium is more potent than sodium cromoglycate against AMP-induced bronchoconstriction in atopic asthmatic subjects. Clin Exp Allergy 1989; 19: 285-91.
    

14. Auty RM. The clinical development of a new agent for the treatment of airway inflammation, nedocromil sodium. Eur J Resp Dis 1986; 69: 120-31.
    

15. Cherniack RM, Wasserman SI, Ramsdell JW, et al. A double-blind multicenter group comparative study of the efficacy and safety of nedocromil sodium in the management of asthma. Chest 1990; 97: 1299-1306.
    

16. Holgate ST. Clinical evaluation of nedocromil sodium in asthma. Eur J Respir Dis 1986; 69: 149-59.
    

17. White MV, Phillips RL, Kaliner MA. Neutrophils and mast cells: nedocromil sodium inhibits the generation of neutrophil-derived histamine-releasing activity. J Allergy Clin Immunol 1991 Apr; 87(4): 812-20.
    

18. Church MK. Reassessment of mast cell stabilizers in the treatment of respiratory disease. Ann Allergy 1989 Mar; 62: 215-9.
    

19. Carrasco E, Sepulveda R. The acceptability, safety, and efficacy of nedocromil sodium in long-term clinical use in patients with perennial asthma. J Int Med Res 1988 Sept-Oct; 16: 394-401.
    

20. Boulet LP, Cartier A, Cockroft DW, et al. Tolerance to reduction of oral steroid dosage in severely asthmatic patients receiving nedocromil sodium. Respir Med 1990; 84: 317-23.
    

21. Robuschi M, Vaghi A, Simone P, Bianco S. Prevention of fog-induced bronchospasm by nedocromil sodium. Clin Allergy 1987 Jan; 17: 69-74.
    

22. Tilade package/container label (Fisons—Canada), Rev 1/16/91, Rec 3/20/91.
    

23. Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993. p. 1227-8.
    

24. Fyans AG, Chatterjee PC, Chatterjee SS. Effects of adding nedocromil sodium (Tilade) to the routine therapy of patients with bronchial asthma. Clin Exp Allergy 1989 Sep; 19(5): 521-8.
    

25. Holgate ST. Clinical evaluation of nedocromil sodium in asthma. Br J Clin Pract Symp Suppl 1987 Nov; 53: 13-21.
    

26. Parish RC, Miller LJ. Nedocromil sodium. Ann Pharmacother 1993; 27: 599-606.
    

27. Joseph M, Rainey DK. Recherches fondamentales sur le nedocromil de sodium. Rev Mal Respir 1992; 9 (suppl 1): R93-R97.
    

28. Brogden RN, Sorkin EM. Nedocromil sodium. An updated review of its pharmacological properties and therapeutic efficacy in asthma. Drugs 1993; 45(5): 693-715.
    

29. Bruijnzeel PL, Warringa RA, Kok PT. Inhibition of platelet-activating factor-and-zymosen-activated serum-induced chemotaxis of human neutrophils by nedocromil sodium, BN 52021 and sodium cromoglycate. Br J Pharmacol 1989; 97: 1251-7.
    

30. Pearce FL. Effect of nedocromil sodium on mediator release from mast cells. J Allergy Clin Immunol 1993; 92: 155-8.
    

31. Callaghan B, Teo NC, Clancy L. Effects of the addition of nedocromil sodium to maintenance bronchodilator therapy in the management of chronic asthma. Chest 1992 Mar; 101: 787-92.
    

32. Tilade package insert (Fisons—US), Rev 4/16/93, Rec 6/14/93.
    

33. Panel comment, 9/1/93.
    

34. Bruijnzeel PLB, Warringa RAJ, Kok PTM, et al. Effects of nedocromil sodium on in vitro induced migration, activation, and mediator release from human granulocytes. J Allergy Clin Immunol 1993; 92: 159-64.
    

35. Joseph MJ, Tsicopoulos A, Tonnel A-B, Capron A. Modulation by nedocromil sodium of immunologic and nonimmunologic activation of monocytes, macrophages, and platelets. J Allergy Clin Immunol 1993; 92: 165-70.
    

36. Panel comment, 8/30/93.
    

37. Panel comment, 8/30/93.
    

38. Panel comment, 8/30/93.
    

39. Panel comment, 8/26/93.
    

40. Panel comment, 8/26/93.
    

41. Panel comment, 8/31/93.
    

42. Panel comment, 9/7/93.
    

43. Panel comment, 8/30/93.
    

44. Panel comment, 8/27/93.
    

45. Panel comment, 9/1/93.
    

46. Panel comment, 8/27/93.
    

47. Panel comment, 8/30/93.
    

48. Panel comment, 8/23/93.
    

49. Zehetner W. Suggested Canadian in vitro requirements for MDIs. Highlights metered-dose inhaler workshop. Ottawa 1990 February 19: 11-2.
    

50. Panel comment, 10/13/93.
    

51. Panel comment, 10/3/93.
    

52. Panel comment, 10/4/93.
    

53. Panel comment, 10/6/93.
    

54. Panel comment, 10/8/93.
    

55. Panel comment, 10/26/93.
    

56. Panel comment, 10/26/93.
    

57. Panel comment, 11/16/93.
    

58. Panel Comment, 11/19/93.
    

59. Panel Comment, 11/20/93.
    

60. Panel Comment, 10/11/93.
    

61. Panel Comment11/20/93.
    

62. Panel Comment, 12/3/93.
    

63. Panel comment, 4/18/94.
    

64. Panel comment, 4/13/94.
    

65. Panel comment, 4/18/94.
    

66. Panel comment, 5/27/94.
    

67. Tilade package insert (Rhone-Poulenc Rorer—US), Rev 7/97, Rec 5/98.
    

68. Tilade (Rhone-Poulenc Rorer). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 1678.
    

69. Tilade package insert (Rhone-Poulenc Rorer—US), Rev 4/98, Rec 7/98.
    

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