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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 141-054 IVOMEC® Premix for Swine, Type A Medicated Article and LINCOMIX® Premix, Type A Medicated Article - original approval

Approval Date: March 28, 1996

I. GENERAL INFORMATION:

NADA 141-054
Sponsor: Merck Research Laboratories
Division of Merck & Co., Inc.
P. O. Box 2000
Rahway, New Jersey 07065
Generic Name: Ivermectin and lincomycin
Trade Name: IVOMEC® Premix for Swine, Type A Medicated Article and LINCOMIX® Premix, Type A Medicated Article
Marketing Status: Over the Counter (OTC)

 

II. INDICATIONS FOR USE

Ivermectin:

For the treatment and control of gastrointestinal roundworms (Ascaris suum, adults and fourth-stage larvae; Ascarops strongylina, adults; Hyostrongylus rubidus, adults and fourth-stage larvae; Oesophagostomum spp., adults and fourth-stage larvae), kidneyworms (Stephanurus dentatus, adults and fourth-stage larvae), lungworms (Metastrongylus spp., adults), lice (Haematopinus suis) and mange mites (Sarcoptes scabiei var. suis).

Lincomycin:

  • Increased rate of weight gain in growing-finishing swine.
  • For control of swine dysentery; for use in swine on premises with a history of swine dysentery, but where symptoms have not yet occurred.
  • For treatment and control of swine dysentery.
  • For reduction in the severity of swine mycoplasmal pneumonia caused by Mycoplasma hyopneumoniae.

 

III. DOSAGE FORM, ROUTE OF ADMINISTRATION, AND RECOMMENDED DOSAGE

The route of administration is oral using a Type C medicated feed dosage form. Ivermectin and lincomycin are marketed as separate Type A medicated articles.

IVOMEC Premix for Swine, Type A Medicated Article, contains 0.6% ivermectin and is added to starter, grower and finisher feeds at 300 g/ton to supply 1.8 g ivermectin per ton (2 ppm) of Type C medicated feed. This feed provides approximately 100 mcg of ivermectin per kg of bodyweight per day. Lincomycin Type A Medicated Article is sold in two concentrations of 20 and 50 grams of lincomycin per pound for preparing Type C medicated feeds at the following recommended dosages.

20 g/ton: For increased rate of gain in growing-finishing swine.

40 g/ton: For control of swine dysentery. For use in swine on premises with a history of swine dysentery, but where symptoms have not yet occurred.

100 g/ton; 40 g/ton: For treatment and control of swine dysentery.

100 g/ton: For treatment of swine dysentery.

200 g/ton: For reduction in the severity of swine mycoplasmal pneumonia caused by Mycoplasma hyopneumoniae.

The resultant feed containing both drugs is then fed as the only feed for durations as specified in 21CFR 558.300 for ivermectin and 21CFR 558.325 for lincomycin, but not for more than seven consecutive days which is the recommended duration for ivermectin. Feed containing ivermectin at 1.8 g/ton and lincomycin at either 20 g/ton or 40 g/ton must be withdrawn 5 days prior to slaughter. Feed containing ivermectin at 1.8 g/ton and lincomycin at either 100 g/ton or 200 g/ton must be withdrawn 6 days prior to slaughter.

 

IV. EFFECTIVENESS

IVERMECTIN:

The efficacy data for ivermectin alone are located in NADA 140-974 FEDERAL REGISTER, November 3, 1993 (58FR 58653).

a. Type of Study:

A trial (ASR 14354) was conducted to evaluate the efficacy of ivermectin, in the presence of lincomycin, against endoparasites.

b. Investigator:

Dr. J. E. Holste
Merck Research Farm
6498 Jade Road
Fulton, Missouri 65251

c. General Design: Forty-eight crossbred piglets were used. There were four treatment groups as follows: nonmedicated control; ivermectin in feed at 2 ppm (1.8 g/ton) from Day 7 to 14; lincomycin in feed at 200 g/ton from Day -7 to 14; and ivermectin in feed at 2 ppm from Day 7 to 14, plus lincomycin at 200 g/ton from Day -7 to 14. For each treatment group, there were six pens of 2 pigs each. On Day -49, each animal was orally administered approximately 20,000 infective larvae of Oesophagostomum spp. The animals were necropsied by replicate for worm counting on Days 28 or 29.

d. Conclusion:

The numbers of adult Oesophagostomum spp. were reduced 100% in the animals given ivermectin either alone or in combination with lincomycin (p > 0.01). The effect of lincomycin and the interaction of lincomycin and ivermectin were not significant (p > 0.10).

(Eds note: The following table consists of 4 columns).

Table 1. Reduction of counts of Oesophagostomum spp. in pigs given feed containing ivermectin, lincomycin or a combination of ivermectin and lincomycin.

______________________________________________________________________________________                                                                                          
                                        Reduction Compared to Control                      
                                ______________________________________________________                                                      
                                                                        Ivermectin(a)        
Nematode                        Ivermectin(a)       Lincomycin(b)       Lincomycin(b)        
______________________________________________________________________________________                                                                                       
Oesophagostomum spp., (Ad)          100%               18.2%                100%           
______________________________________________________________________________________                                                                                      

(Ad) = adults
(a) 2 ppm (1.8 g/ton) in feed Days 7 to 14
(b) 200 g/ton in feed Days -7 to 14

e. Adverse Reactions: None

f. Special Issues:

None

LINCOMYCIN:

Pivotal Dose Confirmation Non-Interference Clinical Study

a. Type of Study:

Assessment of lincomycin efficacy in swine diets at 100 g/ton for 14 days when used in combination with ivermectin at 1.8 g/ton for the first seven days for the treatment of induced swine dysentery.

b. Investigators:

R.A. Rzepkowski, Study Director
Animal Health Therapeutics Research, Unit 7923
The Upjohn Company.

R.J. Yancey, Jr., Study Supervisor
Animal Health Therapeutics Research, Unit 7923
The Upjohn Company.

c. General Design: * Purpose of Study: To compare in feed the efficacy of lincomycin and ivermectin alone or in combination for the treatment of induced swine dysentery.

* Test Animals: Test animals were representative samples from the population for which these products are intended. Ninety-six (96) crossbred pigs (42 gilts, 54 barrows) that averaged 64 days of age and 50 lb in weight were allotted to four treatment groups (24 pigs/treatment). To induce swine dysentery, each pig received two 100 mL oral doses (24 h interval) of a broth culture containing Serpulina hyodysenteriae.

The experiment design is illustrated in Table 2.

(Eds note: The following table consists of 5 columns).

Table 2. Experimental design for pigs with experimentally induced swine dysentery.

_________________________________________________________________________________

                                No. of           No. of           No. of   
Group     Treatment            Pigs/Group       Pens/Group       Pigs/Pen
_________________________________________________________________________________                                                
A         Combination(ab)         24               12               2                
B         Control(c)              24               12               2                
C         Ivermectin(b)           24               12               2                
D         Lincomycin(a)           24               12               2                
_________________________________________________________________________________                                               

(a)Lincomycin at 110 mg/kg (100 g/ton) of feed.
(b)Ivermectin at 2 mg/kg (1.8 g/ton) of feed.
(c)Non-medicated swine feed.

  • Controls: A non-medicated infected control group was included in the study. Treatments and controls were randomly assigned to pens within the 12 blocks of eight pigs each. All personnel conducting the study were unaware of the medications in the feed for treatments A, B, C and D. * Diagnosis: A trained technician diagnosed swine dysentery based on the clinical signs of diarrhea, dysentery and shedding of S. hyodysenteriae in the feces. Treatment was initiated in each group when at least 50% of the pigs were shedding S. hyodysenteriae and at least 25% of the pigs were exhibiting bloody feces.
  • Dosage Forms: LINCOMIX® 50 and IVOMEC® Premixes for swine were mixed into the basal diet at the described levels to produce the medicated feeds.
  • Route of Administration: Orally via medicated feed.
  • Dosages Used:

    Group A:
    Medicated feed containing 110 mg lincomycin plus 2 mg ivermectin per kg feed (100 g lincomycin and 1.8 g ivermectin per ton of feed).

    Group B:
    Unmedicated swine grower diet.

    Group C:
    Medicated feed containing 2 mg ivermectin per kg feed (1.8 g/ton).

    Group D:
    Medicated feed containing 110 mg lincomycin per kg feed (100 g/ton).

  • Test Duration: Twenty-eight (28) day combined treatment and observation period.
  • Pertinent Parameters Measured: Mortality, survival days, dysenteric days, physical activity, and spirochetal shedding days were the pertinent parameters measured.
  • Decision Variables: Percent dysenteric days and percent shedding of S. hyodysenteriae were the primary decision variables.

d. Statistical Analysis:

Statistical analysis was performed on an experimental unit (pen) basis using Type III sums of squares from the general linear models (GLM) procedure of SAS® according to the analysis of variance described in Table 3. The percentages were expressed as pen percentages and a test of normality of the residuals was performed using Wilks' W statistic (alpha= 0.05). The homogeneity of the elements of the test terms was tested using Levene's test at alpha = 0.01.

(Eds note: The following table consists of 9 columns).

Table. 3. Description of source of variation, degrees of freedom (DF) and test term for statistical analysis of treatment effects, and mean squares (MS), F-values (F) and P-values (P) for the significance tests of treatment effects for the two variables used to evaluate the combination feed.

_________________________________________________________________________________
Source       DF    Test Term   Percent Dysenteric            Percent Spirochetal              
                               Days                          Shedding Days  
                               __________________________________________________                  
                               MS       F       P        MS        F       P   
_________________________________________________________________________________
Block        11                49.11    0.78    0.655    46.41     0.28    0.985    
Treatment    3     Residual    328.28   5.23    0.005    1441.67   8.81    0.001    
Residual     33                62.75                     163.72                     
_________________________________________________________________________________

e. Results: The results are presented in Table 4.

(Eds note: The following table consists of 5 columns).

Table 4. Overall means (1,2) of variables by treatment for pigs challenged with Serpulina hyodysenteriae.

________________________________________________________________________________
Variable                 Treatment Groups      
                         _______________________________________________________                 
                         A Combination   B Control   C Ivermectin   D Lincomycin    
________________________________________________________________________________
Percent Mortality            4.2             4.2          4.2            0.0             
Percent Survival Days       96.0            96.0         97.9          100             
Percent Dysenteric Days      8.0a           16.6b        17.5b           8.0a            
Percent Spirochetal         12.4a           28.4b        34.7b          13.8a           
Shedding Days                                                                     
________________________________________________________________________________

1 For all variables except Percent Dysenteric Days and Percent Spirochetal Shedding Days, means indicated are arithmetic means calculated with the pens as the experimental units. Least Squares Means are given for Percent Dysenteric Days and Percent Spirochetal Shedding Days.
2 Significant differences (p < 0.05) among treatment means on each row are indicated with differing superscripts.

f. Conclusions:

These results show that the addition of ivermectin to lincomycin-containing feed did not interfere with the efficacy of lincomycin as therapy for swine dysentery.

g. Adverse Reactions:

None.

h. Special Issues:

None.

Effectiveness Study:

Lincomycin added at the rate of 200 g of lincomycin per 2000 lb of feed is approved as therapy to reduce the severity of lesions caused by Mycoplasma hyopneumoniae in swine. The purpose of this study was to evaluate the in vitro antimicrobial activity of lincomycin and ivermectin, alone and in combination, against strains of M. hyopneumoniae.

The in vitro activity of lincomycin and ivermectin, alone and in combination, against 15 strains of M. hyopneumoniae was determined. In addition, the effect of the glycerol-formal solvent used for ivermectin reference standard on the activity of lincomycin was tested. Against the strains tested, ivermectin was not active with minimum inhibitory concentrations (MIC) for all isolates > 32.0 ug/mL. Lincomycin, lincomycin/ivermectin at a 3.1:1 (w/w) ratio, lincomycin/ivermectin at a 10:1 (w/w) ratio; and lincomycin dissolved in the glycerol-formal ivermectin solvent all yielded MIC values of (< or =) 0.5 ug/mL for all the strains tested. Lincomycin, lincomycin/ivermectin at a 3.1:1 (w/w) ratio, and lincomycin/ivermectin at a 10:1 (w/w) ratio were chosen because they reflect the range of in vivo blood concentrations foe each drug. The MIC values for lincomycin alone and in combination with ivermectin and the solvent, were within one serial dilution with all the strains tested. These results suggest that combining ivermectin with lincomycin does not affect the in vitro activity of lincomycin against M. hyopneumoniae. Table 5 summarizes these data.

Table 5. Summary of minimum inhibitory concentrations (MICs) results obtained with isolates of M. hyopneumoniae against lincomycin and ivermectin, alone and in combination.

Antimicrobial                     MIC Range (ug/mL)  
_____________                     _________________   
Lincomycin                 (< or =) 0.03-0.5                    
L/I 3.1:1(a)                        0.06-0.5                                   
L/I 10:1(b)                (< or =) 0.03-0.5                    
Ivermectin                        > 32.0                                      
L/GF(c)                           < 0.03-0.5                                  
_____________________________________________________________________

(a) LI/3.1:1=lincomycin/ivermectin 3.1:1, lincomycin value reported.
(b) LI/10:1=lincomycin/ivermectin 10:1, lincomycin value reported.
(c) L/GF, lincomycin/glycerol-formal solvent.

Pivotal Pharmacokinetic Study - Non-Interference Study: a. Type of Study:

Pharmacokinetic - Plasma concentrations after either lincomycin alone or lincomycin and ivermectin administered to swine.

b. Investigator:

Scott A. Brown, Study Director
Animal Health Drug Metabolism, Unit 7926
The Upjohn Company.

c. General Design: * Purpose of Study: To compare the steady-state plasma concentrations of lincomycin after administration of lincomycin alone and after administration of lincomycin and ivermectin in swine feed.

  • Test Animals: Thirty-two (32) healthy Yorkshire cross pigs (16 male/16 female), 2-4 months of age weighing 13.7-22.2 kg (30-49 lb). The pigs were randomly assigned to one of two treatment groups with an equal number of males and females allocated into each of the two treatment groups. Both treatment groups received lincomycin for 7 consecutive days (first through seventh day of the study). Treatment Group A then received lincomycin for 7 consecutive days (eighth through fourteenth day of the study), whereas Group B received lincomycin feed for 7 consecutive days (days 15-21 of the study). Treatment Group B received lincomycin plus ivermectin for 7 consecutive days (days 8-14 of the study), whereas Treatment Group A received lincomycin plus ivermectin for 7 consecutive days (days 15-21 of the study). The treatment periods are illustrated by the following diagram.
          Day 0            Day 7           Day 14           Day 21
    Group A |---------------------------------|================|
    Group B |----------------|================|----------------|
    
            --- lincomycin
            === lincomycin plus ivermectin
  • Controls: The design and type of study required no unmedicated control group. * Dosage Forms: LINCOMIX® 50 and IVOMEC® Premixes for swine were mixed into the basal diet at the described levels to produce the medicated feeds.
  • Route of Administration: Orally via medicated feed.
  • Dosages Used: 220 g lincomycin/1000 kg feed (200 g/2000 lb) either alone or with 2.0 g ivermectin/1000 kg feed (1.82 g/2000 lb).
  • Test Duration: Twenty-one (21) days.
  • Pertinent Parameters Measured: Average lincomycin plasma concentrations (Cavg) were evaluated for each pig/treatment by dividing the area under the curve (AUC) determined on Day 13 and on Day 21 (hours 2 and 4 following the 8 AM and 4 PM doses) by the total blood sampling interval (12 hours). All blood samples were analyzed for lincomycin free base by Gas Chromatography/Mass Spectrometry (GC/MS) with electron impact detection.
  • Decision Criteria: To confirm the absence of bias in the treatment comparison due either to a lack of steady state conditions or to the presence of a period by treatment interaction, Cavg values were obtained for each treatment and period (see Table 6). The 90% confidence intervals for lincomycin concentrations on Days 13 and 21 were used to assess potential drug interactions. If the 90% confidence interval for the difference between lincomycin plasma concentrations after lincomycin alone subtracted from those after lincomycin plus ivermectin was greater than -0.20 times the mean lincomycin concentrations after lincomycin alone, the conclusion was that ivermectin did not interfere with lincomycin.

d. Results and Statistical Analysis:

Consistent with the mean values presented in Table 6, no statistically significant period by treatment interactions were observed (P = 0.1550). This verifies that the evaluation of the treatment effects represents an unbiased comparison.

(Eds note: The following table consists of 3 columns).

Table 6. Comparison of Average Lincomycin Blood Levels in Periods 1 and 2 for Each Treatment Group.

____________________________________________________________		
   Period             Treatment             Cavg (ug/mL)     
                                               LSMEAN
     1               lincomycin              0.37383906      
     1            linco/ivermectin           0.41850469      
     2               lincomycin              0.32698437      
     2            linco/ivermectin           0.38898438

The statistical analysis of average plasma concentration after lincomycin alone versus lincomycin plus ivermectin are summarized in Table 7.

(Eds note: The following table consists of 6 columns).

Table 7. Comparisons of least squares means of lincomycin concentrations with and without adjustment for feed consumption.  Unadjusted concentrations are reported in ug/mL, adjusted concentrations are reported in [(ug/mL)/(kg feed/kg BW)].

__________________________________________________________________________________________
Adjusted for     Least Squares Means of       Significance      90% CI of     -0.20x Linco    
Relative              Concentration             Level of       Difference        LSMean          
Feed                (Standard Errors)          Difference                                    
Consumption 
               __________________________                                                                  
                Linco Alone   Lincomycin+                                                  
                              Ivermectin    
__________________________________________________________________________________________
                                                                            
No                0.351         0.404            0.0512       0.028 to 0.07       -0.070          
                 (0.019)       (0.019)                                                    
Yes               6.55          7.52             0.0787       0.436 to 1.49       -1.31           
                 (0.376)       (0.376)
__________________________________________________________________________________________

e. Conclusions: The presence of ivermectin (2.0 g ivermectin/1000 kg feed) in swine feed containing lincomycin hydrochloride (220 g lincomycin/1000 kg feed) does not reduce the systemic concentrations of lincomycin. This demonstrates lack of substantial interference caused by ivermectin on lincomycin pharmacokinetics in swine administered both lincomycin and ivermectin in the feed.

f. Adverse Reactions:

None.

g. Special Issues:

None.

 

V. ANIMAL SAFETY

The target animal safety data for each individual drug are part of their original NADAs and are summarized in the respective FOI summaries.

Ivermectin:

NADA 140-974
FEDERAL REGISTER, November 3, 1993 (58FR 58653).

Lincomycin:

NADA 97-505:
41 FR 26855, Jun. 30, 1976;
47 FR 52145, Nov. 19, 1982;
51 FR 12137, Apr. 9, 1986;
55 FR 23423, Jun. 8, 1990.

 

VI. HUMAN FOOD SAFETY

A. Toxicity Tests:

The original NADAs and Freedom of Information summaries for each individual drug establish the acceptable daily intake of each for human consumption.

Ivermectin:

NADA 140-974
FEDERAL REGISTER, November 3, 1993 (58 FR 58653).

Lincomycin:

NADA 97-505
41 FR 26855, Jun. 30, 1976;
47 FR 52145, Nov. 19, 1982;
51 FR 12137, Apr. 9, 1986;
55 FR 23423, Jun. 8, 1990.

B. Safe Concentration of Residues:

For swine the marker residue tolerance and/or safe concentration of residues for ivermectin and lincomycin are as specified in 21 CFR 556.344 and 21 CFR 556.360, respectively.

C. Residue Depletion Non-Interference Study:

A residue assay non-interference study was conducted. The non-interference by lincomycin in the ivermectin assay was shown in two phases. The derivatization of standards containing 29.0 or 58.0 mcg/mL lincomycin, 100 ng/mL ivermectin or a combination of both analytes demonstrated that (a) lincomycin does not produce a fluorescent derivative either with or without the presence of ivermectin and (b) it does not change the retention time or sensitivity of the ivermectin fluorescent peak. In the second phase, control porcine liver from the study was fortified with approximately 2300 ppb lincomycin, approximately 20 ppb ivermectin or a combination of both. No fluorescent peaks were produced in the analysis of lincomycin by the ivermectin assay. No peaks representing lincomycin were observed under the ivermectin HPLC conditions. The recovery of ivermectin alone from the three fortified samples was 89, 92 and 95%. The recovery of ivermectin from the three samples fortified with about 100 times as much lincomycin as ivermectin was 95, 89 and 95%. These equivalent results indicate that the presence of lincomycin in porcine liver does not interfere with the ivermectin assay. Also, ivermectin at 2 mcg/g was found not to interfere with the microbiological cylinder plate assay for lincomycin.

A tissue residue depletion study was conducted to determine the depletion of the marker residues of ivermectin and lincomycin in liver (target tissue) of swine administered lincomycin at its highest use level of 200 g/ton in combination with ivermectin at its use level of 2 ppm (approximately 100 mcg/kg/day) in complete feed. Medicated animals were given a basal ration containing lincomycin at 200 g/ton on Day 0 through Day 14, then a ration containing lincomycin at 200 g/ton and ivermectin at 2 ppm from Day 15 through Day 21, followed by a non-medicated basal ration until study termination. Three barrows and three gilts were sacrificed at each withdrawal time. The withdrawal times following the end of the combination medication period were 0 (within six hours after removal of medicated feed), 1, 2, 3 and 5 days. One barrow and one gilt served as non-medicated control animals. Marker residue assays were performed on swine livers using the high pressure liquid chromatography-fluorescence and microbiological cylinder/plate assay determinative methods for ivermectin and lincomycin, respectively. The average or mean marker residue concentrations found were as follows:

(Eds note: The following table consists of 5 columns).

                         Ivermectin (ppb)               Lincomycin (ppm)    
   Withdrawal         _______________________        _______________________   
      day             average         range          mean             range 
       
       0                53           35 - 76         0.251        0.153 - 0.414
       1                33           19 - 53         0                  0
       2                17*          10 - 25         0                  0
       3                 8            4 - 13         0                  0
       5                 3            0 -  8         0                  0
           

* Due to illness of one pig from this group, its residue value was discarded and not included in the average. If not excluded the average would be 15 ppb and the range would be 2-25 ppb.

The marker residue tolerance (Rm) for ivermectin in swine liver is 20 ppb. Statistical analysis of the depletion data, using the upper tolerance limit containing 99 percentile of the population with 95% confidence, yields a withdrawal period of 5 days. The withdrawal periods for both ivermectin and lincomycin are unaltered for use of these drugs in combination at their highest approved use levels.

D. Regulatory Methods:

The validated regulatory analytical methods for detection of the marker residue of ivermectin are filed in the Food Additives Manual on display in FDA's Freedom of Information Public Room (Room 12A-30, 5600 Fishers Lane, Rockville, MD 20857).

A microbiological assay method is used to assay tissues for lincomycin residues. The method titled "Determination of Lincomycin Residues in Broiler Chicken Tissues" is filed in the Food Additives Manual on display in FDA's Freedom of Information Public Room (Room 12A-30, 5600 Fishers Lane, Rockville, MD 20857).

 

VII. AGENCY CONCLUSIONS

The data submitted in support of this NADA comply with the requirements of section 512 of the Act and demonstrate that the combination of ivermectin and lincomycin, Type A medicated articles, when mixed to produce a Type C medicated feed and fed to weaned, growing, and finishing pigs under the proposed conditions of use, is safe and effective for the indications stated on the product labeling.

For swine the marker residue tolerance and/or safe concentration of residues for ivermectin and lincomycin are as specified in 21 CFR 556.344 and 21 CFR 556.360, respectively. The marker residue tolerance (Rm) for ivermectin in swine liver is 20 ppb. A tolerance for lincomycin of 0.1 ppm is established for negligible residues in the edible tissues. A residue assay non-interference study was conducted. The non-interference by lincomycin in the ivermectin assay was shown in two phases. A tissue residue depletion study was conducted to determine the depletion of the marker residues of ivermectin and lincomycin in liver (target tissue) of swine administered lincomycin at its highest use level of 200 g/ton in combination with ivermectin at its use level of 2 ppm (approximately 100 mcg/kg/day) in complete feed. This study demonstrates that the withdrawal periods for both ivermectin and lincomycin are unaltered for use of these drugs in combination at their highest approved use levels. The withdrawal times are 5 days for 20 g/ton and 40 g/ton lincomycin in combination with 1.8 g/ton ivermectin and 6 days for 100 g/ton and 200 g/ton lincomycin in combination with 1.8 g/ton ivermectin (21 CFR 558.300 and 21 CFR 558.325).

The original approvals of ivermectin and lincomycin, Type A medicated articles, were for over-the-counter use. Approved products containing ivermectin and lincomycin alone, for the same claims as are on the label for the combination product, are on the market. Adequate directions for use have been written for the layman, and the conditions for use prescribed on the labeling are likely to be followed in practice. Therefore, the Center for Veterinary Medicine (CVM) has concluded that this product shall have over-the-counter marketing status.

Several efficacy trials using the combination were performed at various doses of lincomycin. A dose confirmation non-interference study was conducted to evaluate the efficacy of ivermectin (1.8 g/ton), in the presence of lincomycin (200 g/ton), against endoparasites. A dose confirmation non-interference clinical study was performed to assess the efficacy of lincomycin at 100 g/ton for 14 days when used in combination with ivermectin at 1.8 g/ton for the first seven days for the treatment of induced swine dysentery. An effectiveness study was performed to evaluate the in vitro antimicrobial activity of lincomycin and ivermectin, alone and in combination, against strains of M. hyopneumoniae. Lincomycin added at the rate of 200 g/ton is approved as therapy to reduce the severity of lesions caused by Mycoplasma hyopneumoniae in swine. A pharmacokinetic non-interference study was performed to compare the steady-state plasma concentrations of lincomycin after administration of lincomycin alone (200 g/ton) and after administration of lincomycin (200 g/ton) and ivermectin (1.8 g/ton) in swine feed. These studies demonstrated that ivermectin and lincomycin do not interfere with the efficacy of each other and that both drugs are efficacious in the presence of one another.

Under section 512(c)(2)(F)(ii) of the Federal Food, Drug, and Cosmetic Act, this approval for food-producing animals qualifies for THREE years of marketing exclusivity beginning on the date of the approval because the application contains reports of new clinical or field investigations (other than bioequivalence or residue studies) essential to this approval and conducted or sponsored by the applicant.

 

VIII. LABELING

  1. Draft Type B medicated feed Blue Bird labeling:
    • Ivermectin at 36.4-728 g/ton and lincomycin at 1.0-20 g/ton
    • Ivermectin at 18.2-364 g/ton and lincomycin at 1.0-20 g/ton
    • Ivermectin at 91-910 g/ton and lincomycin at 1.0-10 g/ton
    • Ivermectin at 182-910 g/ton and lincomycin at 1.0-5.0 g/ton
  2. Draft Type C medicated feed Blue Bird labeling:
    • Ivermectin at 1.8 g/ton and lincomycin at 200.0 g/ton
    • Ivermectin at 1.8 g/ton and lincomycin at 100.0 g/ton
    • Ivermectin at 1.8 g/ton and lincomycin at 40 g/ton
    • Ivermectin at 1.8 g/ton and lincomycin at 20 g/ton

Copies of these labels may be obtained by writing to the:

Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855