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    IVERMECTIN

    First draft prepared by
    Dr K.N. Woodward
    Veterinary Medicines Directorate
    Ministry of Agriculture, Fisheries and Food
    Weybridge, Surrey, United Kingdom

    1.  EXPLANATION

         Ivermectin (a mixture of > 80% 22,23-dihydroavermectin B1a
    (H2 B1a) and no more than 20% 22,23-dihydroavermectin B1b
    (H2 B1b) had previously been evaluated at the thirty-sixth
    meeting of the Joint FAO/WHO Expert Committee on Food Additives
    (Annex 1, reference 91), when an ADI of 0-0.2 g/kg bw was
    established based on a NOEL of 0.1 mg/kg bw/day for maternal
    toxicity in the CF1 mouse and a safety factor of 500.

         Since that time, additional data have become available which
    are summarized and discussed in the following monograph. Where
    necessary, data presented in the original monograph (Annex 1,
    reference 92) are also discussed in this updated version.

    2.  BIOLOGICAL DATA

    2.1  Biochemical Aspects

    2.1.1  Absorption

    2.1.1.1   Mice

         Radio-labelled ivermectin (3H-H2 B1a mixed with
    unlabelled ivermectin to give a specific activity of 544 Ci/mg) was
    administered in a single oral dose to CF1 mice, 7 weeks old, as a
    solution in sesame oil, by gavage at 0.4 mg/kg bw. Blood samples
    were taken at 0.5, 1, 2, 6, 8, 12, 48 and 96 h after dosing.

         Greater than 62% of the dose was absorbed as indicated by
    comparison of the plasma concentration-time curves with those
    obtained from a group of mice given intravenous doses. Peak plasma
    concentrations (80-100 ng/ml) occurred between 6 and 12 h after
    administration, but levels of 2-3 ng/ml were present at 96 h. The
    area under the curve (AUC) was 2733 ng-h/ml (Merck & Co. Inc.,
    1987a).

    2.1.1.2  Humans

         Healthy male volunteers were given 6, 12 or 15 mg tablets as
    single oral doses of ivermectin (approximately 100, 200 or 250 g/kg
    bw). Mean peak plasma concentrations were 18, 31 and 49 ng/ml,
    respectively, at a mean time of approximately 4 h after dosing. Mean
    AUCs were 247, 513 and 820 ng-h/ml, respectively (Merck & Co. Inc.,
    1987b).

    2.2  Toxicological Studies

    2.2.1  Comparative toxicity: CF1 
           mouse vs rat and rabbit

         The toxicity of ivermectin in animals was discussed
    comprehensively in the previous monograph (Annex 1, reference 92).

         The data clearly demonstrated that the CF1 mouse is more
    sensitive to the toxic effects of orally administered ivermectin in
    a number of studies than the rabbit, rat or dog. These include
    acute, subacute and reproductive studies. These differences are
    evident in the teratogenicity studies with ivermectin (and with the
    related compound, abamectin), as shown in Table 1.

    2.2.2  Comparative toxicity : ivermectin vs abamectin

         Ivermectin differs from abamectin in that it lacks a double
    bond in one of the lactone rings at C22-C23. Several studies,
    but notably subchronic (13-18 weeks) studies in dogs, teratogenicity
    studies in mice, rabbits and rats, and multigeneration studies in

        Table 1.  Results of teratogenicity studies with ivermectin and abamectin
                                                                                                   

                              CF1 mouse                   rabbit                   rat

                      abamectin   ivermectin     abamectin   ivermectin   abamectin    ivermectin
                                                                                                   

    Maternal
    toxicity
    NOEL                0.05         0.1          1.0          3.0         1.6           5.0
    MEL                 0.075        0.2          2.0a         6.0         2.0a         10.0

    Developmental
    toxicity
    NOEL                0.2          0.2          1.0          1.5         1.6           5.0
    MEL                 0.4          0.4          2.0a         3.0         3.0          10.0
                                                                                                   

    NOE  = no-observed-effect level in mg/kg bw per day.
    MEL  = minimum effect level in mg/kg bw per day.
    a  effect (cleft palate) not seen at maximum dose tested (2.0 mg/kg bw).
    

    rats, suggest that abamectin and ivermectin have a similar order of
    toxicity (Annex 1, reference 92; Merck & Co. Inc., 1976, 1977a,b;
    1982a,b). In fact, abamectin appears to be marginally more toxic
    than ivermectin in all these studies. Consequently, the negative
    mutagenicity studies on ivermectin and the negative carcinogenicity
    studies with abamectin indicate that ivermectin has no carcinogenic
    potential. The main signs of toxicity in the 94-week study in mice
    with abamectin were tremors; the NOEL was 4 mg/kg bw/day. In the
    105-week study in rats with abamectin, tremors were again the main
    treatment-related effect. The NOEL was 1.5 mg/kg bw/day (Annex 1,
    reference 92; Merck & Co. Inc., 1983a).

    2.2.3  Acute toxicity studies

    2.2.3.1  Cattle

         Groups of 6-month old male and female Friesan calves were given
    subcutaneous injections or oral treatments with 4 mg/kg bw
    ivermectin (20 times the therapeutic dose). A third group was given
    a micelle formulation by subcutaneous injection at 1.4 mg/kg bw (7
    times the therapeutic dose).

         The main signs of toxicity in animals given ivermectin orally
    or by subcutaneous injection were depression and ataxia. Animals
    given the oral dose became incoordinate and recumbent. Of the 6

    animals treated (3 male, 3 female) in this way, one died. The death
    appeared to be partly due to a long-standing lung condition. The
    remainder recovered. All the animals given ivermectin subcutaneously
    recovered (Merck & Co. Inc., 1983b).

    2.2.3.2  Sheep

         A group of 6 (3 male, 3 females) German merino lambs (8 months)
    were given a single oral treatment of 4 mg/kg bw. Approximately 5-8
    h after treatment, the ewes produced dark brownish-red urine. Signs
    of depression including recumbency and incoordination were noted.
    All the animals recovered within 7 days (Merck & Co. Inc., 1981a).

    2.2.3.3  Horses

         In this study, 6 thoroughbred mares (5-12 years), 8 Arab cross
    and quarterhorse cross stallions (2-8 years) and 8 Arab cross foals
    (3-5 months) were given 2 mg/kg bw ivermectin as an oral paste on
    two consecutive days (10 times the therapeutic dose). Depression and
    impairment of vision were the main signs seen following drug
    administration. All the affected horses recovered within 5 days
    (Merck & Co. Inc., 1982c).

    2.2.4  Reproduction studies

    2.2.4.1  Comparison of reproductive effects in laboratory species

         An examination of the mouse, rat and rabbit reproductive data
    and the teratology studies reviewed in the original monograph (Annex
    1, reference 92) shows that birth defects occur only at maternally
    toxic doses of ivermectin. Moreover, the types of defect, typically
    cleft palate, are those usually associated with maternotoxic effects
    rather than frank teratogenicity (see Table 1).

    2.2.4.2  Cattle

         Pregnant hereford or hereford/angus cows received 400 g/kg bw
    ivermectin at monthly intervals for a total of 6 treatments. The
    first treatment was at day 90 of pregnancy. A group of 7 pregnant
    cows were given no treatments. All the treated animals calved
    normally and no abnormalities were noted in the calves. There were
    no significant differences in weights between calves from control
    and treated cows (Merck & Co. Inc., 1981b).

         Jersey heifers (126) were given either vehicle control or
    ivermectin at 400 g/kg bw (twice the therapeutic dose)
    subcutaneously, on the following days after insemination:

                        7, 19 and 35
                   or   10, 22 and 42
                   or   13, 25 and 49
                   or   16, 28 and 56.

         Fifty-two pregnancies were confirmed in the treated groups and
    53 in the controls. There were no significant differences in the
    treated groups when compared with controls for the numbers of calves
    carried to term, perinatal deaths or 3-month survival. No
    treatment-related effects were seen (Merck & Co. Inc., 1981c).

         A similar study was conducted with a total of 42 Friesian and
    12 Jersey heifers. These were treated in the same way with 400 g/kg
    bw ivermectin at the same time intervals after insemination as those
    in the study described previously. There were no significant
    differences between treated animals and controls in the numbers of
    animals carrying pregnancy to term, fetal anomalies, the numbers of
    dead calves or in the birthweights of calves (Merck & Co. Inc.,
    1981d).

    2.2.4.3  Pigs

         Six groups of 7 Yorkshire crossbred sows were given vehicle
    control or 600 g/kg bw ivermectin by subcutaneous injection on days
    1 and 18, or 6 and 24, or 12 and 30 of gestation. Animals were
    examined during gestation, at birth and until 35 days of age. At
    this time, 25% from each litter were necropsied for examination for
    terata.

         There were no significant increases in the incidence of any
    effect that could be attributed to compound administration (Merck &
    Co. Inc., 1982d).

    2.2.4.4  Sheep

         Coopworth ewes (326) were treated orally with vehicle or with
    400 g/kg bw (twice the therapeutic dose) with one of 3 regimens:

         day  0 of gestation to day 7 and day 21 to day 28
         day  7 of gestation to day 14 and day 28 to day 35
         day 14 of gestation to day 22 and day 35 to day 43.

         All lambs born alive were weighed and clinically examined after
    birth and at 3 and 6 months. All dead fetuses, stillborn lambs and
    lambs dying after birth were necropsied and most of these were
    radiographed.

         No effects which could be attributed to ivermectin treatment
    were noted (Merck & Co. Inc., 1981e).

    2.2.4.5  Horses

         A total of 32 pregnant Welsh pony-type mares were either
    untreated or given ivermectin (600 g/kg bw) as an oral paste using
    the following regimes:

         -    on the first Monday following day 0 and every two weeks
              thereafter for 6 treatments total;

         -    on the second Monday following day 0 and every two weeks
              thereafter for 6 treatments total;

         -    on the first Monday following day 0 and every week
              thereafter for 12 treatments total.

         There were no significant differences between untreated and
    treated groups with respect to foal birth weights or anatomical and
    clinical abnormalities, except for two foals in the treated group
    that showed transitory weakness. At 3 months of age, there were no
    differences between foals from treated or untreated mares. At age
    4-6 months, 3 cases of cryptorchidism were noted in foals born to
    treated mares compared with one of the untreated animals. However,
    because of the small numbers involved, statistical analysis was not
    possible, and the condition is common in colts. The results do not
    suggest a major effect of ivermectin in the pregnant mare (Merck &
    Co. Inc., 1982e).

         Groups of 4 pregnant mares (variety of breeds) were treated
    orally with ivermectin (600 g/kg bw) in the same manner as that
    described in the preceding study.

         There were no significant differences in the number of live
    offspring produced by ivermectin-treated animals when compared with
    controls. Foals from ivermectin-treated mares were similar in all
    respects clinically to those from untreated mares. Cryptorchidism
    was only seen in controls (Merck and Co. Inc., 1982f).

    2.2.4.6  Adverse reproductive reports following ivermectin use

         Ivermectin has been widely used in veterinary medicine for a
    number of years. Although the number of pregnant animals treated is
    unknown, the incidence of adverse reproductive effects following
    clinical use is extremely low in all species (Table 2).

    2.3  Observations in humans

         In humans infected with  Onchocerca volvulus or other
    parasites, the major effects following the administration of
    ivermectin are attributable to the Mazzotti reaction, a severe
    inflammatory response. Symptoms include an intense pruritus,
    erythema, oedema, vesicle and

        Table 2.  Incidence of adverse reproductive reports following use of
              ivermectin in animals*
                                                                                  

                                         Adverse reproductive reports

    Species           Doses sold       No. of reports       No. of animals
                      (million)
                                                                                  

    Pigs                  61               10                   46

    Cattle              1213               11                   67

    Horses                63               25                   30

    Dogs                 340                3                    4

    Sheep                820                5                   58

    TOTAL               2497               54                  205
                                                                                  

    *    includes animals with known clinical problems which may affect
         reproductive function (parvovirus, brucellosis, equine rhinopneumonitis,
         trauma, etc.); adverse reproductive effects include abortion,
         stillbirth, and infertility) (Greene, 1991).
    

    papule formation and scaling. Adenitis, fever and hypotension may
    occur and severe inflammatory changes may be noted in both the
    anterior and posterior segments of the eye. The reaction is thought
    to be due to an acute exacerbation of the host immune responses to
    microfilariae, associated with migration of microfilariae into the
    blood and other body fluids (Ackerman  et al., 1990).

    2.3.1  Observations in children

         In a trial to investigate the safety and efficacy of ivermectin
    in the treatment of  Onchocerca volvulus in children, 103 subjects
    aged 6-13 years were given a single oral dose of 150 g/kg bw. The
    major adverse reaction was a Mazzotti-type response. Cases of oedema
    and peripheral oedema were classified as being "probably" due to the
    drug and myalgia and headache as "possibly" related. None of the
    effects was serious (Lariviere, 1988).

    2.3.2  Observations in adults

         Reports on studies of over 26 000 patients treated with
    ivermectin for parasitic diseases, largely onchocerciasis, suggest
    that single oral doses of up to 200 g/kg bw produced no major
    effects except for those resulting from effects on the parasite
    (Table 3). Symptoms also included headaches which may be due to the
    Mazzotti reaction but it should be noted that these have also been
    reported in healthy volunteers given the drug at approximately 100
    g/kg bw (Annex 1, reference 92). Similar findings were made when
    the combined results from 8 community trials were analysed (De Sole
     et al., 1989b). A total of approximately 1.5 million people have
    been treated with ivermectin worldwide and no deaths attributable to
    the drug have been noted (Greene, 1991).

    2.3.3  Observations in pregnant women

         In a 3-year study in Liberia, 203 children born to women
    inadvertently treated with ivermectin during pregnancy were
    identified. There was no increased incidence of birth defects when
    compared with untreated mothers in the same population or in a
    reference population (Pacque  et al., 1990).

    2.3.4  Effects on prothrombin time

         Two patients were found to have prolonged prothrombin times
    after treatment with ivermectin (Homeida  et al., 1988). However
     in vitro and  in vivo studies in humans have failed to reproduce
    this effect (Hay  et al., 1990; Richards  et al., 1989), and it
    seems unlikely that the reported cases were due to ivermectin
    treatment.

    2.3.5  Adverse reactions in humans following accidental exposure to
           ivermectin

         There are approximately 40 reports of self-injection with
    ivermectin solutions intended for animal use. The major effect noted
    was pain at the injection site but nausea, paresthesia, variable
    blood pressure, urticaria and cellulitis have been reported.
    Dermatitis was the main reaction following dermal exposure. There
    were approximately 10 reports of accidental ingestion of ivermectin
    solution or tablets by adults; adverse effects noted included
    mydriasis, vomiting, tachycardia and somnolence. (Greene, 1991).

        Table 3.  Observations in patients orally treated with ivermectin
                                                                                            

    Number of      Dose,          Main effects noted                Reference
    patients       g/kg bw
                                                                                            

    86             50-200         Pruritus                          Pappayliou et al., 1987

    50             50-200         Arthralgia, fever, pruritus       Jacobsen & Aziz, 1987

    1278           100-200        Well tolerated. Myalgia and       Neu & Aziz, 1987
                                  headache incidence higher at
                                  highest dose

    85             150-200        Well tolerated                    White et al., 1987

    14             200            Well tolerated                    White et al., 1987

    49             100-200        No serious adverse reactions      Greene et al., 1985

    32             5-50           Well tolerated                    Aziz et al., 1982

    50             150            No major effects                  Addiss et al., 1991

    19             50-200         Transient ischemia,               Awadzi et al., 1984, 1985
                                  delayed choroidal perfusion

    59             200            Tachycardia, hypotension          Awadzi et al., 1986
                                  Ocular changes                    Dadzie et al., 1987, 1989

    14911          130-200        13 cases of severe fever          De Sole et al., 1989ab,
                                  2 cases of life threatening       1990
                                  dyspnea

    30             200            Mazzotti reactions                Diallo et al., 1986

    32 (mean       150            No significant effects on         Dukuly et al., 1990
    age 61)                       electrocardiogram

    30             200            Well tolerated                    Greene et al., 1985

    40             25-200         Sore throat and cough at 100      Kumaraswani et al., 1988
                                  and 200 g/kg bw but only in
                                  patients with high
                                  microfilaria burden
                                                                                            

    Table 3. cont'd  Observations in patients orally treated with ivermectin
                                                                                            

    Number of      Dose,          Main effects noted                Reference
    patients       g/kg bw
                                                                                            

    7699           150            No severe reactions; 1.3% with    Pacque et al., 1989a,b,
    (15 yrs +)                    Mazzotti reaction                 1991

    35)            100-200        Well tolerated                    Richard-Lenoble et al.,
    17)                                                             1988

    30             200            Headache and fever                Richards et al., 1991
                   200+200
                   (consecutive
                   days)

    30             200            No ocular effects                 Taylor et al., 1986

    39             100-200        No ocular effects                 Taylor et al., 1989

    200            100-200        No major adverse reactions at     White et al., 1987
                                  150 g/kg bw. Hypotension
                                  (1 case) at 200 g/kg bw

    1400           150            Mild-moderate reactions seen      Paque et al., 1991
                                  after first dose, most
                                  ascribable to Mazzotti-type
                                  reactions. Incidence less in
                                  subsequent years
                                                                                            
    
    3.  COMMENTS

         The Committee reappraised the developmental toxicity of
    ivermectin and reviewed the human data including a large amount of
    new information made available since its thirty-sixth meeting. The
    information clearly demonstrates that the CF1 mouse is extremely
    sensitive to the toxicity of ivermectin. In no species are there
    data to suggest that the drug is a teratogen in the absence of
    maternal toxicity. Various toxicity studies in rats and rabbits in
    addition to those in cattle, pigs, sheep, and horses emphasize the
    particular susceptibility of the CF1 mouse to ivermectin toxicity.
    Despite the extremely wide use of ivermectin, there is no evidence
    of significant incidences of adverse effects on reproductive
    performance in treated animals and the very limited data on
    reproductive toxicity in humans indicate that ivermectin does not
    increase the incidence of birth defects.

         The main effects noted in field and community-based trials with
    ivermectin in humans infected with  Onchocerca spp. have been those
    arising from the death of the parasites, the so-called Mazzotti
    reaction, which is characterized by arthralgia, pruritus, fever,
    hypertension, tachycardia, headache, and ocular changes. Neither in
    these studies nor during ivermectic treatment of other parasitic
    diseases in humans in Africa, South America, the Caribbean, and
    certain other areas has a subset of atypically sensitive individuals
    been detected. Furthermore, the adverse effects experienced by the
    small number of persons accidentally exposed to doses (often of
    veterinary preparations) higher than customary human doses are in
    keeping with those noted in several test animal species.

    4.  EVALUATION

         In the light of the above findings, the Committee decided to
    amend its previous conclusions. Taking into account the absence of
    major effects in humans, the data indicating that the compound was a
    developmental toxicant rather than an overt teratogen, and the
    extreme sensitivity of the CF1 mouse to these effects, The
    Committee concluded that a safety factor of 100 was justified.
    However, as the CF1 mouse was the most sensitive species studied,
    the ADI should continue to be based on the NOEL of 0.1 mg/kg bw/day
    for maternal toxicity in that species. On this basis, an ADI of 0-1
    g kg/bw was established.

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    See Also:
       Toxicological Abbreviations
       Ivermectin (WHO Food Additives Series 27)
       IVERMECTIN (JECFA Evaluation)
       Ivermectin (PIM 292)