ROXITHROMYCIN
 0.0 OVERVIEW
 A. Roxithromycin is a macrolide antibiotic related to erythromycin.
 B. DOSING INFORMATION: Adults: Usual oral doses are 150 mg twice a day or 300 mg once
daily for 10 days. Children: Usual doses are 2.5 to 5 mg/kg every 12 hours for 10 days.
 C. PHARMACOKINETICS: Roxithromycin is rapidly absorbed; peak serum levels occur 2 hours
after administration. Penetrates well into most body fluids and tissues except into saliva and
CNS (in the absence of meningeal inflammation); volume of distribution is 0.44 L/kg; elimination
half-life is 12 hours. The drug is hydrolyzed to several metabolites with unknown activity; the
majority is excreted in the feces, with smaller amounts appearing in the urine and expired air.
 D. CAUTIONS: The most common adverse effects are nausea, diarrhea, abdominal cramps, and
anorexia. The serum half-life of roxithromycin may increase in the presence of severe renal or
hepatic failure, and dosage modification may be required.
 E. CLINICAL APPLICATIONS: Roxithromycin is useful in the treatment of several types of
infections including nongonococcal urethritis, streptococcal pharyngitis, skin and soft tissue
infections, upper and lower respiratory tract infections, isosporiasis, Lyme disease, and otitis
media. In these situations, roxithromycin has been shown to be essentially equivalent to
erythromycin.
 1.0 DOSING INFORMATION
 1.1 DOSAGE FORMS
 A. Information on specific products and dosage forms can be obtained by referring to
the Product Index.
 B. Roxithromycin is not being pursued in the United States. However, the drug is
marketed in Italy, France, Germany, Switzerland, Netherlands, and South Africa (Pers
Comm, 1998).
 C. SYNONYMS
1.
2.
RU-28965
RU-965
 1.3 ADULT DOSAGE
 1.3.1 NORMAL DOSE
 A. ORAL
 1. GENERAL INFECTIONS
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 a. SUMMARY: For most infections, oral roxithromycin is
effective in doses of 150 milligrams twice a day or 300
milligrams once daily (Fachinfo Rulid(R), 1998; Mandell et al,
1990). Therapy should be continued for at least 2 days after
resolution of symptoms, and for at least 10 days in
streptococcal infections, urethritis, cervicitis, and
cervicovaginitis. The maximum duration of therapy is 4
weeks. Doses should be taken in the morning and evening
before meals (Fachinfo Rulid(R), 1998).
2. GENITOURINARY INFECTIONS
 a. Roxithromycin is effective in the treatment of
NONGONOCOCCAL URETHRITIS and CERVICOVAGINITIS
in doses of 150 milligrams twice a day or 300 milligrams
once a day (Pedreira et al, 1988; van der Willigen et al, 1988;
Vitse et al, 1988; Lassus & Seppala, 1987).
3. ISOSPORIASIS
 a. Oral roxithromycin 2.5 milligrams/kilogram every 12 hours
for 15 days is effective in the treatment of ISOSPORIASIS in
adults (Musey et al, 1988).
4. LYME DISEASE
 a. In the treatment of LYME DISEASE, roxithromycin 300
milligrams in combination with cotrimoxazole 320
milligrams/1600 milligrams twice a day for 21 days is
effective (Pedersen & Friis-Moller, 1991).
5. RESPIRATORY TRACT INFECTIONS
 a. In the treatment of upper and LOWER RESPIRATORY
TRACT INFECTIONS including PNEUMONIA, COMMUNITYACQUIRED PNEUMONIA, BRONCHITIS, LUNG
ABSCESSES, BRONCHIECTASIS, TONSILLITIS,
PHARYNGITIS, RHINOPHARYNGITIS, and SINUSITIS,
roxithromycin in oral doses of 150 milligrams twice a day for
10 to 14 days is generally effective (Ortqvist et al, 1996;
Peterslund et al, 1989; Young et al, 1989; Astarloa et al,
1988; Bazet et al, 1988; Grassi et al, 1988; Fernandez
MacLoughlin et al, 1988; Steiner et al, 1988; Gentry, 1987;
Kafetzis & Blanc, 1987).
 b. In acute OTITIS MEDIA, doses of 5 to 9
milligrams/kilogram/day for 8 to 12 days, results in cure rates
of 88% to 96% (Casellas et al, 1988; Stamboulian et al,
1988).
 6. SKIN INFECTIONS
 a. In SKIN INFECTIONS and SOFT TISSUE INFECTIONS, 150
milligrams twice a day for 10 days in adults is effective for
IMPETIGO and PYODERMATITIS (Bazet et al, 1988;
Stamboulian et al, 1988; Agache et al, 1987; Kafetzis &
Blanc, 1987).
 1.3.2 DOSAGE IN RENAL FAILURE
 A. Dosage adjustments have been suggested not to be required with
roxithromycin in patients with severe renal insufficiency (Lebrec et al, 1988;
Puri & Lassman, 1987; Periti & Mazzei, 1987). Other investigators, however,
have reported significant delays in roxithromycin elimination in patients with a
creatinine clearance of less than 15 milliliters/minute, and recommend
doubling the dosing interval in these patients to avoid accumulation
(Halstenson et al, 1990).
 1.3.3 DOSAGE IN HEPATIC INSUFFICIENCY
 A. No dosage adjustment of roxithromycin is required in patients with
documented cirrhosis (Lebrec et al, 1988; Puri & Lassman, 1987; Periti &
Mazzei, 1987); however, the elimination half-life of roxithromycin is increased
in the presence of alcoholic liver disease (Young et al, 1989; Nilsen, 1987) and
dosage adjustment may be required in patients with hepatic dysfunction. The
manufacturer recommends halving the usual dose for patients with severe
hepatic dysfunction (Fachinfo Rulid(R), 1998).
 1.3.4 DOSAGE IN GERIATRIC PATIENTS
 A. Although peak plasma roxithromycin concentrations are increased and
serum half-life prolonged in the elderly as compared to young, healthy
volunteers, no dosage modification is required in these patients (Nilsen et al,
1988; Nilsen, 1987).
 1.4 PEDIATRIC DOSAGE
 1.4.1 NORMAL DOSE
 A. ORAL
 1. GENERAL INFECTION
 a. SUMMARY: For the treatment of ear, throat, respiratory,
skin and urogenital infections, the recommended dose range
of roxithromyin for children under 40 kg is 5 to 7.5
milligrams/kilogram/day in two divided doses. Therapy
should be continued for at least 2 days after resolution of
symptoms, and for at least 10 days in streptococcal
infections, urethritis, cervicitis, and cervicovaginitis. The
maximum duration of therapy is 4 weeks. Doses should be
taken in the morning and evening before meals (Fachinfo
Rulid(R) junior, 1998).
 b. The recommended dose for children weighing 7 to 13 kg
is 25 milligrams twice daily (Fachinfo Rulid(R) junior, 1998).
 c. The recommended dose for children weighing 14 to 26 kg
is 50 milligrams twice daily (Fachinfo Rulid(R) junior, 1998).
 d. The recommended dose for children weighing 27 to 40 kg
is 100 milligrams twice daily (Fachinfo Rulid(R) junior, 1998).
 2. BRONCHIECTASIS
 a. Preliminary data indicate that oral roxicithromycin 4
milligrams/kilogram twice daily for 12 weeks is effective in
reducing airway responsiveness in children with
bronchiectasis (various etiologies). Additional studies are
needed to fully evaluate the clinical utility and safety of
roxithromycin for this indication (Koh et al, 1997).
 3. EAR INFECTIONS
 a. Preliminary data indicate that oral roxithromycin in doses
of 2.5 to 5 milligrams/kilogram every 12 hours for 5 to 6 days
is effective in the treatment of ear infections, including
OTITIS, in pediatric patients (Mandell et al, 1990; DemotesMainard et al, 1989; Young et al, 1989; Bazet et al, 1988;
Grassi et al, 1988; Begue et al, 1987; Herron, 1987; Kafetzis
& Blanc, 1987).
 4. RESPIRATORY TRACT INFECTIONS
 a. Preliminary data indicate that oral roxithromycin in doses
of 2.5 to 5 milligrams/kilogram every 12 hours for 5 to 6 days
is effective in the treatment of respiratory tract infections,
including PERTUSSIS, TONSILLITIS, PHARYNGITIS,
RHINOPHARYNGITIS, and SINUSITIS in pediatric patients
(Mandell et al, 1990; Demotes-Mainard et al, 1989; Young et
al, 1989; Bazet et al, 1988; Grassi et al, 1988; Begue et al,
1987; Herron, 1987; Kafetzis & Blanc, 1987).
 5. SKIN INFECTIONS
 a. Preliminary data indicate that oral roxithromycin in doses
of 2.5 to 5 milligrams/kilogram every 12 hours for 5 to 6 days
is effective in the treatment of SKIN INFECTIONS and SOFT
TISSUE INFECTIONS in pediatric patients (Mandell et al,
1990; Demotes-Mainard et al, 1989; Young et al, 1989; Bazet
et al, 1988; Grassi et al, 1988; Begue et al, 1987; Herron,
1987; Kafetzis & Blanc, 1987).
 1.4.2 DOSAGE IN RENAL FAILURE
 A. Dosage adjustments have been suggested not to be required with
roxithromycin in patients with severe renal insufficiency (Lebrec et al, 1988;
Puri & Lassman, 1987; Periti & Mazzei, 1987). Other investigators, however,
have reported significant delays in roxithromycin elimination in patients with a
creatinine clearance of less than 15 milliliters/minute, and recommend
doubling the dosing interval in these patients to avoid accumulation
(Halstenson et al, 1990).
 1.4.3 DOSAGE IN HEPATIC INSUFFICIENCY
 A. No dosage adjustment of roxithromycin is required in patients with
documented cirrhosis (Lebrec et al, 1988; Puri & Lassman, 1987; Periti &
Mazzei, 1987); however, the elimination half-life of roxithromycin is increased
in the presence of alcoholic liver disease (Young et al, 1989; Nilson, 1987) and
dosage adjustment may be required in patients with hepatic dysfunction. The
manufacturer recommends halving the usual dose for patients with severe
hepatic dysfunction (Fachinfo Rulid(R), 1998).
 2.0 PHARMACOKINETICS
 2.1 ONSET AND DURATION
 2.1.1 ONSET
 A. INITIAL RESPONSE:
 2.1.2 DURATION
 A. SINGLE DOSE:
 1. BACTERIAL INFECTION, oral: 12 hours (Demotes-Mainard et al,
1989).
 a. Serum roxithromycin concentrations remain above
minimum inhibitory concentrations for most susceptible
pathogens for at least 12 hours after an oral dose of 2.5
mg/kg (Demotes-Mainard et al, 1989).
 2.2 DRUG CONCENTRATION LEVELS
 2.2.1 THERAPEUTIC
 A. TIME TO PEAK CONCENTRATION:
 1. ORAL: 1 to 2 hours (Kafetzis et al, 1988; Kees et al, 1988; Lassman
et al, 1988; Tremblay et al, 1988a).
 a. In adults, peak plasma levels (Cmax) of approximately 6,
10, and 12 mcg/mL are reached after single oral doses of
roxithromycin 150, 300, and 450 mg, respectively (Lassman
et al, 1988; Tremblay et al, 1988a).
 b. In children receiving oral roxithromycin 2.5 mg/kg every 12
hours for 6 days, mean peak serum levels (Cmax) are
approximately 8 to 10 mcg/mL (Demotes-Mainard et al,
1989).
 2.3 ADME
 2.3.1 ABSORPTION
 A. BIOAVAILABILITY (F):
 1. ORAL:
 a. Roxithromycin is rapidly absorbed (Lassman et al, 1988;
Tremblay et al, 1988a; Nilsen, 1987).
 B. EFFECTS OF FOOD: minimal (Segre et al, 1988; Puri & Lassman, 1987).
 1. Administration of oral roxithromycin 15 minutes after a standard
meal has been shown to attenuate peak serum levels and to delay
time to peak serum levels; oral bioavailability is decreased by 21%.
This effect is not considered clinically important. Administration 15
minutes before meals does not influence oral bioavailability (Segre et
al, 1988; Puri & Lassman, 1987).
 2. The administration of single oral doses of roxithromycin 300 mg
with milk instead of water has been shown to increase its
bioavailability by approximately 15%; this interaction is not likely to be
of clinical significance (Lassman et al, 1988; Puri & Lassman, 1987).
 2.3.2 DISTRIBUTION
 2.3.2.1 DISTRIBUTION SITES
 A. TOTAL PROTEIN BINDING: 85% to 96% (Zini et al, 1988;
Reynolds, 1997; Begue et al, 1987; Wise et al, 1987).
 1. Roxithromycin is mainly bound to alpha-1-acid
glycoprotein (Zini et al, 1988; Begue et al, 1987; Wise et al,
1987).
 2. Roxithromycin is 96% bound at trough concentrations and
86% at peak concentrations (Reynolds, 1997).
 B. OTHER DISTRIBUTION SITES:
 1. ACNE LESIONS, fair (Akamatsu & Horio, 2001).
 a. A mean concentration of 0.54 mcg/mL was found
in acne vulgaris lesions of 5 patients who received
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oral roxithromycin 150 mg twice daily for 2 weeks.
The 90% minimum inhibitory concentration (MIC-90)
for Propionibacterium acnes was considered to be
0.1 mcg/mL (Akamatsu & Horio, 2001).
2. AQUEOUS HUMOR, excellent (Mandell et al, 1990).
 a. Roxithromycin penetrates into the aqueous
humor, reaching concentrations ranging from 50%
to 200% of serum concentrations (Mandell et al,
1990).
3. BLISTER FLUID, good (Wise et al, 1987).
 a. Roxithromycin penetrates well into blister fluid,
producing concentrations approximately 85% of
those achieved in the plasma (Wise et al, 1987).
4. CEREBROSPINAL FLUID, limited (Puri & Lassman, 1987).
 a. Roxithromycin traverses the blood-brain barrier
poorly. One study found no detectable roxithromycin
in the CSF of volunteers with normal meninges who
received 150 mg every 12 hours (Puri & Lassman,
1987). Others have stated that roxithromycin
exhibits excellent penetration through the bloodbrain barrier (Bowman, 1990; Gasser & Dusleag,
1990); however, there is no evidence to substantiate
this claim.
5. GENITAL TISSUES, good (De Grandi et al, 1988; Botto et
al, 1988; Bergogne-Berezin, 1987).
 a. Roxithromycin distributes relatively well into
female genital tract tissues. In patients undergoing
total hysterectomy, serum concentrations of
approximately 2 mg/kg were found in the
MYOMETRIUM, OVARIES, and OVIDUCTS 4 hours
after multiple oral doses of 150 mg. The
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tissue/serum ratio in these patients was 0.27 to 0.34
(De Grandi et al, 1988; Bergogne-Berezin, 1987).
 b. Roxithromycin penetrates readily into PROSTATIC
FLUID, producing levels comparable to those
observed in the serum (Botto et al, 1988).
6. LEUKOCYTES, excellent (Anderson et al, 1987; Carlier et
al, 1987).
 a. Roxithromycin accumulates avidly into
macrophages and polymorphonuclear neutrophils;
intracellular/extracellular ratios have ranged from 14
to 190 (Anderson et al, 1987; Carlier et al, 1987).
7. PERIODONTAL TISSUES, good (Del Tacca et al, 1990).
 a. Roxithromycin penetrates well into gingiva and
alveolar bone. After a loading dose of 300 mg
followed by 150 mg every 12 hours for 3 doses,
levels of approximately 4.5 mcg/mL and 6.5 mcg/mL
were observed in alveolar bone and gingiva,
respectively. This corresponded to tissue/plasma
ratios of about 1.5 and 1.25, respectively (Del Tacca
et al, 1990).
8. PLACENTA, good (Mandell et al, 1990).
 a. Although the clinical significance is unknown,
roxithromycin crosses the placenta; concentrations
30% to 40% of those in maternal serum are found in
newborn serum (Mandell et al, 1990).
9. PULMONARY TISSUE, good (Chastre et al, 1987)
 a. Overall, roxithromycin exhibits good penetration
into the respiratory tract. Although it displays low
penetration into PULMONARY EPITHELIAL LINING
FLUID, it does accumulate into ALVEOLAR
MACROPHAGES at concentrations 2 to 10 times
those achieved in the plasma (Chastre et al, 1987).
 b. Other studies have found that roxithromycin
penetrates well into PULMONARY SECRETIONS,
SINUS MUCOSA, LUNG TISSUE, and SPUTUM,
producing concentrations equal to or exceeding
plasma concentrations (De Rose et al, 1988;
Dewever, 1988; Kropec et al, 1988; Rimoldi et al,
1988; Tremblay et al, 1988; Bergogne-Berezin,
1987).
 c. The ability of roxithromycin to penetrate
BRONCHIAL SECRETIONS was studied in critically
ill patients after repeated doses. Patients with
respiratory failure, with an endotracheal tube in
place, received oral roxithromycin 300 mg initially,
followed by 150 mg every 12 hours for a total of 7
doses. The average trough concentration of
roxithromycin was 1.01 mcg/mL in bronchial
secretions; the average peak concentration in
bronchial secretions was 4.71 mcg/mL, occurring 2
to 4 hours after the dose (Boccazzi & Langer, 1991).
 10. SALIVA, neglible (Del Tacca et al, 1990; Smith et al,
1989).
 a. Roxithromycin exhibits little to no penetration into
the saliva; after oral administration, it has been
found at extremely low levels or not detected at all in
the saliva (Del Tacca et al, 1990; Smith et al, 1989;
Acar et al, 1988; Puri & Lassman, 1987).
 11. SKIN, excellent (Campa et al, 1990).
 a. Roxithromycin exhibits a high degree of
penetration into the skin. After a 300 mg loading
dose followed by 150 mg every 12 hours for 3
doses, a mean peak skin level of 31.3 mg/kg
occurred 4 hours after the last dose. The elimination
half-life in the skin was 6 hours (Campa et al, 1990).
 12. SYNOVIAL FLUID, good (Meirovich et al, 1988;
Bergogne-Berezin, 1987).
 a. Roxithromycin penetrates into synovial fluid,
attaining levels essentially equivalent to those
reached in the plasma (Meirovich et al, 1988;
Bergogne-Berezin, 1987).
 13. TEAR FLUID, excellent (Acar et al, 1988; BergogneBerezin, 1987).
 a. Roxithromycin concentrations reached in tear
fluid are approximately twice those reached in the
plasma (Acar et al, 1988; Bergogne-Berezin, 1987).
 14. TONSILS, excellent (Begue et al, 1988; Begue et al,
1987).
 a. Roxithromycin penetrates variably into the tonsils.
After a single 300-mg dose of roxithromycin, the
tissue/serum ratio was 0.16. After one 300-mg dose
followed by 150 mg every 12 hours for 3 doses, the
tonsil/serum ratio was 0.23 (Galioto et al, 1988).
 b. Roxithromycin concentrations in infected tonsils
and adenoids may exceed those in the plasma
severalfold. In children receiving roxithromycin 2.5
mg/kg every 12 hours, serum concentrations were
approximately 2 to 8 mg/L. Tonsil tissue
concentrations in these patients ranged from
approximately 2 to 6 mg/kg, and concentrations in
the adenoids ranged from approximately 15 to 19
mg/kg (Begue et al, 1988; Begue et al, 1987).
 2.3.2.2 DISTRIBUTION KINETICS
 A. DISTRIBUTION HALF-LIFE: 5 hours (Kees et al, 1988).
 B. VOLUME OF DISTRIBUTION (Vd): 0.43 to 0.44 L/kg (Halstenson et
al, 1990).
 1. The apparent volume of distribution of roxithromycin is
0.43 to 0.44 L/kg, both in normal patients and in patients in
severe renal failure (Halstenson et al, 1990).
 2.3.3 METABOLISM
 2.3.3.1 METABOLISM SITES AND KINETICS
 A. LIVER, limited (Reynolds, 1997).
 2.3.3.2 METABOLITES
 A. descladinose derivative metabolite, inactive (McLean et al, 1988;
Puri & Lassman, 1987; Simon & Stille, 1997).
 1. Approximately 20% of a radioactively marked dose is
excreted as the descladinose derivative (Fachinfo Rulid(R),
1998).
 B. N-monodesmethyl roxithromycin, inactive (Simon & Stille, 1997;
McLean et al, 1988; Puri & Lassman, 1987).
 1. Approximately 5% of a radioactively marked dose is
excreted as the N-mono-desmethyl derivative (Fachinfo
Rulid(R), 1998).
 C. N-didesmethyl, inactive (Simon & Stille, 1997; McLean et al, 1988;
Puri & Lassman, 1987).
 1. Approximately 5% of a radioactively marked dose is
excreted as the N-didesmethyl derivative (Fachinfo Rulid(R),
1998).
 2.3.4 EXCRETION
 2.3.4.1 BREAST MILK
 A. BREASTFEEDING: Safe
 1. Less than 0.05% of an administered dose of roxithromycin
is excreted in the breast milk (Lassman et al, 1988).
 2.3.4.2 KIDNEY
 A. RENAL CLEARANCE: 6 mL/minute (Halstenson et al, 1990).
 B. RENAL EXCRETION: 7% to 12% (Reynolds, 1997; Lassman et al,
1988; McLean et al, 1988).
 2.3.4.3 OTHER
 A. TOTAL BODY CLEARANCE: 49 mL/min (Halstenson et al, 1990).
 B. OTHER EXCRETION:
 1. FECES, 53% (McLean et al, 1988; Bergogne-Berezin,
1987; Puri & Lassman, 1987).
 2. PULMONARY, 13% to 15% (Reynolds, 1997; Puri &
Lassman, 1987; McLean et al, 1988).
 a. About 13% of an oral dose of roxithromycin is
excreted via the pulmonary route, in expired air
(McLean et al, 1988; Puri & Lassman, 1987).
 2.3.5 HALF-LIFE
 2.3.5.1 PARENT COMPOUND
 A. ELIMINATION HALF-LIFE: 12 hours (Birkett et al, 1990; Kafetzis et
al, 1988; Lassman et al, 1988; Tremblay et al, 1988a; Nilsen, 1987).
 1. In children receiving oral roxithromycin 2.5 mg/kg every 12
hours for 5 to 6 days, the elimination half-life is 19 to 21
hours; this increase over the half-life observed in adults is
thought to be due to an increased volume of distribution in
pediatric patients (Demotes-Mainard et al, 1989; Begue et al,
1987).
 3.0 CAUTIONS
 3.1 CONTRAINDICATIONS
 A. Hypersensitivity to roxithromycin
 3.2 PRECAUTIONS
 A. Patients with severe hepatic or renal impairment
 3.3 ADVERSE REACTIONS
 3.3.1 BLOOD
 A. HEMATOLOGIC EFFECTS
 1. Transient EOSINOPHILIA and THROMBOCYTOSIS have been
reported in patients receiving roxithromycin 150 mg twice a day for 10
days, although a causal relationship has not been established
(Peterslund et al, 1989; Agache et al, 1987).
 2. LYMPHOPENIA has also been reported with roxithromycin; whether
this is directly related to the drug is not known (Agache et al, 1987).
 3.3.2 CARDIOVASCULAR
 A. QT PROLONGATION
 1. Severe QT INTERVAL PROLONGATION occurred in a 72-year-old
man when ROXITHROMYCIN was added to therapy (Woywodt et al,
2000). The patient had severe congestive heart failure, for which he
was taking furosemide, digoxin, captopril, aspirin, and amiodarone.
He was hospitalized for suspected pneumonia. His electrocardiogram
(ECG) showed normal QT intervals (QT interval 380 ms; QTc 390 ms
(Bazett's formula corrected QT interval)). A course of roxithromycin
150 mg twice daily was initiated. On day 3, he was found to have QT
and QTc intervals of 680 ms and 660 ms, respectively. Serum
electrolytes were normal, the patient had no chest pain, and serum
levels of digoxin and amiodarone were normal. Roxithromycin,
digoxin, and amiodarone were withdrawn, and his QT interval
gradually improved. The authors concluded that the addition of
roxithromycin to concomitant digoxin and amiodarone had caused the
patient's QT interval prolongation. Close monitoring is recommended
when roxithromycin is given to patients who might be predisposed to
cardiac disturbances.
 3.3.3 CENTRAL NERVOUS SYSTEM
 A. CENTRAL NERVOUS SYSTEM EFFECTS
 1. HEADACHE and tiredness occur in 1% to 5% of patients receiving
roxithromycin, but these effects are mild and do not usually lead to
discontinuation of therapy (Worm, 1990; Worm et al, 1989).
 3.3.4 ENDOCRINE/METABOLIC
 A. METABOLIC EFFECTS
 1. HYPERGLYCEMIA was noted in 2 of 38 patients treated with
roxithromycin 150 mg twice a day for 10 days; however, a causal
relationship has not been established (Agache et al, 1987).
 3.3.5 GASTROINTESTINAL
 A. GASTROINTESTINAL EFFECTS
 1. NAUSEA, DIARRHEA, ABDOMINAL CRAMPS, and ANOREXIA are
the most frequently occurring adverse effects associated with
roxithromycin, developing in approximately 5% of patients treated
(Worm, 1990; Worm et al, 1989; Melcher et al, 1988).
 B. PANCREATITIS
 1. Roxithromycin was reported to cause pancreatitis in a 54-year-old
woman. The patient had been treated previously with other antibiotics,
including erythromycin; however, the symptoms of pancreatitis
occurred after roxithromycin was started and stopped when it was
discontinued. The successive use of erythromycin, followed by
roxithromycin may have aggravated the pancreatitis (Souweine et al,
1991).
 3.3.6 KIDNEY/GENITOURINARY
 A. GENITOURINARY EFFECTS
 1. VULVOVAGINAL CANDIDIASIS occurred in 1 of 40 patients
receiving roxithromycin 300 mg/day for 7 days; however, it is highly
unlikely that this was drug-related (Worm et al, 1989).
 2. RENAL FAILURE occurred in one of 31 patients receiving
roxithromycin 150 mg twice a day; however, a cause-effect
relationship was not established (Poirier, 1991).
 3.3.7 LIVER
 A. HEPATOTOXICITY
 1. FULMINANT HEPATIC FAILURE, possibly induced by
ROXITHROMYCIN, occurred in a previously healthy 5-year-old boy.
The patient was treated with a 5-day course of roxithromycin 50 mg
twice daily for a dry cough, fever, and anorexia. He had accidentally
ingested yellow food coloring 1 day after initiation of roxithromycin.
The day following completion of roxithromycin, he developed an
ERYTHEMATOUS, MACULOPAPULAR, GENERALIZED RASH and
occasional VOMITING. Three days later he exhibited JAUNDICE,
DARK URINE, and PALE STOOLS; frequency of vomiting increased.
His liver function tests were markedly elevated (alanine
aminotransferase (ALT) was 30 times the upper limit of normal). There
were signs of increasing liver dysfunction, with progression to
HEPATIC ENCEPHALOPATHY. Because of worsening liver function,
the boy was given a liver transplantation. A month after
transplantation, he was discharged to home. Using the Naranjo
algorithm, roxithromycin was found to be a "possible" causative agent;
however, the authors noted that because of the severity of the
reaction, a number of questions related to the algorithm could not be
answered (Easton-Carter et al, 2001).
 2. Fulminant acute hepatitis was reported in a 23-year-old woman
after receiving roxithromycin 150 mg twice daily for a genital
chlamydia infection. The reaction was characterized by jaundice and
increased ALT which appeared two days after stopping five days of
roxithromycin treatment. Liver function tests returned to normal
approximately three weeks later (Pedersen et al, 1993).
 3. JAUNDICE was reported in a 43-year-old man after taking roxithromycin 150
mg twice a day for 8 days for a respiratory tract infection. AST (SGOT) and
ALT (SGPT) were substantially elevated, and alkaline phosphatase and serum
bilirubin were elevated greater than 3-fold from baseline. Liver function tests
resolved over the following 3 weeks (Delcourt et al, 1990).
 4. Asymptomatic elevations in liver function tests may occur in patients
receiving roxithromycin, but these are short-lived and resolve upon completion
of therapy (Poirier, 1991; Worm, 1990; Worm et al, 1989; Melcher et al, 1988).
 3.3.10 SKIN
 A. DERMATOLOGIC EFFECTS
 1. Mild ITCHING occurs in 1% to 5% of patients receiving usual doses of
roxithromycin, but this usually does not lead to discontinuation of therapy
(Poirier, 1991; Worm, 1990; Worm et al, 1989).
 B. NAIL DISCOLORATION
 1. A possible case of nail discoloration was reported following therapy with
roxithromycin. After two separate courses of roxithromycin therapy (150 mg
twice daily), the patient experienced light to brown pigmentation affecting all of
the finger nails; the pigmentation worsened after each two-week course of
roxithromycin. The toe nails were not affected. Culture results from the nails
revealed no evidence of either fungal or bacterial infection. The discoloration
eventually faded, and completely disappeared after six months (Dawn et al,
1995).
 3.3.12 OTHER
 A. OVERDOSE See POISINDEX(R) Management "MACROLIDE ANTIBIOTICS"
 B. SUPERINFECTION
 1. Neither superinfection nor ANTIBIOTIC-ASSOCIATED DIARRHEA have been
reported with roxithromycin. Although suppression of normal flora and
secondary colonization with gram-negative organisms has been observed,
normal intestinal flora is usually reestablished within 7 days of discontinuation
of the drug. Roxithromycin does not appear to adversely influence colonization
resistance against overgrowth (Pecquet et al, 1991; Vollaard et al, 1987).
 3.4 TERATOGENICITY/EFFECTS IN PREGNANCY
 A. TERATOGENICITY
 1. Australian Drug Evaluation Committee's (ADEC) Category B1 (ADEC, 1996).
 See Drug Consult reference: "PREGNANCY RISK CATEGORIES"
 2. Although the clinical significance is unknown, roxithromycin crosses the placenta;
concentrations 30% to 40% of those in maternal serum are found in newborn serum
(Mandell et al, 1990).