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RIFAMPIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Rifampin is a semi-synthetic macrocyclic antibiotic with a wide spectrum of antibacterial activity.

Specific Substances

    1) NSC 113926
    2) Rifaldazine
    3) Rifampicin
    4) Rifampicinum
    5) Rifamycin AMP
    6) CAS 13292-46-1
    1.2.1) MOLECULAR FORMULA
    1) C43-H58-N4-O12

Available Forms Sources

    A) FORMS
    1) FORMULATIONS
    a) CAPSULES: 150 mg and 300 mg maroon and scarlet capsules (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    b) INTRAVENOUS: Rifampin for injection is available in glass vials containing 600 mg rifampin (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    B) USES
    1) Rifampin is used in the treatment of all forms of tuberculosis. It is also used for the treatment of asymptomatic carriers of Neisseria meningitidis to eliminate meningococci from the nasopharynx; however rifampin is not indicated for the treatment of meningococcal infection because of the possibility of the rapid emergence of resistant organisms (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Rifampin is used to treat all forms of tuberculosis. The initial phase of therapy consists of a 3-drug regimen that includes rifampin, isoniazid, and pyrazinamide that is administered for 2 months, followed by maintenance therapy with rifampin and isoniazid for at least 4 months.
    B) PHARMACOLOGY: Rifampin, a semisynthetic macrocyclic antibiotic derivative of rifamycin SV (derived from Streptomyces mediterranei), inhibits DNA-dependent RNA polymerase activity in susceptible mycobacterium tuberculosis organisms. It can interact with bacterial RNA polymerase. Disruption of RNA synthesis interrupts protein synthesis, leading to cell death. However, it does not inhibit the mammalian enzyme.
    C) TOXICOLOGY: The mechanism of toxicity for rifamycin derivatives remains unknown.
    D) EPIDEMIOLOGY: Fatalities have occurred in both adults and children; the minimum lethal dose appears to be highly variable and may depend on underlying comorbidities (ie, hepatic insufficiency).
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Nausea, vomiting, jaundice, diarrhea, headache, drowsiness, dizziness, mental confusion and mild, self-limited cutaneous reactions (flushing and itching with or without a rash) have been observed with therapy. Other events may include: flushing and itching of the skin with or without a rash (typically not a hypersensitivity reaction), visual disturbances, fever, muscular weakness, pain in extremities, and generalized numbness. Laboratory findings may demonstrate transient abnormalities in liver function tests (eg, elevated serum bilirubin, alkaline phosphatase, serum transaminases), leukopenia, hemolytic anemia, and decreased hemoglobin, and elevations in BUN and serum uric acid.
    2) INFREQUENT: Thrombocytopenia has been observed in patients receiving intermittent high-dose therapy.
    3) RARE: Agranulocytosis, disseminated intravascular coagulation, hemolysis, hemoglobinuria, hematuria, acute renal failure, psychoses, anaphylaxis have been reported rarely with therapy.
    4) CHRONIC USE: Hepatitis and jaundice may be noted following chronic therapeutic administration of rifamycin antibiotics and is most notable in patients with chronic liver disease, alcoholism, and old age.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Patients are likely to present with nausea and vomiting; the vomitus may appear orange to red in color. Other symptoms include: abdominal pain, pruritus, headache, and increasing lethargy. Brownish-red or orange discoloration of the skin and bodily fluids (ie, urine, sweat, saliva, tears, and feces) can develop quickly following overdose; the degree of discoloration appears to be dose-dependent. Transient alterations in liver enzymes and bilirubin levels may be observed. Facial and/or periorbital edema have been observed in some adults and children following overdose.
    2) SEVERE TOXICITY: Hepatotoxicity (ie, liver enlargement, tenderness, elevated liver enzyme and bilirubin concentrations) can develop after a severe overdose. Symptoms may be more severe in patients with a history of impaired liver function. Jaundice may develop soon after severe exposure. A large ingestion can rarely result in seizures, dysrhythmias, pulmonary edema, cardiac arrest and death.
    0.2.20) REPRODUCTIVE
    A) Rifampin is classified as FDA pregnancy category C. Rifampin has been reported to cross the placental barrier and appear in cord blood; however, the effect of rifampin, alone or in combination with other antituberculosis drugs, on the human fetus is unknown. When rifampin is given during the last several weeks of pregnancy, postnatal hemorrhages may occur in the mother and infant. In animal studies, spina bifida, cleft palate, imperfect osteogenesis, and embryotoxicity have been reported in rodents and rabbits. Rifampin is known to be excreted into maternal breast milk.
    0.2.21) CARCINOGENICITY
    A) Rifampin use was associated with accelerated growth of lung carcinoma in a few case reports, but a causal relationship with the drug has not been established.

Laboratory Monitoring

    A) Monitor serum electrolytes, renal function, hepatic enzymes, bilirubin levels, and INR symptomatic patients; monitor until patient recovery.
    B) Obtain a baseline CBC following a significant overdose.
    C) Obtain a baseline ECG and institute continuous cardiac monitoring following a significant overdose.
    D) Plasma rifampin levels may be useful to confirm overdoses, but are not readily available and are not useful in guiding therapy.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Gastrointestinal symptoms (eg, nausea, vomiting, abdominal pain, diarrhea) should be anticipated. Administer IV fluids in patients with significant vomiting and/or diarrhea. Antiemetics may be necessary to control severe nausea and vomiting. Monitor vital signs and assess liver enzymes and bilirubin levels. Monitor neuro function; lethargy is an early finding. Reversible brownish-red or orange discoloration of the skin and bodily fluids is likely to occur and is dose-dependent.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Alterations in mental status may develop; symptoms may be significant in patients with underlying hepatic disease. Monitor liver enzymes and bilirubin levels until evidence of patient recovery. There have been rare reports of conduction abnormalities, hypotension, seizures and pulmonary edema following severe toxicity. Monitor vital signs, neuro status, obtain a baseline ECG and institute cardiac monitoring. Treat seizures with benzodiazepines, barbiturates as necessary. Perform a chest radiograph in a symptomatic patient.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital GI decontamination is not recommended due to the potential for CNS depression.
    2) HOSPITAL: Administer activated charcoal, if the ingestion is relatively recent and the patient is alert and able to protect their airway. Repeat administration of activated charcoal may be beneficial since rifamycin antibiotics undergo enterohepatic circulation. However, there are no clinical trials documenting the efficacy of this procedure. Gastric lavage may also be indicated following a recent, potentially lethal (more than 12 g) ingestion.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following mild to moderate toxicity. However, patients with severe toxicity may develop significant alterations in mental status, or other symptoms that may require intubation.
    E) ANTIDOTE
    1) There is no known antidote.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Extracorporeal procedures are unlikely to be beneficial following overdose based on protein binding and its extensive volume of distribution.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic (other than mild nausea) child or adult with an inadvertent minor (1 or 2 pills) exposure may be monitored at home.
    2) OBSERVATION CRITERIA: Patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children or adults who are symptomatic after inadvertent exposure should be referred to a healthcare facility for evaluation and treatment. Patients may be discharged to home after 6 hours, if symptoms improve after treatment and laboratory studies remain normal.
    3) ADMISSION CRITERIA: Patients with persistent symptoms despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Call a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) Underlying hepatic insufficiency may produce more severe toxicity. Monitor liver enzymes until they return to normal. Patients should also be monitored for renal and hematologic (ie, thrombocytopenia, neutropenia) toxicity.
    I) PHARMACOKINETICS
    1) Rifampin is readily absorbed from the gastrointestinal tract. Following absorption, rifampin is rapidly eliminated in the bile, and enterohepatic circulation ensues (progressive deacetylation occurs in approximately 6 hours). Rifampin is widely distributed in the body. It is approximately 80% protein bound. In adults, the mean half-life in serum is 3.35 hours (+/- 0.66 hours) after a 600 mg oral dose and 5.08 hours (+/- 2.45 hours) after a 900 mg dose. Half-life is likely to increase in patients with a history of renal insufficiency. Up to 30% of the drug is excreted in the urine; approximately half of the drug is excreted unchanged.
    J) DIFFERENTIAL DIAGNOSIS
    1) Coingestants (ie, antipsychotics, opioids, antidepressants, anticonvulsants) may produce significant CNS depression. Discoloration of the skin associated with rifampin exposure is reversible and usually self-limited; "red man syndrome" has been associated with other antibiotics (ie, vancomycin). Rifamycins are potent inducers of cytochrome P450 oxidative enzymes which may produce numerous drug interactions (ie, warfarin, cyclosporine, phenytoin, opioids and oral contraceptives).

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established. ADULT: Fatalities have been reported at doses ranging from 14 to 60 g. Some authors note that rifampin may cause fatal intoxications especially in patients with hepatic dysfunction, alcohol abuse or lack of previous rifampin treatment. PEDIATRIC: Nonfatal overdoses of 100 mg/kg for 1 to 2 doses have been reported in children ranging from 1 to 4 years old.
    B) THERAPEUTIC DOSE: ADULT: ORAL or IV: 10 mg/kg in a single daily dose; not to exceed 600 mg/day. PEDIATRIC: ORAL or IV: 10 to 20 mg/kg; not to exceed 600 mg/day.

Clinical Effects

Summary Of Exposure

    A) USES: Rifampin is used to treat all forms of tuberculosis. The initial phase of therapy consists of a 3-drug regimen that includes rifampin, isoniazid, and pyrazinamide that is administered for 2 months, followed by maintenance therapy with rifampin and isoniazid for at least 4 months.
    B) PHARMACOLOGY: Rifampin, a semisynthetic macrocyclic antibiotic derivative of rifamycin SV (derived from Streptomyces mediterranei), inhibits DNA-dependent RNA polymerase activity in susceptible mycobacterium tuberculosis organisms. It can interact with bacterial RNA polymerase. Disruption of RNA synthesis interrupts protein synthesis, leading to cell death. However, it does not inhibit the mammalian enzyme.
    C) TOXICOLOGY: The mechanism of toxicity for rifamycin derivatives remains unknown.
    D) EPIDEMIOLOGY: Fatalities have occurred in both adults and children; the minimum lethal dose appears to be highly variable and may depend on underlying comorbidities (ie, hepatic insufficiency).
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Nausea, vomiting, jaundice, diarrhea, headache, drowsiness, dizziness, mental confusion and mild, self-limited cutaneous reactions (flushing and itching with or without a rash) have been observed with therapy. Other events may include: flushing and itching of the skin with or without a rash (typically not a hypersensitivity reaction), visual disturbances, fever, muscular weakness, pain in extremities, and generalized numbness. Laboratory findings may demonstrate transient abnormalities in liver function tests (eg, elevated serum bilirubin, alkaline phosphatase, serum transaminases), leukopenia, hemolytic anemia, and decreased hemoglobin, and elevations in BUN and serum uric acid.
    2) INFREQUENT: Thrombocytopenia has been observed in patients receiving intermittent high-dose therapy.
    3) RARE: Agranulocytosis, disseminated intravascular coagulation, hemolysis, hemoglobinuria, hematuria, acute renal failure, psychoses, anaphylaxis have been reported rarely with therapy.
    4) CHRONIC USE: Hepatitis and jaundice may be noted following chronic therapeutic administration of rifamycin antibiotics and is most notable in patients with chronic liver disease, alcoholism, and old age.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Patients are likely to present with nausea and vomiting; the vomitus may appear orange to red in color. Other symptoms include: abdominal pain, pruritus, headache, and increasing lethargy. Brownish-red or orange discoloration of the skin and bodily fluids (ie, urine, sweat, saliva, tears, and feces) can develop quickly following overdose; the degree of discoloration appears to be dose-dependent. Transient alterations in liver enzymes and bilirubin levels may be observed. Facial and/or periorbital edema have been observed in some adults and children following overdose.
    2) SEVERE TOXICITY: Hepatotoxicity (ie, liver enlargement, tenderness, elevated liver enzyme and bilirubin concentrations) can develop after a severe overdose. Symptoms may be more severe in patients with a history of impaired liver function. Jaundice may develop soon after severe exposure. A large ingestion can rarely result in seizures, dysrhythmias, pulmonary edema, cardiac arrest and death.

Heent

    3.4.2) HEAD
    A) WITH POISONING/EXPOSURE
    1) FACIAL EDEMA has been reported following overdoses (Broadwell et al, 1978; Meisel & Brower, 1980).
    a) INCIDENCE: Periorbital or facial edema was seen in 18 of 19 children who received an inadvertent overdose of 100 mg/kg (Bolan et al, 1986), and in a young adult who ingested 12 g (Gross & Dellinger, 1988).
    1) Holdiness (1989) states that periorbital or facial edema occurred in 72.4% of "redman syndrome" cases that he reviewed (Holdiness, 1989).
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) SCLERAL DISCOLORATION does not appear until 6 to 10 hours after exposure. Sclerae may appear yellow-orange in color (Broadwell et al, 1978). Brownish-red or orange discoloration can occur in tears following exposure (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIAC FINDING
    1) WITH POISONING/EXPOSURE
    a) Hypotension, sinus tachycardia, ventricular dysrhythmias and cardiac arrest have been reported in some fatal cases of rifampin overdose (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: One day after intentionally ingesting 60 g rifampin, a 26-year-old man had sinus tachycardia with nonspecific T-wave abnormalities on ECG. The patient experienced cardiac arrest following brief seizure activity and died (Broadwell et al, 1978).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema has been rarely observed in some fatal cases (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    b) CASE REPORTS: Death was attributed to severe acute toxic pulmonary edema in a 28-year-old man who ingested 14 to 15 g of rifampin (Plomp et al, 1981). In another case, pulmonary edema found at autopsy was attributed to chronic dapsone taken concurrently with intermittent rifampin (Lau, 1995).
    c) CASE REPORT: Nonspecific interstitial shadowing was observed on chest X-ray in a fatal rifampin overdose in a 26-year-old man (Broadwell et al, 1978).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported with therapy (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    B) ALTERED MENTAL STATUS
    1) WITH THERAPEUTIC USE
    a) Drowsiness, inability to concentrate, mental confusion, and behavioral changes have developed with therapeutic use (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) Lethargy is likely to occur shortly after ingestion. More severe symptoms (ie, obtundation) may be observed in patients with underlying hepatic disease (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    b) CASE REPORT: Progressive lethargy and obtundation were reported 6 hours after the intentional ingestion of an unknown quantity of rifampin (Meisel & Brower, 1980).
    C) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures have been observed in some fatal cases (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    b) CASE REPORT: A 26-year-old man experienced brief, generalized seizure activity then death about 48 hours following the ingestion of 60 g rifampin (Broadwell et al, 1978).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Signs and symptoms occurring with overdosage may include nausea, vomiting, intense abdominal pain and diarrhea (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010; Gross & Dellinger, 1988; Broadwell et al, 1978; Newton & Forrest, 1975).
    b) INCIDENCE: Nausea and vomiting are common overdose effects of these agents and likely to occur shortly after ingestion (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010; Villarino et al, 1997; Osborn, 1994), with the vomitus often orange to red in color (Prod Info Rifadin(R), rifampin, 1996).
    B) ABNORMAL COLOR
    1) WITH POISONING/EXPOSURE
    a) BODY FLUID DISCOLORATION: A dose-dependent brownish-red to orange discoloration of skin, saliva, tears, sweat, urine, and feces may occur, which is reversible (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010). Discoloration of mucous membranes of the mouth and nasopharynx is common in poisonings (Broadwell et al, 1978; Osborn, 1994).
    C) ESOPHAGITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Pill-induced esophagitis due to oral rifampin has been reported in a 70-year-old man. The capsule was found partially embedded in the neopharynx. A barium swallow identified an upper esophageal obstruction consistent with edema related to pill-induced esophagitis. Predisposing factors included age, bedridden state, GERD, concurrent medications, and a neopharyngeal stricture (Smith et al, 1999).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Conventional doses may produce elevations in liver enzymes (ie, elevations in serum bilirubin, alkaline phosphatase, serum transaminases) (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010; Villarino et al, 1997; Meisel & Brower, 1980; Konietzko & Burkhardt, 1971) and intermittent therapy can cause hepatitis and hepatic failure. Hepatic toxicity may be more frequent in patients with prior hepatic insufficiency and in those patients on intermittent therapy. Concomitant therapy with isoniazid results in elevated liver enzymes and bilirubin in approximately one-third of patients, which is often self-limited and reverses after about 2 weeks in most patients with continuation of therapy (Osborn, 1994).
    b) RISK FACTOR/COMBINATION THERAPY: Drug-induced toxic hepatitis appears more frequently and with greater severity during combination therapy with isoniazid and rifampin compared to single drug therapy. This is observed more frequently in children (Steele et al, 1991). Fatal and severe hepatitis has been reported in a man and a woman, respectively, following combination therapy with rifampin and pyrazinamide for the treatment of latent tuberculosis infection (CDC, 2001).
    c) CASE SERIES: Twenty-one patients developed severe hepatitis after receiving rifampin-pyrazinamide (2-month therapy regimen for latent tuberculosis). Liver failure and death occurred in 5 patients (Anon, 2001).
    d) CASE REPORT: Progressive jaundice, hepatomegaly and cholestasis with eosinophilia was reported in a 71-year-old man taking therapeutic daily dapsone and monthly rifampin for tuberculoid leprosy. The patient deteriorated with hepatorenal syndrome, and death was attributed to drug-induced multiorgan damage (Lau, 1995).
    2) WITH POISONING/EXPOSURE
    a) SUMMARY: Transient increases in liver enzymes and/or bilirubin have been observed following overdose. Hepatic impairment may be significant in patients with a prior history of hepatic insufficiency (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    b) CASE REPORT: Mild liver impairment was reported in a patient who ingested 12 g of rifampin. Liver enzymes returned to normal within 5 days following symptomatic care, and the patient's recovery was uneventful (Prod Info Rifadin(R), rifampin, 1996).
    c) CASE REPORT: Total serum bilirubin peaked at 5.4 mg/dL following a 12 g rifampin overdose in a 14-year-old girl. She recovered following symptomatic care (Wong et al, 1984).
    B) BILIRUBIN LEVEL - FINDING
    1) WITH THERAPEUTIC USE
    a) Meisel et al (1980) reported that rifampin serum concentrations of greater than 100 mcg/mL can interfere with the bilirubin assay and result in spurious hyperbilirubinemia (Meisel & Brower, 1980). Following an overdose, a decline in elevated serum bilirubin concentration may correspond with plasma clearance of rifampin.

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL COLOR
    1) WITH POISONING/EXPOSURE
    a) Urine discoloration, a reddish to orange color, is commonly observed following overdose (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010; Broadwell et al, 1978; Osborn, 1994).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal failure (ARF) is uncommon with therapeutic use (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010), and is usually associated with intermittent or interrupted therapy (Cohn et al, 1985) and in many cases associated with tubular lesions (De Vriese et al, 1998). This may be a result of an antibody-mediated immune reaction. Acute renal failure may occur in association with eosinophilia, skin reactions, and hepatorenal syndrome.
    b) RISK FACTORS: De Vriese et al (1998) have identified 4 patterns of rifampicin-associated ARF: acute tubular necrosis (most common), rapidly progressive glomerulonephritis, acute interstitial nephritis, and light chain proteinuria. Many of the patients who developed acute tubular necrosis also developed hemolytic anemia and/or thrombocytopenia, which the authors speculate may be due to an antibody with anti-I specificity (De Vriese et al, 1998).
    c) CASE REPORT: A patient on intermittent rifampin for lepromatous leprosy developed anuria one day after restarting rifampin following a 3 month drug-free period. The patient deteriorated, with coma and severe jaundice. He was diagnosed with uremic coma, acidosis, and malnutrition. Improvement occurred following 4 days of 5 hour hemodialysis sessions. Renal biopsy showed extensive tubular destruction with interstitial fibrosis. inflammatory cellular infiltration, and marked tubular changes (Rajan et al, 1987)The author reported 2 other similar cases of intermittent rifampin resulting in drug-induced acute tubular necrosis, confirmed on renal biopsy.
    d) CASE REPORT: A 71-year-old woman developed ARF (serum creatinine 5.86 mg/100 mL, BUN 80 mg/dL) with severe hemolytic anemia after ingestion of her second dose of rifampin. She had previously taken rifampin 2 years earlier for a period of 2 months. Renal function improved following discontinuation of rifampin and hemodialysis (De Vriese et al, 1998).
    e) CASE REPORT: A 70-year-old man, who had taken rifampin 4 years previously, ingested one unprescribed dose and presented a few hours later with acute renal failure (serum creatinine 7.1 mg/dl and BUN 95 mg/dl), positive Coombs test, and thrombocytopenia (platelets 39,000). Renal biopsy showed glomerular damage and renal tubular necrosis (Addario C, Tricerri A & Vangeli M et al, 1994).
    f) CASE REPORT: Acute eosinophilic interstitial nephritis, seen on percutaneous renal biopsy, and most likely secondary to intermittent therapeutic rifampin use was reported in a 61-year-old woman. Hemodialysis was started, and the patient began to improve after 4 days (Katz & Lor, 1986).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia, hemolytic anemia, methemoglobinemia, hypothrombinemia, transient leukopenia, and anemia have been reported following chronic ingestion of therapeutic dose (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    b) There have been rare reports of disseminated intravascular coagulation and agranulocytosis with therapeutic use (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Thrombocytopenia has been developed most frequently following high-dose intermittent therapy, but has also developed after resumption of interrupted treatment. The effect is usually reversible, if rifampin is discontinued as soon as purpura occurs (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010). It has also been noted that conventional doses may produce thrombocytopenia and purpura. An immune-mediated mechanism is suggested (Krivoy et al, 2001).
    b) CASE REPORT: A 27-year-old man developed severe thrombocytopenia (platelets 10 x 10(9)/L) with associated spontaneous intracranial hemorrhage following approximately 4 months therapy with rifampin 600 mg/day and isoniazid 300 mg/day. Rifampin was discontinued and 3 days later his platelet count rose to 180 x 10(9)/L (Kindelan et al, 1994).
    c) CASE REPORT: Thrombocytopenia (platelets 39,000) and a positive Coombs test were reported in a 70-year-old man following a 300 mg dose of rifampin after a 4 year interruption of this drug. Platelets returned to normal after 4 weeks (Addario C, Tricerri A & Vangeli M et al, 1994).
    d) CASE REPORT: Severe and persistent rifampin-induced thrombocytopenia, hemolytic anemia, slight intravascular hemolysis and high serum levels of IgE, without renal function impairment, were reported in a 40-year-old woman. An in-vitro lymphocyte toxicity assay was performed to determine the relationship between her prescribed drugs and adverse events. The cytotoxicity results were 61% for rifampin (above 20% is frankly positive) and negative for other drugs.
    C) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Patients developing acute renal failure during intermittent or interrupted rifampin therapy frequently develop hemolytic anemia or thrombocytopenia concomitantly, which is likely the result of an antibody-mediated immune reaction (De Vriese et al, 1998).
    b) CASE REPORT: A 71-year-old woman developed acute renal failure with severe hemolytic anemia (hemoglobin 7.4 g/100 mL, leukocytes 41,700/microL, and 85% neutrophils) when starting rifampin after a 2 year therapy interruption. Serum lab tests showed rifampin-dependent IgG and IgM antibodies causing red blood cell lysis via interaction with the I antigen on erythrocyte surfaces (De Vriese et al, 1998).
    D) EOSINOPHIL COUNT RAISED
    1) WITH POISONING/EXPOSURE
    a) Eosinophilia has been reported in one patient following a suicide attempt (Meisel & Brower, 1980; Ducobu et al, 1982).
    E) PROTHROMBIN TIME LOW
    1) WITH THERAPEUTIC USE
    a) Hypoprothrombinemia has been reported in a patient with longstanding primary biliary cirrhosis with associated low levels of vitamin K who was treated with rifampin for a month (Van Steenbergen & Vermylen, 1995).
    F) METHEMOGLOBINEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 74-year-old man, with a negative Coombs test, developed methemoglobinemia, with serum methemoglobin 55% the day of rifampin therapy and 33% the day after rifampin. He had been taking 900 mg rifampin twice weekly with isoniazid 450 mg. The patient had also developed acute renal failure and hemolytic anemia (Luzio & De Matos, 1996).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DISCOLORATION OF SKIN
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: The most striking and unique feature of rifampin poisoning, occurring rapidly following overdoses, is a bright orange and red discoloration of the skin which can be partially removed by washing (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010; Broadwell et al, 1978; Osborn, 1994; Meisel & Brower, 1980). The degree of discoloration is dependent on the amount ingested (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    1) ONSET: In a review of overdoses, the average time of onset of the pigmentation was 2.2 hours with a range of 0.5 to 24 hours (Holdiness, 1989).
    B) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Flushing and itching of the skin (with or without rash) are usually mild and self-limited. The cutaneous reactions do not appear to be hypersensitivity reactions (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    b) Hand and facial pruritus has been reported in health professionals handling rifampin powder (Anker & Bang, 1981; DeSousa et al, 1987). Diphenhydramine has been effective in ameliorating cutaneous reactions (Fan-Havard et al, 1988).
    c) Rash and pruritus are common adverse effects of these drugs, occurring in 6% of adolescents (n=157) in one study (Villarino et al, 1997).
    2) WITH POISONING/EXPOSURE
    a) Pruritus is likely to occur following overdose (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010; Bolan et al, 1986).
    b) Intense pruritus was reported in an adult following the ingestion of 60 g of rifampin (Broadwell et al, 1978) and in a 14-year-old girl after ingestion of 12 g (Wong et al, 1984)Wong et al, 1984).
    C) ANGIOEDEMA
    1) WITH THERAPEUTIC USE
    a) Edema of the face and extremities has been reported with therapeutic use (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) Rifamycin antibiotic overdoses may be expected to produce angioedema (Meisel & Brower, 1980). Facial and periorbital edema have been observed in children following overdose (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) Muscular weakness and pains in the extremities have been reported with therapeutic use of rifampin (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    b) CASE REPORT: Proximal muscle weakness accompanied by symmetrical proximal muscle wasting was reported as an adverse effect of rifampin in a 44-year-old woman (Jenkins & Emerson, 1981).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DISORDER OF IMMUNE FUNCTION
    1) WITH THERAPEUTIC USE
    a) SUMMARY: High-dose intermittent therapy or reinstitution of therapy may result in antibody-mediated immune reactions, including autoimmune anemia, thrombocytopenia, and renal failure (Krivoy et al, 2001; De Vriese et al, 1998; Addario C, Tricerri A & Vangeli M et al, 1994). Effects seen with conventional doses include elevations in liver enzymes, thrombocytopenia, and purpura. Signs and symptoms occurring with overdosage may include hepatomegaly with tenderness and rapidly developing increase in direct and total bilirubin.
    b) CASE REPORT: A 71-year-old woman who restarted rifampin after a 2 year interruption developed acute renal failure and severe hemolytic anemia on the second day of therapy. Tests on the patient's serum revealed rifampicin-dependent immunoglobulin G (IgG) and IgM antibodies which interacted with the I antigen on erythrocyte surfaces causing red blood cell lysis. The authors speculate that in this and similar cases, the I antigen expressed on tubular epithelium may be the target structure whereby rifampin-antibody complexes lead to tubular cell destruction (De Vriese et al, 1998).
    B) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Patients have occasionally developed pruritus, urticaria, rash, pemphigoid reaction, erythema multiforme including Stevens-Johnson Syndrome, toxic epidermal necrolysis, vasculitis, eosinophilia, sore mouth, sore tongue, and conjunctivitis with rifampin therapy. there have been rare reports of anaphylaxis (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    b) CASE REPORT: Hogenauer (1995) reported hypersensitivity with fever, urticaria, and bilateral pulmonary infiltrates which cleared with discontinuation of rifampin. Symptoms returned when the patient was rechallenged 15 days later (Hogenauer et al, 1995).
    c) CASE REPORT: An anaphylactic reaction due to reexposure to rifampin resulted in dyspnea, vomiting, confusion, fever, erythema, and severe hypotension 15 minutes after dosing in a 33-year-old woman. The patient was diagnosed with an extensive cerebral infarct, apparently due to severe rifampin-induced anaphylactic hypotension. Two years later the patient continued to have partial mixed aphasia (Martinez et al, 1998).
    C) INFLUENZA-LIKE SYMPTOMS
    1) WITH THERAPEUTIC USE
    a) An immune-mediated influenza-like syndrome is an adverse effect seen with therapeutic high dose and/or intermittent rifampin dosing (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010; Jarvis & Lamb, 1998; Osborn, 1994).

Reproductive

    3.20.1) SUMMARY
    A) Rifampin is classified as FDA pregnancy category C. Rifampin has been reported to cross the placental barrier and appear in cord blood; however, the effect of rifampin, alone or in combination with other antituberculosis drugs, on the human fetus is unknown. When rifampin is given during the last several weeks of pregnancy, postnatal hemorrhages may occur in the mother and infant. In animal studies, spina bifida, cleft palate, imperfect osteogenesis, and embryotoxicity have been reported in rodents and rabbits. Rifampin is known to be excreted into maternal breast milk.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of rifampin in pregnant women (Prod Info RIFADIN(R) oral capsules, 2013; Prod Info RIFADIN(R) IV intravenous injection, 2013).
    B) ANIMAL STUDIES
    1) RODENTS - Congenital malformations (mostly spina bifida) were increased at oral doses of 150 to 250 mg/kg/day (about 1 to 2 times the maximum recommended human dose based on body surface area) given to rats during organogenesis. Oral doses of 50 to 200 mg/kg (about 0.2 to 0.8 times the maximum recommended human dose based on body surface area) given to pregnant mice also resulted in a dose-dependent increase in cleft palate in fetuses (Prod Info RIFADIN(R) oral capsules, 2013; Prod Info RIFADIN(R) IV intravenous injection, 2013).
    2) RABBITS - Imperfect osteogenesis was reported after pregnant rabbits were given rifampin doses up to 200 mg/kg/day (about 3 times the maximum recommended human dose based on body surface area) (Prod Info RIFADIN(R) oral capsules, 2013; Prod Info RIFADIN(R) IV intravenous injection, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified rifampin as FDA pregnancy category C (Prod Info RIFADIN(R) oral capsules, 2013; Prod Info RIFADIN(R) IV intravenous injection, 2013).
    B) PLACENTAL BARRIER
    1) Rifampin has been reported to cross the placental barrier and appear in cord blood (Prod Info RIFADIN(R) oral capsules, 2013; Prod Info RIFADIN(R) IV intravenous injection, 2013).
    C) HEMORRHAGE
    1) When rifampin is given during the last several weeks of pregnancy, postnatal hemorrhages may occur in the mother and infant (Prod Info RIFADIN(R) oral capsules, 2013; Prod Info RIFADIN(R) IV intravenous injection, 2013).
    D) ANIMAL STUDIES
    1) RABBITS - Embryotoxicity was reported after pregnant rabbits were given rifampin doses up to 200 mg/kg/day (about 3 times the maximum recommended human dose based on body surface area) (Prod Info RIFADIN(R) oral capsules, 2013; Prod Info RIFADIN(R) IV intravenous injection, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Rifampin is reportedly not found in breast milk but further quantitative data is required for accurate evaluation (White & White, 1980). Some data suggest that following maternal ingestion of rifampin 600 mg, 0.05% of the dose is distributed into breast milk in 24 hours. Assuming a body weight of 3.5 kg, the amount of rifampin ingested by nursing infants is estimated to be 0.085 mg/kg or 0.57% of the usual therapeutic pediatric dose (15 mg/kg). The authors suggest that the risk of adverse reactions in infants of nursing mothers receiving rifampin is minimal (Snider & Powell, 1984).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info RIFADIN(R) oral capsules, 2013; Prod Info RIFADIN(R) IV intravenous injection, 2013).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Rifampin use was associated with accelerated growth of lung carcinoma in a few case reports, but a causal relationship with the drug has not been established.
    3.21.3) HUMAN STUDIES
    A) LUNG CARCINOMA
    1) Rifampin use was associated with accelerated growth of lung carcinoma in a few case reports, but a causal relationship with the drug has not been established (Prod Info RIFADIN(R) IV intravenous injection, 2013; Prod Info RIFADIN(R) oral capsules, 2013).
    3.21.4) ANIMAL STUDIES
    A) HEPATOMA
    1) Hepatomas were observed when female mice (C3Hf/DP) were given rifampicin 20 to 120 mg/kg (0.1 to 0.5 times the maximum human clinical dose based on body surface area) for 60 weeks followed by an observation period of 46 weeks. There was no evidence of tumorigenicity in male C3Hf/DP mice (Prod Info RIFADIN(R) IV intravenous injection, 2013; Prod Info RIFADIN(R) oral capsules, 2013).

Genotoxicity

    A) No statistically significant differences in frequency of chromosomal aberrations and sister-chromatid exchanges were evident before treatment and after drug exposure between 2 groups of patients; one group untreated, the other receiving isoniazid, rifampin, and pyrazinamide for 2 months (Ekmekçi & Sayli, 1995). An increased frequency of chromosomal aberrations was observed in vitro in the lymphocytes of patients treated with rifampin, isoniazid, and pyrazinamide or streptomycin, rifampin, isoniazid, and pyrazinamide. No evidence of mutagenicity was observed in prokaryotic (Salmonella typhi, Escherichia coli) and eukaryotic (Saccharomyces cerevisiae) bacteria, Drosophila melanogaster, or ICR/Ha Swiss mice. Chromatid breaks were noted when whole blood cell cultures were treated with rifampin (Prod Info RIFADIN(R) IV intravenous injection, 2013; Prod Info RIFADIN(R) oral capsules, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes, renal function, hepatic enzymes, bilirubin levels, and INR symptomatic patients; monitor until patient recovery.
    B) Obtain a baseline CBC following a significant overdose.
    C) Obtain a baseline ECG and institute continuous cardiac monitoring following a significant overdose.
    D) Plasma rifampin levels may be useful to confirm overdoses, but are not readily available and are not useful in guiding therapy.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor hepatic enzymes and bilirubin levels and renal function closely; monitor until patient recovery.
    2) Rifampin serum levels may confirm overdose, but are not readily available and are not useful in guiding therapy.
    B) LABORATORY INTERFERENCE
    1) Elevated total bilirubin levels may be false positive due to interference by rifampin with the assay for bilirubin. Interference can be noted at rifampin levels of 100 mcg/mL or greater (Meisel & Brower, 1980).
    C) HEMATOLOGIC
    1) Monitor CBC following a significant overdose.
    4.1.3) URINE
    A) URINALYSIS
    1) Rifampin metabolites in urine have been reported to cause a false-positive urine melanin pigment reaction when testing for disseminated malignant melanoma (melanogens in urine) with the qualitative von Jaksch test (Altundag & Barista, 1998).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain a baseline ECG and institute continuous cardiac monitoring following a significant overdose. Conduction abnormalities have occurred in some fatal overdoses (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).

Methods

    A) CHROMATOGRAPHY
    1) Serum and urine levels of rifampin and its metabolites may be quantitated using high-pressure liquid chromatography (Weber et al, 1983; Plomp et al, 1981) and spectrophotometry (Jack, 1978).
    B) IMMUNOASSAY
    1) Krivoy et al (2001) reported a modified in vitro lymphocyte toxicity assay, with results read by an ELISA reader, to determine a diagnosis of drug-induced cytotoxicity phenomenon in lieu of the classical de- and rechallenge procedure. This method was used in a case of drug-induced severe and persistent thrombocytopenia to determine the causative drug, which was rifampin.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with persistent symptoms despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic (other than mild nausea) child or adult with an inadvertent minor (1 or 2 pills) exposure may be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Call a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children or adults who are symptomatic after inadvertent exposure should be referred to a healthcare facility for evaluation and treatment. Patients may be discharged to home after 6 hours, if symptoms improve after treatment and laboratory studies remain normal.

Monitoring

    A) Monitor serum electrolytes, renal function, hepatic enzymes, bilirubin levels, and INR symptomatic patients; monitor until patient recovery.
    B) Obtain a baseline CBC following a significant overdose.
    C) Obtain a baseline ECG and institute continuous cardiac monitoring following a significant overdose.
    D) Plasma rifampin levels may be useful to confirm overdoses, but are not readily available and are not useful in guiding therapy.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital GI decontamination is not recommended due to the potential for CNS depression.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Administer activated charcoal, if the ingestion is relatively recent and the patient is alert and able to protect their airway. Repeat administration of activated charcoal may be beneficial since rifamycin antibiotics undergo enterohepatic circulation. However, there are no clinical trials documenting the efficacy of this procedure. Gastric lavage may also be indicated following a significant recent (first 2 to 3 hours) ingestion.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    C) MULTIPLE DOSE ACTIVATED CHARCOAL
    1) Due to the enterohepatic circulation of these drugs, multiple dose activated charcoal may be of value in the clearance of these drugs from the body following severe overdoses (Prod Info Priftin(R), rifapentine, 1998; Osborn, 1994). However, there are no clinical trials documenting the efficacy of this procedure, and its routine use is NOT recommended.
    2) Consider a second dose of activated charcoal in patients with severe toxicity or worsening toxic effects despite initial decontamination.
    D) GASTRIC LAVAGE
    1) May be considered after a recent, potentially lethal (more than 12 g) overdose.
    2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    3) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    4) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    5) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    6) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no specific antidote for rifampin overdosage.
    2) In most cases, symptoms of overdose are limited to gastrointestinal events (ie, nausea, vomiting, abdominal pain). IV fluids and antiemetics may be required.
    3) Monitor CNS function; significant alterations in mental status may develop in the presence of hepatic disease.
    4) Cardiac dysrhythmias, hypotension, seizures and pulmonary edema have been reported rarely in severe cases.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes, renal function, hepatic enzymes and bilirubin concentration, and INR in symptomatic patients; monitor until patient recovery.
    a) Abnormal liver enzymes and other laboratory tests returned to normal in 3 to 7 days in patients that recovered following overdose (Holdiness, 1989).
    2) Obtain a baseline CBC following a significant overdose.
    3) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with evidence of conduction abnormalities.
    4) Plasma rifampin levels may be useful to confirm overdoses, but are not readily available and are not useful in guiding therapy.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    E) EXPERIMENTAL THERAPY
    1) N-ACETYLCYSTEINE (ANIMAL STUDY): In one animal study, n-acetylcysteine (hepatoprotective dose 100 mg/kg/day) prevented the induction of oxidative hepatic injury in young Wistar rats treated with hepatotoxic doses of isoniazid and rifampicin (50 mg/kg/day each intraperitoneally in sterile water) over a 3-week period, except in one animal which showed a mild degree of portal triaditis. In contrast, treatment with isoniazid and rifampicin alone caused hepatic lesions in all treated animals, which varied from a mild to moderate degree of portal triaditis, lobular inflammation, and patchy necrosis (Attri et al, 2000).

Enhanced Elimination

    A) SUMMARY
    1) Extracorporeal procedures are unlikely to be beneficial following overdose based on its protein binding and extensive volume of distribution.
    B) PERITONEAL DIALYSIS
    1) LACK OF EFFICACY: Peritoneal dialysis plays an insignificant role in the removal of these drugs. Kumar et al (1989) found negligible removal of rifampin in an overdose of 4.5 grams in an 11-month-old girl. Only 50 mg of the drug was cleared over 15 exchanges (Kumar et al, 1989).

Abstracts

Case Reports

    A) COMBINATION THERAPY
    1) ISONIAZID, ETHAMBUTOL, AND RIFAMPIN OVERDOSE: Several cases of accidental and intentional overdoses involving the 3 major antituberculosis drugs have been reported. Only one uneventful case, however, has been reported including all 3 agents.
    a) Ducobu et al (1982) presents the intentional overdose of a 40-year-old depressive man ingesting 6 g isoniazid, 20 g ethambutol, and 9 g rifampin. He was admitted to the hospital 2 hours postingestion. Complications included mild lactic acidosis and eosinophilia. Since overdose with single agents has been associated with a variety of symptoms, it is possible that complications did not develop due to prompt hemodialysis. Four hours postingestion, a 3 hour hemodialysis was initiated and the patient later received 10 g of pyridoxine. Confirmation of overdose was based on history from the family (Ducobu et al, 1982).
    B) ADULT
    1) SURVIVAL: An 18-year-old woman ingested 12 g of rifampin and noticed pruritus and orange skin, tears, and urine 3 hours later. Presenting symptoms included headache, lethargy, and nausea. Slight periorbital edema was present. The total bilirubin peaked on the following day at 2.8, with a direct level of 1.5. All other liver function studies were normal. Recovery was uneventful (Gross & Dellinger, 1988).
    2) SURVIVAL: Hepatotoxicity and skin discoloration occurred following acute overdose of rifampin (12 g) in a 55-year-old man. One hour following ingestion, the patient became flushed, diaphoretic, and vomited. He developed bright red skin resembling a boiled lobster. Maximal plasma concentrations of rifampin were 400 micrograms/mL at 12 hours and mild liver function abnormalities were observed (bilirubin 3.7 mg%, alkaline phosphatase 24 ka Units/L, SGOT 61 International Units/L). Orange discoloration of the sweat was observed, and the plasma and urine were noted to have a deep red color. Gastric lavage was performed resulting in a bright orange return. The patient remained symptomatically well and liver function tests returned to normal within 2 days. Skin and plasma discolorations gradually faded (Newton & Forrest, 1975).
    3) FATAL: A fatal rifampin overdose occurred in a 28-year-old man who ingested 14 to 15 g of his roommate's rifampin. The presumed interval between rifampin overdose and death was approximately 8 to 10 hours. Postmortem concentrations of rifampin in the blood, urine, bile, and liver were 55 mcg/mL, 475 mcg/mL, 313 mcg/mL, and 373 mcg/g, respectively. There was an intense orange discoloration of the skin and mucous membranes. The cause of death was attributed to severe acute toxic pulmonary edema. The brain and kidneys were found to be congested and edematous. Postmortem blood and urine alcohol levels were 1.1 g/L and 1.4 g/L, respectively (Plomp et al, 1981).
    4) FATAL: A fatal rifampin overdose occurred in a 28-year-old man who was also receiving ethambutol. Dose and duration were unspecified. Necropsy revealed a pink coloration of the skin, internal organs, and lining of the aorta. The urine was bright red. Spectrophotometry and chromatography revealed a rifampin blood concentration of 182 micrograms/mL. The ethambutol blood concentration was reported to be 84 micrograms/mL. The rifampin urine concentration measured 3.3 mg/mL and the ethambutol urine concentration measured 6.8 mg/mL (Jack, 1978).

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established. ADULT: Fatalities have been reported at doses ranging from 14 to 60 g. Some authors note that rifampin may cause fatal intoxications especially in patients with hepatic dysfunction, alcohol abuse or lack of previous rifampin treatment. PEDIATRIC: Nonfatal overdoses of 100 mg/kg for 1 to 2 doses have been reported in children ranging from 1 to 4 years old.
    B) THERAPEUTIC DOSE: ADULT: ORAL or IV: 10 mg/kg in a single daily dose; not to exceed 600 mg/day. PEDIATRIC: ORAL or IV: 10 to 20 mg/kg; not to exceed 600 mg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) RIFAMPIN
    a) TUBERCULOSIS: ORAL or IV: 10 mg/kg in a single daily dose, not to exceed 600 mg/day(Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    b) ENDOCARDITIS: 900 to 1200 mg IV daily in 3 divided doses (Giessel et al, 2000).
    7.2.2) PEDIATRIC
    A) RIFAMPIN
    1) BACTERIAL MENINGITIS/CSF SHUNT INFECTIONS and STAPHYLOCOCCUS AUREUS OR EPIDERMIDIS
    a) 10 to 20 mg/kg/day IV divided every 12 to 24 hours (maximum 600 mg daily) in combination with vancomycin (Tunkel et al, 2004; Fan-Havard & Nahata, 1987; Vichyanond & Olson, 1984).
    INFECTIVE ENDOCARDITIS
    b) Prosthetic valve, oxacillin-susceptible or -resistant staphylococcal strains or culture-negative: 20 mg/kg/day IV or orally divided every 8 hours (maximum 300 mg/dose) for a minimum of 6 weeks, in combination with appropriate antimicrobial therapy (Baddour et al, 2005).
    c) Documented Bartonella, culture-positive: 10 mg/kg IV or orally every 12 hours (maximum dose 300 mg/dose) for 2 weeks AND doxycycline 1 to 2 mg/kg IV or orally every 12 hours (maximum dose 200 mg/day) for 6 weeks (Baddour et al, 2005).
    PROPHYLAXIS FOR HIGH-RISK CONTACTS OF INVASIVE H. INFLUENZAE TYPE B DISEASE
    d) 20 mg/kg orally every 24 hours for 4 days. Maximum 600 mg/dose (CDC, 1993; Green et al, 1992).
    PROPHYLAXIS FOR HIGH-RISK CONTACTS OF INVASIVE MENINGOCOCCAL DISEASE
    e) 10 mg/kg orally every 12 hours for 2 days. Maximum 600 mg/dose (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010; Simmons et al, 2000).
    STAPHYLOCOCCAL INFECTIOUS DISEASE, SYNERGY
    f) 10 to 20 mg/kg/day orally or IV in divided doses every 12 to 24 hours. Maximum 600 mg/dose (Kaplan, 2006; Le & Lieberman, 2006; Gang et al, 1999; Vichyanond & Olson, 1984).

    2) TUBERCULOSIS
    a) Initial Phase: 10 to 20 mg/kg orally once daily (maximum 600 mg/day) in combination with isoniazid, and pyrazinamide (with or without ethambutol) orally for 2 months (Centers for Disease Control and Prevention et al, 2009; Anon, 2003).
    b) Two weeks of daily 3-drug therapy followed by 6 weeks of twice weekly 3-drug therapy has been used successfully for the initial phase (Al-Dossary et al, 2002).
    c) Continuation Phase: 10 to 20 mg/kg orally once daily (maximum 600 mg/day) in combination with isoniazid for 4 months (if not HIV-infected) or 7 months (HIV-infected or disseminated disease). May also be given 2 or 3 times weekly (Centers for Disease Control and Prevention et al, 2009; Swaminathan et al, 2005; Anon, 2003; Te Water Naude et al, 2000). Children with HIV infection and severe immunosuppression should receive daily or 3 times weekly dosing only (Centers for Disease Control and Prevention et al, 2009).
    d) Directly observed therapy (DOT) is recommended for all children with tuberculosis.

Minimum Lethal Exposure

    A) CASE REPORTS
    1) ADULT
    a) Of 5 suicidal adult ingestions of 20 to 100 times the therapeutic dose of rifampin, 2 resulted in fatality (Newton & Forrest, 1975; Meisel & Brower, 1980; Broadwell et al, 1978; Plomp et al, 1981; Gross & Dellinger, 1988). Both patients had a history of alcohol abuse. The doses ingested were 14 g (Plomp et al, 1981) and 60 g (Broadwell et al, 1978).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) SUMMARY: Acute rifampin overdosage has been reported to result in nausea, vomiting, headache, increasing lethargy shortly after ingestion and red-orange discoloration of skin, urine, and sweat is usually proportional to the amount ingested (color changes are reversible) (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    2) PEDIATRIC: Nonfatal overdoses of 100 mg/kg for 1 to 2 doses have been reported in children ranging from 1 to 4 years old (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    3) ADULT: Nonfatal acute overdoses have occurred in adults following ingestions of 9 to 12 g rifampin (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    4) Holdiness (1989) states that 14 g of rifampin are required before cardiovascular-pulmonary arrest occurs.
    B) HIGH THERAPEUTIC DOSES
    1) Toxicity is mild with conventional rifampin daily doses. However, with intermittent high dose schedules, severe systemic reactions have occurred (probably immunologic in origin) including acute renal failure, acute pancreatitis, thrombocytopenia, hemolysis, and bronchospasm.

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) THERAPEUTIC: Peak plasma levels after a single therapeutic dose (10 mg/kg) range from 7 to 12 mcg/mL (Nitti et al, 1972).
    2) A single 600 mg dose can result in a peak plasma concentration averaging 7 mcg/mL within 1 to 4 hours (Wong et al, 1984), but may vary from 4 to 32 mcg/mL (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) ADULT: The peak rifampin level was 400 mcg/mL at 12 hours after ingestion of 12 g by an adult (Newton & Forrest, 1975).
    b) TEENAGER: Peak rifampin level was reported to be 204 mcg/mL at 5 hours after ingestion of 12 g rifampin by a 14-year-old girl (Wong et al, 1984).
    c) INFANT: A rifampin serum level of 26.6 mcg/mL was reported in an 11-month-old girl following the accidental ingestion of 4.5 g rifampin (Kumar et al, 1989).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 885 mg/kg (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010)
    B) LD50- (ORAL)RAT:
    1) 1720 mg/kg (Prod Info RIFADIN(R) oral capsules, intravenous injection, 2010)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The rifamycin antimycobacterial agents act by selectively inhibiting bacterial DNA-DEPENDENT RNA polymerase of susceptible strains of mycobacteria and other organisms, but not in mammalian cells, thus suppressing the initiation of chain formation in RNA synthesis (Osborn, 1994) .

Toxicologic Mechanism

    A) THROMBOCYTOPENIA: A proposed mechanism(s) for the development of rifampin-induced thrombocytopenia and hemolysis is reactive metabolite(s) and/or rifampin metabolites (eg, desacetylrifampin and/or formylrifampin) covalently linking to host blood cell proteins, forming hapten-protein conjugates. The cell membrane is consequently damaged by the anti-drug antibody. Also, a cytotoxic response against blood cells may occur in response to the aberrant expression of hapten-conjugate on cellular membranes in conjunction with major histocompatibility complex I molecules. This may give rise to rifampin-induced immune hemolytic anemia, intravascular hemolysis, hemoglobinuria and/or thrombocytopenia. Rifampin-associated IgG antibodies may be generated (Krivoy et al, 2001).

Physicochemical

Physical Characteristics

    A) Rifampin is a red-brown crystalline powder, which is freely soluble in chloroform, soluble in ethyl acetate and methanol, and very slightly soluble in water at a neutral pH (Prod Info rifampin oral capsules, 2006; Prod Info RIFATER(R) oral tablets, 2008).

Molecular Weight

    A) 822.94 (Prod Info rifampin oral capsules, 2006; Prod Info RIFATER(R) oral tablets, 2008)

References

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