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HYPERICUM PERFORATUM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Hypericum, or St. John's wort, is a plant extract from the flowering tops of Hypericum perforatum which has been used as a tonic, a tranquilizing agent and an antiviral. The flowering tops of this plant have some astringent and diuretic properties.

Specific Substances

    1) Amber touch-and-heal
    2) Basant, extract
    3) Blut kraut
    4) Herba hyperici
    5) Herbe de milleperitius
    6) Herrogottsblut
    7) Hexenkraut
    8) Hyperforin
    9) Hypericaceae
    10) Hyperici herba
    11) Hyperici oleum
    12) Hypericin
    13) Hypericum perforatum
    14) Johanniskraut
    15) John's wort
    16) Klamath weed
    17) LI 160
    18) Goatweed
    19) Millepertuis
    20) Rosin rose
    21) St. John's Wort
    22) Walpurgiskraut
    23) CAS 548-04-9 (hypericin)

Available Forms Sources

    A) SOURCES
    1) The form of Hypericum perforatum, sold as an OTC herbal, is derived from plant extracts with constituents such as naphthodianthrones, flavonoids, phloroglucinols and xanthones. The active agent is generally considered to be hypericin, a naphthodianthrone. Amounts of this active agent vary widely in different parts of the plant, under various growth conditions and at different times of the year (Anon, 1997). Firenzuoli & Gori (1999) suggested that Hypericum perforatum extract, as a standardized and titrated extract of flavonoids, hyperforin and hypericin, should be the standard product sold to consumers for treatment of depression (Firenzuoli & Gori, 1999).
    B) USES
    1) Uses have included management of depression, anxiety and insomnia. Other older traditional uses, when taken orally, have included treatment of gastritis and use as a diuretic. Topically it has been used as an astringent (Anon, 1997; Linde et al, 1996).
    2) Hypericum perforatum extracts are licensed in Germany for use in the treatment of depression, anxiety, and sleep disorders (Linde et al, 1996).
    3) Herbal medications such as hypericum are not classified by the FDA as "drugs". Hypericum perforatum is considered a dietary supplement, a subclassification of foods. Thus, supplement products are not subject to the same strict quality-control regulations as standard pharmaceuticals (Gaster & Holroyd, 2000).

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: Hypericum perforatum, or St. John's Wort, is available as an over-the-counter herbal supplement, used to treat depression, anxiety, insomnia, and gastritis. It is also used as an antiviral, antibacterial, and as a topical analgesic. Topically it has been used as an astringent.
    B) PHARMACOLOGY: Hypericum is a plant extract from the flowering tops of Hypericum perforatum. Biologic activity of this plant's extract comes from constituents such as naphthodianthrones, flavonoids, phloroglucinols and xanthones. The active agent is generally considered to be hypericin, a naphthodianthrone. Amounts of this active agent vary widely in different parts of the plant, under various growth conditions, and at different times of the year. The mechanism of the antidepressant effect of St. John's Wort has not been fully determined. Multiple mechanisms and extract constituents may be involved. It is likely a result of synergistic and/or additive effects of several different constituents of St. John's Wort. In vitro, hyperformin inhibited the uptake of norepinephrine, dopamine, L-glutamate, and GABA. Hypericum has been proposed to cause an inhibition of serotonin (5-HT) uptake by postsynaptic receptors, an inhibition of monoamine oxidase, and an alteration of biogenic amine synthesis. It is probably a stronger serotonin reuptake inhibitor than a monoamine oxidase inhibitor.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Reported adverse effects following chronic therapeutic use of hypericum extract have included phototoxicity, gastrointestinal irritation, fatigue, confusion, and tiredness. Allergic reactions have also been reported as an adverse effect.
    E) WITH POISONING/EXPOSURE
    1) Minimal toxicity data is available, but severe effects are not expected. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. SEROTONIN SYNDROME: Although not likely, serotonin syndrome or serotonin syndrome-like events are theoretically possible if a large quantity of hypericum extract is ingested or a patient is susceptible to this syndrome. Serotonin syndrome may also result from the additive effects of taking an SSRI and St. John's wort concurrently. Hypertension, mental status changes, hyperthermia, muscle rigidity, tremor, confusion, agitation, and restlessness may occur, particularly in elderly patients. Seizures may develop in severe cases of serotonin syndrome.
    0.2.20) REPRODUCTIVE
    A) There is little data concerning the effects of hypericum extract during pregnancy. However, 1 human study and 2 case reports have failed to demonstrate an increase in major malformations or fetal adverse events with St. John's wort. Until further data are available, St. John's wort is not recommended for use during pregnancy.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor for clinical evidence of serotonin syndrome (eg, hypertension, mental status changes, hyperthermia, muscle rigidity, tremor, confusion, agitation, and restlessness).

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Correct any significant fluid and/or electrolyte abnormalities in patients with gastroenteritis.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Severe effects are not expected. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. SEROTONIN SYNDROME: Serotonin syndrome may occur if a large quantity of hypericum extract is ingested or taken concurrently with other antidepressants, such as serotonin reuptake inhibitors or MAO inhibitors. Treat the patient aggressively with benzodiazepines and cooling, if needed. Cyproheptadine may be considered. Patients with severe serotonin syndrome (ie, severe hyperthermia, agitation, rigidity, hypertension, tachycardia, acidosis) may require neuromuscular paralysis. Seizures may develop in severe cases of serotonin syndrome. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions or severe serotonin syndrome.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) Failure to recognize or misdiagnose toxicity after a drug interaction. When managing a suspected overdose, the possibility of multidrug involvement should be considered. Consider another etiology, if a patient has severe toxicity.
    I) PHARMACOKINETICS
    1) Median Tmax ranged from 5.5 to 6 hours following oral administration of hypericum extract 300 to 1800 mg (equivalent to 250 to 1500 mcg hypericin) in 12 healthy volunteers. Vd at steady-state was reported to be 162 L (median; range 34 to 346) after oral hypericin 250 mcg 3 times daily for 14 days in 13 healthy volunteers. The half-life of hypericin after oral doses of 255 to 285 mg hypericum extract (equivalent to 900 mcg hypericin) varies widely, from 10 to 37 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Serotonin syndrome from another agent. Eliminate neuroleptic malignant syndrome; anticholinergic toxicity; sympathomimetic overdose (eg, cocaine, amphetamines); or ethanol, benzodiazepine, barbiturate, or baclofen withdrawal.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: Toxic dose is unknown. Single doses of hypericum extract up to 3600 mg were given with no reported adverse effects.
    B) DOSES: ADULT: Doses of 300 mg of the alcohol extract 3 times daily have been used in the treatment of mild to moderate depression. It has been reported that 500 to 900 mg of hypericum extract per day is equivalent to 1000 to 2700 mcg total hypericin daily. In clinical trials, daily doses of hypericin and hypericum extract ranged from 0.4 to 2.7 mg and 300 to 1000 mg, respectively. CHILD: Hypericum extract 250 mg/day (equivalent to 500 mcg per day total hypericin) has been used in children greater than 6 years old.

Clinical Effects

Summary Of Exposure

    A) USES: Hypericum perforatum, or St. John's Wort, is available as an over-the-counter herbal supplement, used to treat depression, anxiety, insomnia, and gastritis. It is also used as an antiviral, antibacterial, and as a topical analgesic. Topically it has been used as an astringent.
    B) PHARMACOLOGY: Hypericum is a plant extract from the flowering tops of Hypericum perforatum. Biologic activity of this plant's extract comes from constituents such as naphthodianthrones, flavonoids, phloroglucinols and xanthones. The active agent is generally considered to be hypericin, a naphthodianthrone. Amounts of this active agent vary widely in different parts of the plant, under various growth conditions, and at different times of the year. The mechanism of the antidepressant effect of St. John's Wort has not been fully determined. Multiple mechanisms and extract constituents may be involved. It is likely a result of synergistic and/or additive effects of several different constituents of St. John's Wort. In vitro, hyperformin inhibited the uptake of norepinephrine, dopamine, L-glutamate, and GABA. Hypericum has been proposed to cause an inhibition of serotonin (5-HT) uptake by postsynaptic receptors, an inhibition of monoamine oxidase, and an alteration of biogenic amine synthesis. It is probably a stronger serotonin reuptake inhibitor than a monoamine oxidase inhibitor.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Reported adverse effects following chronic therapeutic use of hypericum extract have included phototoxicity, gastrointestinal irritation, fatigue, confusion, and tiredness. Allergic reactions have also been reported as an adverse effect.
    E) WITH POISONING/EXPOSURE
    1) Minimal toxicity data is available, but severe effects are not expected. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. SEROTONIN SYNDROME: Although not likely, serotonin syndrome or serotonin syndrome-like events are theoretically possible if a large quantity of hypericum extract is ingested or a patient is susceptible to this syndrome. Serotonin syndrome may also result from the additive effects of taking an SSRI and St. John's wort concurrently. Hypertension, mental status changes, hyperthermia, muscle rigidity, tremor, confusion, agitation, and restlessness may occur, particularly in elderly patients. Seizures may develop in severe cases of serotonin syndrome.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Mild to moderate hypertension may theoretically occur following a large overdose, since hypericum has some (very minor) monoamine oxidase inhibitor properties. Hypertension may occur as part of the serotonin syndrome which may occur when hypericum is ingested with a monoamine oxidase inhibitor or with a serotonin reuptake inhibitor, with an indirect acting sympathomimetic drug. A rapid and irregular pulse may also occur (Buckley & Faunce, 2003; Bladt & Wagner, 1994).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) A clinical syndrome resembling a sedative/hypnotic effect may occur, and may include: lethargy, confusion, weakness and fatigue. This syndrome has been reported as a drug interaction when hypericum is taken concurrently with a SSRI (Gordon, 1998).
    2) Tiredness was reported in 0.4% of patients in a risk/benefit study of 3250 patients (Woelk et al, 1993).
    B) NEUROPATHY
    1) CASE REPORT: A case of polyneuropathy was reported in a 35-year-old woman who consumed 500 mg/day of ground whole St John's wort for 4 weeks. She developed stinging pain on sun exposed areas, including her face, and the dorsum of both hands, arms, and legs. The pain increased with cooling and decreased with warming. No skin burns were apparent. Symptoms improved 3 weeks after stopping the herbal medication, and gradually disappeared over 2 months (Bove, 1998).
    C) SEROTONIN SYNDROME
    1) Although not likely, serotonin syndrome or serotonin syndrome-like events are theoretically possible if a large quantity of hypericum is ingested or a patient is susceptible to this syndrome. Serotonin syndrome may also result from the additive effects of taking an SSRI and hypericum concurrently. Fever, sweating, tremor, flushing, confusion, agitation, and other stimulant effects may occur, particularly in elderly patients (Buckley & Faunce, 2003; Bladt & Wagner, 1994; Ernst, 2002; Brown, 2000; Gordon, 1998).
    2) CASE REPORT: Serotonin syndrome, resulting from an interaction of St. John's wort and paroxetine, was reported in a previously healthy 61-year-old woman. The patient had discontinued St. John's wort (600 mg/day) 3 days prior to presentation and had started paroxetine 20 mg on the day of presentation. Presenting signs/symptoms included agitation, marked akathisia, involuntary movements of all extremities, hyperreflexia and rigidity in all extremities. Blood pressure and heart rate were elevated; creatine kinase peaked at 1024 U/L. The patient recovered following symptomatic care. The authors suggested the prolonged elimination half-life of St. John's wort and initiation of paroxetine therapy resulted in serotonin syndrome (Waksman et al, 2000).
    D) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures may develop in severe cases of serotonin syndrome (Radomski et al, 2000; Fink, 1996).
    E) MANIC BEHAVIOR
    1) Emergent-manic symptoms in predisposed patients have been reported following induction of Hypericum, but are uncommon. Onset of mania in these patients generally occurs shortly after exposure to Hypericum perforatum (2 to 4 weeks) (Ernst, 2002; Moses & Mallinger, 2000; Pies, 2000).
    F) INSOMNIA
    1) Sleep difficulty was reported in 11 of 14 patients who were not diagnosed with a psychiatric disorder. Vivid dreams and insomnia were the most common adverse effects in these patients, reported across all dosages from 300 to 1200 mg/day (Beckman et al, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) In a safety study of hypericum extract in 3250 patients, gastrointestinal irritation was the most frequently reported adverse effect (0.6%) and included nausea, abdominal pain, loss of appetite, and diarrhea (Woelk et al, 1993).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC LIVER DISEASE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 79-year-old woman who was taking Hypericum perforatum, copaiba, levothyroxine, omega 3, glucosamine, and chondroitin, presented with a 1-month history of jaundice. On presentation, she was also tachycardic (100 beats/min) and laboratory results revealed elevated liver enzymes and hyperbilirubinemia. Following the discontinuation of all medications, except for levothyroxine, her laboratory results normalized (Agollo et al, 2014).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) Rats fed St. John's wort were found to have no significant tissue lesions, and no major effects on liver copper, zinc, or iron levels were noted (Garrett et al, 1982).
    2) HEPATIC ENZYMES INCREASED
    a) Significant increases in liver enzymes (ALT, AST, LDH and GGT) and hyperbilirubinemia were reported in sheep given toxic doses of hypericum extract (Kako et al, 1993).

Genitourinary

    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) BUN INCREASED
    a) Increased BUN was reported in sheep given toxic doses of hypericum extract (Kako et al, 1993).

Hematologic

    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA
    a) Sheep given toxic doses of hypericum extract developed decreased hemoglobin, red blood cell count, and packed cell volumes. The severity was significant by day 7 and escalated by day 14. Hemolytic anemia probably developed due to the effect of hypericin on intact erythrocytes causing cell structure damage or damaging permeability of the cell (Kako et al, 1993).
    2) LEUKOCYTOSIS
    a) Sheep given toxic hypericum extract doses developed leukocytosis, which may have reflected tissue damage (Kako et al, 1993).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE RIGIDITY
    1) WITH POISONING/EXPOSURE
    a) Muscular rigidity may occur as a result of a large overdose or from the concurrent use of hypericum and a SSRI.
    B) MUSCULOSKELETAL FINDING
    1) WITH POISONING/EXPOSURE
    a) CREATINE PHOSPHOKINASE INCREASED
    1) Elevation in creatine phosphokinase, as well as other manifestations of serotonin syndrome, resulted from an interaction between hypericum and paroxetine in one patient (Waksman et al, 2000).
    3.15.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CREATINE PHOSPHOKINASE INCREASED
    a) An increase in creatine phosphokinase (CK) was reported in sheep given toxic doses of hypericum perforatum (Kako et al, 1993).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) FINDING OF THYROID FUNCTION
    1) In a small retrospective case-control study (n=37) of patients with elevated TSH levels, a suggestive (not conclusive) association between St. John's wort and elevated TSH levels was reported. Four of the 37 patients had been taking the herbal for 3 to 6 months prior to TSH measurements. A larger prospective study is needed to confirm this association (Ferko & Levine, 2001).
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOGLYCEMIA
    a) Decreased blood glucose levels were reported in sheep given toxic doses of the Hypericum perforatum plant (Kako et al, 1993).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) Allergic reactions, including skin rash and pruritus, were reported in 0.5% of patients in a risk/benefit study of 3250 patients (Woelk et al, 1993).

Reproductive

    3.20.1) SUMMARY
    A) There is little data concerning the effects of hypericum extract during pregnancy. However, 1 human study and 2 case reports have failed to demonstrate an increase in major malformations or fetal adverse events with St. John's wort. Until further data are available, St. John's wort is not recommended for use during pregnancy.
    3.20.3) EFFECTS IN PREGNANCY
    A) CASE REPORT
    1) Two human cases of St. John's wort used during pregnancy demonstrated no immediate observable adverse effects. A 38-year-old woman began taking St. John's wort 900 mg daily 24 weeks into her pregnancy and continued until 24 hours before delivery. There were no problems with the pregnancy, except for late onset of thrombocytopenia with a platelet count of 88,000. Her baby developed jaundice on the fifth day after birth, but recovered. The patient resumed St. John's wort at 300 mg daily on the 20th day after delivery while breastfeeding. A 43-year-old woman became pregnant while taking fluoxetine and methylphenidate. She discontinued those medications and began St. John's wort 900 mg daily, which she continued throughout the pregnancy. Although no adverse effects were noted in either newborn, the authors concluded that St. John's wort should be avoided in pregnancy, with tricyclic antidepressants and fluoxetine being safer choices (Grush et al, 1998).
    B) COHORT STUDY
    1) In a Canadian, prospective, observational study comparing pregnancies exposed to St. John's wort (n=54) and those exposed to conventional pharmacologic treatment for depression (n=54) and those with no depression or known teratogenic exposure (n=54), there was no significant difference in the rate of major malformations, live births, or prematurity between the St. John's wort and comparator groups. Of the 54 pregnancies exposed to St. John's wort (average dose, 615 mg), 49 occurred only during first trimester, 7 continued into the second and third trimester, and 5 occurred only in the second and third trimester. The rate of major malformations was 5.3% (2 of 38) with St. John's wort (1 obstructed ureter; 1 hypospadias), 4.2% (2 of 48) with conventional therapy (1 plagiocephaly; 1 esophageal atresia with tracheoesophageal fistula), and 0% with no exposure (p=0.26). The rate of live birth and prematurity did not significantly differ with St. John's wort compared with conventional therapy or no exposure (Moretti et al, 2009).
    C) ANIMAL STUDIES
    1) MICE: Birth weights were decreased but no long-term behavioral deficits were noted in mice exposed to St. John's wort throughout gestation. Mice were fed 0.75 mg St. John's wort for every gram of food or a placebo for 2 weeks before conception and during gestation. Male pups from the treatment group were significantly lower in birth weight than were placebo-exposed pups (1.68 g and 1.75 g, respectively). No long-term impact on fertility or behavior was found (Rayburn et al, 2000).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) CASE REPORT
    1) In one case report, a 38-year-old woman who had taken St. John's wort (900 mg/day) throughout pregnancy resumed ingesting the herb at 300 mg/day on her 20th day of breastfeeding. The infant did not experience any side effects (Grush et al, 1998a).
    2) In one study, hyperforin and hypericin, 2 major active components of St. John's wort, were measured in the breast milk of a woman taking St. John's wort (300 mg 3 times daily). Only hyperforin was excreted into breast milk in low concentrations. In the infant's plasma, hyperforin and hypericin levels were below the lower limit of quantification (LQ) (LQ hypericin: 0.2 nanograms (ng)/mL; LQ hyperforin: 0.5 ng/mL) (Klier et al, 2002).
    B) COHORT STUDY
    1) In a prospective, observational, cohort study, the safety of St. John's wort in nursing mothers and their infants was evaluated. Three groups were compared; 33 nursing women receiving St. John's wort (group 1), 101 disease-matched women who did not take St. John's wort, enrolled as disease-matched controls (group 2), and 33 age-and parity-matched women (group 3). Overall, a higher frequency of side effects (2 cases of colic, 2 cases of drowsiness, and 1 case of lethargy) was noted in group 1 infants (St. John's wort dose 704.9 +/- 463.6 mg/day, for a duration of 1.5 +/- 1.7 months, starting at 4.2 +/- 3.6 months postpartum; the mean duration of infant St. John's wort exposure 2.1 +/- 3.5 months) when compared with the 2 control groups (1 case of colic in each control group). A statistically significant higher rate of prescription antidepressant use was noted in group 1 women (42.4%; 14/33) when compared with group 2 (17.8%; 18/101). A change in milk production due to St. John's wort use was not observed (Lee et al, 2003).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) When St. John's wort 300, 900, and 2700 mg/kg were given to rats and dogs for 26 weeks, the lowest dose that showed any toxicity, produced nonspecific systemic changes but no changes in fertility, was 900 mg/kg (Leuschner, 1996/1997).

Genotoxicity

    A) Results of genotoxicity tests, in-vitro and in-vivo, with Syrian hamster embryo cells, fur spot test of the mouse, and chromosome aberration test with the bone marrow cells of the Chinese hamster all proved negative (Okpanyi et al, 1990). No mutagenic potential for hypericum extract was shown.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) PHOTOSENSITIVITY
    1) A rare but potentially serious adverse effect is photosensitization, which is caused by a red fluorescent pigment, hypericin, contained in the herb. Phototoxicity results from ingestion of hypericum extract and sun exposure. Skin contact does not appear to cause this reaction. Animals as well as humans may be affected. At higher doses, or with chronic use, sunburn-like lesions, rash, pruritus and inflammation of the mucous membranes may occur (Ernst, 2002; Lane-Brown, 2000; Gaster & Holroyd, 2000; Bove, 1998; Chavez & Chavez, 1997).
    2) CASE REPORT: A 61-year-old woman developed recurring elevated itching erythematous lesions in areas exposed to sunlight after taking an oral preparation of St. John's wort for three years. No significant reactions occurred with routine patch testing and photopatch testing was negative. The authors demonstrated a decrease of the MED-UVB, which was reversible, after an oral photoprovocation test with the herbal extract (Golsch et al, 1997).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PHOTOSENSITIVITY
    a) Range animals are susceptible to phototoxicity with hypericum. In livestock it is referred to as hypericism or "light sickness". Reactions may include severe erythema and edema of the skin, conjunctiva, and buccal mucosa. The affected skin may become dry and necrotic after the erythema and edema subside (Chavez & Chavez, 1997).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor for clinical evidence of serotonin syndrome (eg, hypertension, mental status changes, hyperthermia, muscle rigidity, tremor, confusion, agitation, and restlessness).
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Methods

    A) CHROMATOGRAPHY
    1) Kerb et al (1996) describe a reversed phase high performance liquid chromatography (HPLC) procedure for quantification of hypericum extract from human plasma and urine (Kerb et al, 1996).

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 severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor for clinical evidence of serotonin syndrome (eg, hypertension, mental status changes, hyperthermia, muscle rigidity, tremor, confusion, agitation, and restlessness).

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) 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).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Correct any significant fluid and/or electrolyte abnormalities in patients with gastroenteritis.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Severe effects are not expected. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. SEROTONIN SYNDROME: Serotonin syndrome may occur if a large quantity of hypericum extract is ingested or taken concurrently with other antidepressants, such as serotonin reuptake inhibitors or MAO inhibitors. Treat the patient aggressively with benzodiazepines and cooling, if needed. Cyproheptadine may be considered. Patients with severe serotonin syndrome (ie, severe hyperthermia, agitation, rigidity, hypertension, tachycardia, acidosis) may require neuromuscular paralysis. Seizures may develop in severe cases of serotonin syndrome. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4) Monitor for clinical evidence of serotonin syndrome (eg, hypertension, mental status changes, hyperthermia, muscle rigidity, tremor, confusion, agitation, and restlessness).
    C) SEIZURE
    1) Seizures may develop in severe cases of serotonin syndrome (Radomski et al, 2000; Fink, 1996).
    2) 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).
    3) 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 .
    4) 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).
    5) 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).
    6) 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).
    7) 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) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    9) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    10) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    E) SEROTONIN SYNDROME
    1) Theoretically, due to its mechanism of action of inhibiting serotonin reuptake, it is possible that an overdose of hypericum could result in serotonin syndrome. However, the amount of hypericum extract needed to induce this effect is probably very large. It is possible if hypericum is ingested concomitantly with another agent which increases brain serotonin (serotonin reuptake inhibitor, MAOI, tricyclic antidepressants, etc.) serotonin syndrome may result.
    2) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    3) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    4) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    5) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    6) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    7) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    8) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    9) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).
    F) HYPERSENSITIVITY REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: Toxic dose is unknown. Single doses of hypericum extract up to 3600 mg were given with no reported adverse effects.
    B) DOSES: ADULT: Doses of 300 mg of the alcohol extract 3 times daily have been used in the treatment of mild to moderate depression. It has been reported that 500 to 900 mg of hypericum extract per day is equivalent to 1000 to 2700 mcg total hypericin daily. In clinical trials, daily doses of hypericin and hypericum extract ranged from 0.4 to 2.7 mg and 300 to 1000 mg, respectively. CHILD: Hypericum extract 250 mg/day (equivalent to 500 mcg per day total hypericin) has been used in children greater than 6 years old.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) ORAL: Doses of 300 milligrams of the alcohol extract 3 times daily have been used in the treatment of mild to moderate depression (Haensgen et al, 1993; (Woelk et al, 1993; Schmidt & Sommer, 1993; Vorbach et al, 1993; Harrer et al, 1993).
    a) It has been reported that 500 to 900 milligrams of hypericum extract per day is equivalent to 1000 to 2700 micrograms total hypericin daily (Fachinformation, 1996).
    b) Daily doses of hypericin and hypericum extract ranged from 0.4 to 2.7 milligrams and 300 to 1000 milligrams, respectively, in clinical trials (Linde et al, 1996).
    7.2.2) PEDIATRIC
    A) ROUTE OF ADMINISTRATION
    1) ORAL - Hypericum extract 250 milligrams per day (equivalent to 500 micrograms per day total hypericin) has been recommended in children greater than 6 years old (Fachinformation, 1996).

Maximum Tolerated Exposure

    A) ACUTE
    1) Single, acute doses up to 3600 mg of hypericum extract were given to healthy subjects with no reported adverse effects (Gaster & Holroyd, 2000).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ADULT
    a) Plasma levels of combined hypericin and pseudohypericin were reported to be up to 278 micrograms/liter following doses as high as 3600 milligrams of hypericum perforatum extract in volunteers (Kerb et al, 1995).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) HYPERICUM PERFORATUM LINN., EXTRACT
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) >1 g/kg (RTECS , 2002)
    2) LD50- (INTRAPERITONEAL)RAT:
    a) >1 g/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) ANTIDEPRESSIVE EFFECTS: Hypericum has been proposed to cause an inhibition of serotonin (5-HT) uptake by postsynaptic receptors, an inhibition of monoamine oxidase, and an alteration of biogenic amine synthesis. It is probably a stronger serotonin reuptake inhibitor than a monoamine oxidase inhibitor. An in-vitro study demonstrated that standardized hypericum extract resulted in 50% inhibition of 5-HT uptake in rat synaptosomes at concentrations of 6.2 mcg/mL (Perovic & Mueller, 1995). Hypericum has been shown to possibly enhance both 5-HT and noradrenaline transmission in forebrain limbic brain circuits important for mood control, which may underlie its antidepressant effects (Misane & Ogren, 2001).
    1) Bennett et al (1998) suggested a combination contribution of inhibition of 5-HT uptake, norepinephrine uptake, and inhibition of MAO or COMT, with each one too weak by itself to account for the overall antidepressant effect. In another study, serotonin reuptake was inhibited by 50% in mouse brain synaptosomes following hypericum extract dose of 15 mcg/mL, while a dose of 20 mcg/mL resulted in only 20% monoamine oxidase inhibition. Hypericum extract 0.01% to 0.1% also demonstrated 50% synaptosomal norepinephrine reuptake inhibition and some beta-adrenergic and muscarinic receptor inhibition at higher concentrations (Mueller & Schaefer, 1996).
    2) Only minimal monoamine oxidase inhibiting properties of hypericum extract following in vitro and ex vivo studies with rat brain homogenates could be demonstrated (Bladt & Wagner, 1994; Thiede & Walper, 1994). The authors concluded that the antidepressant effects of hypericum could not be explained in terms of MAO inhibition.
    3) In vitro studies have shown an almost reversible MAO inhibition of type A and B for hypericin when treating rat brain mitochondria with selective inhibitors. Inhibition of type A MAO by hypericin was greater than type B MAO inhibition (Suzuki et al, 1984).
    4) Demisch et al (1989) studied the components of hypericum extract for MAO inhibiting properties and found xanthon, flavon and flavonols but not flavanols to be potent and selective MAO type-A inhibitors, whereas the coumarin derivative preferentially affected MAO type-B activity. These authors concluded that a selective MAO type-A inhibitor could contribute to antidepressant effects of hypericum perforatum extracts (Demisch et al, 1989).
    5) Multiple mechanisms and extract constituents may be involved in the antidepressant action of hypericum extracts; they may also possess neuroprotective and analgesic effects. A major pharmacologically active constituent of hypericum perforatum extract is hyperforin, which has been shown to induce significant inhibition of various ion channels. It acts via interaction with calmodulin or through calmodulin-activated pathways involving at least one second messenger (Krishtal et al, 2001).
    B) ANTIVIRAL EFFECTS: In-vitro and in-vivo studies of hypericin and its principal derivative, pseudohypericin, have shown that these agents possess considerable antiretroviral effect. In mice infected with Friend leukemia and radiation leukemia viruses, spread of disease was inhibited and survival was prolonged by single-dose hypericin (Meruelo et al, 1988). It is speculated that hypericin and pseudohypericin both interfere with the manufacture of viral components (gag-encoded precursor polyproteins) and directly inactivate mature retroviruses (Lavie et al, 1989).
    1) Lipid-enveloped viruses and retroviruses appear to be inactivated by hypericum extracts, as opposed to unenveloped viruses, such as adenoviruses and polio viruses, which are resistant to hypericin (Chavez & Chavez, 1997; Tang et al, 1990).

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