Appendix II: Side Effects, Adverse Effects, Precautions, and Warnings

HerbSide and Adverse EffectsPrecautions and Warnings
St. John's Wort* (Hypericum) 43

*While prescription drugs may seem to have more adverse events associated with them, this may only be a result of the closer scrutiny required of them by the FDA.
Stomach complaints, allergic reactions, fatigue, phototoxicity, photosensitivity, photoallergy, nausea, dizziness, tiredness, restlessness, headaches, vomiting, diarrhea, irritability, edema, erythema, rash, and rare cases of acute neuropathy.Toxic effects have been reported in sheep and other grazing animals and were seen in the form of facial edema and photosensitization. Photosensitization only seems to occur in humans when the dosage taken is 30 to 50 times higher that recommended. Because of the photosensitivity, persons of fair skin or who burn easily should use caution when exposed to the sun.

Interaction with other drugs can occur therefore taking other medications with hypericum is not recommended.

The safety of using hypericum during pregnancy or lactation has not been proven so it should be avoided.

The results are unclear about mixing alcohol and hypericum. Generally, consuming alcohol is not recommended while taking hypericum.

FDA warnings indicate that St. John's wort is an inducer of the CYP 450 3A4 metabolic pathway. Many prescription drugs used to prevent conditions such as transplant rejection or pregnancy (oral contraceptives) are metabolized via this pathway, health care providers should alert patients about these potential drug interactions.
Imipramine Pamoate (TOFRANIL-PM®) 37 Cardiovascular: Orthostatic hypotension, hypertension tachycardia, palpitation, myocardial infraction, arrhythmias, heart block, ECG changes, precipitation of congestive heart failure, stroke.
Psychiatric: Confusion (in elderly) with hallucinations, disorientation, delusions, anxiety, restlessness, agitation, insomnia and nightmares, hypomania, exacerbation of psychosis.
Anticholinergic: Dry mouth and, rarely, associated sublingual adenitis, blurred vision, disturbances of accommodation, mydriasis, constipation, paralytic ileus, urinary retention, delayed micturition, dilation of the urinary tract.
Neurological: Numbness, tingling, paresthesias of extremities, incoordination, ataxia, tremors, peripheral neuropathy, extrapyramidal symptoms, seizures, alterations in EEG patterns, tinnitus.
Allergic: Skin rash, petechiae, urticaria, itching, photsensitization, edema (general or of face and tongue), drug fever, cross-sensitivity with desipramine.
Hematologic: Bone marrow depression including agranulocytosis, eosinophilia, purpura, thrombocytopenia.
Gastrointestinal: Nausea and vomiting, anorexia, epigastric distress, diarrhea, peculiar taste, stomatitis, abdominal cramps, black tongue.
Endocrine: Gnecomastia in the male, breast enlargement and galactorrhea in the female, increased or decreased libido, impotence, testicular swelling, elevation or depression of blood sugar levels, inappropriate antidiuretic hormone (ADH) secretion syndrome.
Other: Jaundice (simulating obstructive), altered liver function, weight gain or loss, perspiration, flushing, urinary frequency, drowsiness, dizziness, weakness and fatigue.
Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise.

Other reported reactions include convulsions, emotional instability, syncope, and collapse.

Extreme caution should be used when given to patients with cardiovascular disease due to the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infraction, strokes, and tachycardia.
Patients with a history of seizure disorder should be monitored since this drug has been shown to lower the seizure threshold.

Drug interactions with guanethidine clonidine, or similar agents; methylphenidate hydrochloride.

May impair ability to operate automobiles or machinery.

May enhance the CNS depressant effects of alcohol.

Not to be used in children of any age.

Possible benefits must be weighed against possible hazards to mother and child when used during pregnancy or lactation.

May alter glycemic control of diabetic patients.

Interaction with other drugs has been reported.
Amitriptyline Hydrochloride (ELAVIL®) 37 Allergic: Skin rash, urticaria, photosensitization, edema of the face and tongue.
Anticholinergic: Dry mouth, blurred vision, disturbance of accommodation, constipation, paralytic ileus, urinary retention, dilation of urinary tract, increased ocular pressure, and mydriasis.
Cardiovascular: Orthostatic hypotension, hypertension, tachycardia, palpitations, myocardial infraction, arrhythmias, heart block, stroke, syncope, and nonspecific ECG changes and changes in AV conduction.
CNS and Neuromuscular: Confusional states, disturbed concentration, disorientation, delusions, hallucinations, excitement, anxiety, restlessness, insomnia, nightmares, numbness, tingling and paresthesias of the extremities, peripheral neuropathy, incoordination, ataxia, tremors, seizures, alteration in EEG patterns, extrapyramidal symptoms, including abnormal involuntary movements and tardive dyskinesia, dysarthria, nightmares, tinnitus, drowsiness, dizziness, weakness, fatigue, headache and syndrome of inappropriate ADH (antidiuretic hormone) secretion.
Endocrine: Testicular swelling and gynecomastia in the male, breast enlargement and galactorrhea in the female, increased or decreased libido, lowering of blood sugar levels, and impotence.
Gastrointestinal: Nausea, epigastric distress, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, rarely hepatitis (including altered liver function and jaundice), parotid swelling, black tongue.
Hematologic: Bone marrow depression, including agranulocytosis, leukopenia, eosinophilia, purpura, thrombocytopenia.
Other: Weight gain or loss, increased perspiration, urinary frequency, and alopecia.
Body as a Whole: Lupus-like syndrome (migratory arthritis positive ANA and rheumatoid factor).
Digestive: Hepatic failure and ageusia.
Withdrawal Symptoms: After prolonged administration, abrupt cessation of treatment may produce nausea, headache, and malaise.

Gradual dosage reduction has been reported to produce, within two weeks, transient symptoms including irritability, restlessness, and dream and sleep disturbance.

These symptoms are not indicative of addiction. Rare instances have been reported of mania or hypomania occurring within 2-7 days following cessation of chronic therapy with tricyclic antidepressants.
Abrupt cessation of treatment after prolonged administration may produce nausea, headache, and malaise. These are not indicative of addiction.

Should not be given concomitantly with MAOIs. May block the antihypertensive action of guanethidine or similarly acting compounds. Patients should have close supervision if using thyroid medication, alcohol, barbiturates and other CNS depressants, and disulfiram

Patients with cardiovascular disorders should be watched closely.
Close supervision is required when given to hyperthyroid patients or those receiving thyroid medication.

Possible benefits must be weighed against possible hazards to mother and child when used during pregnancy or lactation.

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop.
Not recommended for children under 12 years of age.

Should be used with caution with patients with impaired liver function.

Elevation and lowering of blood sugar levels have bee reported.

Drug interaction can happen with drugs metabolized by P450 2D6.

Clinically significant effects have been reported with tricyclic antidepressants when used concomitantly with cimetidine. Caution is advised if patients receive large doses of ethchlorvynol concurrently. May impair ability to operate automobiles or machinery.
Fluoxetine Hydrochloride (PROZAC®) 37 Body as a Whole: Frequent -- chills. Infrequent -- chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide attempt. Rare -- abdominal syndrome acute, hypothermia, intentional injury, neuroleptic malignant syndrome, photosensitivity.
Cardiovascular System: Frequent -- hemorrhage, hypertension. Infrequent -- angina pectoris, arrhythmia, hemorrhage, congestive heart failure, hypotension, migraine, vascular headache. Rare -- atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasytoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythima, ventricular extrasystoles, ventricular fibrillation.
Digestive System: Frequent -- increased appetite. Infrequent -- aphthous stomatitis, dysphagia, cholelithiasis, colitis, eructation, esophagitis, gastritis, gastorenteritis, glossitis, gum hemorrhage, hyperchorhydria, increased salvation, liver function tests abnormal, melena, stomatitis, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, thirst. Rare -- biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of the colon, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema.
Endocrine System: Infrequent -- hypothyroidism. Rare -- diabetic acidosis, diabetes mellitus.
Hemic and Lymphatic System: Infrequent -- anemia, ecchymosis. Rare -- blood dyscrasia, hypochromic anemia, leukopenia, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia.
Metabolic and Nutritional: Frequent -- weight gain. Infrequent -- dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema. Rare -- alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased.
Musculosketal System: Infrequent -- arthritis bone pain, bursitis, leg cramps, tenosynovitis. Rare -- arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis
Nervous System: Frequent -- agitation, amnesia confusion, emotional lability, sleep disorder. Infrequent -- abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, nueralgia, neuropathy, neurosis, paranoid reaction, personality disorder, psychosis, vertigo. Rare -- abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia extrapyramidal syndrome, foot drop, hyperesthesia neuritis, paralysis, reflexes decreased, reflexes increased, stupor.
Respiratory System: Infrequent -- asthma, epistaxis, hiccup, hyperventilation. Rare -- apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor.
Skin and Appendages: Infrequent -- acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash. Rare -- furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea.
Special Senses: Frequent -- ear pain, taste perversion, tinnitus. Infrequent -- conjunctivitis, dry eyes, mydriasis, photophobia. Rare -- blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect.
Urogenital System: Frequent -- urinary frequency. Infrequent -- abortion, albuminuria, amenorrhea, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation, fibrocystic breast, hematuria, leukorrhea, menorrhagia, metrorrhagia, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage. Rare -- breast enlargement, glycosuria, hypomenorrhea, kidney pain, oliguria, priapism, uterine hemorrhage, uterine fibroids enlarged.
Rash and possible allergic events, associated with fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria and mild transaminase elevation.

In premarket trials, 2 patients developed a serious cutaneous systemic illness.

Although rare, some patients have developed systemic events possibly related to vasculitis. Death has occurred in association with these systemic events.

Anaphylactoid events, including bronchospasm, angioedema, and urticaria alone and in combination, have been reported.

Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported. These events have occurred with dyspnea as the only preceding symptom.

Should be used with caution with patients who have seizures.

Caution should be used when treating patients with concomitant systemic illnesses.

May alter glycemic control of diabetic patients.

Motor vehicle and machinery operation on may be affected.

Patients who have become or are planning on becoming pregnant, or are nursing an infant should advise their physician.
Paroxetine Hydrochloride (PAXIL®) 37 Body as a Whole: Frequent -- chills, malaise. Infrequent -- allergic reaction, carcinoma, face edema, moniliasis, neck pain. Rare -- abscess, adrenergic syndrome, cellulitis, neck rigidity, pelvic pain, peritonitis, ulcer.
Cardiovascular System: Frequent -- hypertension, syncope, tachycardia. Infrequent -- bradycardia, condition abnormalities, electrocardiogram abnormal, hematoma, hypotension, migraine, peripheral vascular disorder. Rare -- angina pectoris, arrhythmia, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, throbophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles.
Digestive System: Infrequent -- bruxism, colitis, dysphagia, eructation, gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, mouth ulceration, rectal hemorrhage, ulcerative stomstitis. Rare -- aphthous stomatitis, bloody diarrhea, bulimia, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gastritis, gum hemorrhage, hematemesis, hepatitis, ileus, intestinal obstruction, jaundice melena, peptic ulcer, salivary gland enlargement, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth cavities, tooth malformation.
Endocrine System: Rare -- diabetes mellitus, hyperthyroidism, hypothyroidism, and thyroiditis.
Hemic and Lymphatic Systems: Infrequent -- anemia, leukopenia, lymphadenopathy, purpura. Rare -- abnormal erythrocytes, basophilia, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia.
Metabolic and Nutritional: Frequent -- edema, weight gain, weight loss. Infrequent -- hyperglycemia, peripheral edema, SGOT increased, SGPT increased, thirst. Rare -- alkaline phosphatase increased, bilirubinemia, BUN increased, creatinie phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased.
Musculoskeletal System: Frequent -- arthralgia. Infrequent -- arthritis. Rare -- arthrosis, bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, and tetany.
Nervous System: Frequent -- amnesia, CNS stimulation, concentration impaired, depression, emotional lability, vertigo. Infrequent -- abnormal thinking, akinesia, alcohol abuse, ataxia, convulsion, depersonalization, dystonia, hallucination, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, lack of emotion, manic reaction, neurosis, paralysis, paranoid reaction. Rare -- abnormal electroencephalogram, abnormal gait, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, delirium, delusions, diplopia, drug dependence, dysarthria, dyskinesia, euphoria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hypokinesia, hysteria, libido increased, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychosis, psychotic depression, reflexes decreased, reflexes increased, stupor, trismus, withdrawal syndrome.
Respiratory System: Frequent -- cough increased, rhinitis. Infrequent -- asthma, bronchitis, dysponea, epistaxis, hyperventilation, pneumonia, respiratory flu, sinusitis, voice alteration. Rare -- emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, and sputum increased.
Skin and Appendages: Frequent -- pruritus. Infrequent -- acne, alopecia, dry skin, ecchymosis, eczema, furunculosis, urticaria. Rare -- angioedema, contact dermatitis, erythema nodosum, erythema multiforme, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, maculopapular rash, photosensitivity, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, and vesiculobullous rash.
Special Senses: Frequent -- tinnitus. Infrequent -- abnormality of accommodation, conjunctivitis, ear pain, eye pain, mydriasis, otitis media, taste loss, visual field defect. Rare -- amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, keratoconjunctivitis, night blindness, otitis externa, parosmia, photophobia, ptosis, and retinal hemorrhage.
Urogenital System: Infrequent -- abortion, amenorrhea, breast pain, cystitis, dysmenorrhea, dysuria, hematuria, menorrhagia, nocturia, polyuria, urethritis, urinary incontinence, urinary retention, urinary urgency, vaginitis. Rare -- breast atrophy, breast carcinoma, breast enlargement, breast neoplasm, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney function, abnormal kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, prostatic carcinoma, pyuria, urethritis, uterine spasm, urolith, vaginal moniliasis, vaginal hemorrhage.
Potential for interaction with MAOIs. Should not be taken in combination with a MAO, and a 14-day waiting period is recommended between the discontinuation of one and the starting of the other.

There have been reports of serious, sometimes fatal reactions, including hypertherma, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include agitation progressing to delirium and coma.

Should be used with caution on patients with history of mania and seizures.

Older patients who are on diuretics or who are otherwise volume depleted should be watched for hyponatremia.

Cases of abnormal bleeding have been reported (mostly ecchymosis and purpura).

Caution is advisable when using with certain concomitant systemic illnesses.

Patients should be cautioned about operating motor vehicle and machinery.

Patients should avoid alcohol while taking the drug.

Patients should advise their physician if they become or plan to become pregnant or if they are nursing an infant.
Phenelzine Sulfate (NARDIL®) 37 Common:
Nervous System: Dizziness, headache, drowsiness, sleep disturbances (including insomnia and hypersomnia), fatigue, weakness, tremors, twitching, myoclonic movements, hyperreflexia.
Gastrointestinal: Constipation, dry mouth, gastrointestinal disturbances, elevated serum transaminases (without accompanying signs and symptoms).
Metabolic: Weight gain.
Cardiovascular: Postural hypotension, edema.
Genitourinary: Sexual disturbances, e.g., anorgasmia and ejaculatory disturbances.

Less Common:
Nervous System: Jitteriness, palilalia, euphoria, nystagmus, paresthesia.
Gastrointestinal: Urinary retention.
Metabolic: Hypernatremia.
Dermatologic: Skin rash, sweating.
Special Senses: Blurred vision, glaucoma.
Less Frequent:
Nervous System: Ataxia, shock-like coma, toxic delirium, manic reaction, convulsions, acute anxiety reaction, precipitation of schizophrenia, transient respiratory and cardiovascular depression followed by ECT.
Gastrointestinal: Fatal progressive necrotizing hepatocellular damage in a few patients, reversible jaundice.
Hematologic: Leukopenia.
Immunologic: Lupus-like syndrome.
Metabolic: Hypermetabolic syndrome (which may include but not limited to hyperpyrexia, tachycardia, muscular rigidity, elevated DK levels, metabolic acidosis, hypoxia, and coma, and may resemble an overdose).
Respiratory: Edema of the glottis.
General: Fever associated with increased muscle tone. Withdrawal may be associated with nausea, vomiting, and malaise.
The most serious changes involve changes in blood pressure.

Occurrence of hypertensive crisis, which has sometimes been fatal.

The following foods should be avoided; pickled herring, liver, dry sausage, broad bean pods, sauerkraut, cheese, beer and wines, alcohol-free and reduced-alcohol beer and wine products, yeast extract, meat extract, excessive amounts of chocolate and caffeine, and any spoiled or improperly refrigerated, handled, or stored protein-rich foods.
Interaction with other medications.

Not recommended for children under 16 years of age.

Patients should advise their physician if they become or plan to become pregnant or if they are nursing an infant.

Caution should be used when treating epileptic patients.

Glucose metabolism may be affected, so caution is advised when treating diabetic patients.
May cause excessive stimulation in schizophrenic patients; in manic-depressive states, may result in a swing from a depressive to a manic phase. Over stimulation may include increased anxiety, agitation, and manic symptoms.

May cause restlessness or insomnia; some weakness, drowsiness, episodes of dizziness or dry mouth; nausea, diarrhea, abdominal pain or constipation.

Tachycardia, significant anorexia, edema, palpitation, blurred vision, chills, and impotence have been reported. Headaches without blood pressure elevation have occurred. Rare instances of hepatitis and skin rash.

Should be reserved for patients that do not respond to other antidepressants.

Possible benefits must be weighed against possible hazards to mother and child when used during pregnancy or lactation.

Patients should be warned about food that should not be eaten during use of the drug.

Other drug and medication interactions have been reported.

A hypertensive crisis is associated with the drug and has been fatal. Blood pressure should be followed closely.

Glucose metabolism may be affected, so caution is advised when treating diabetic patients.

Caution is advised with hyperthyroid patients.

From: St. John's Wort

Cover of Minnesota Health Technology Assessments
Minnesota Health Technology Assessments [Internet].
Minnesota Health Technology Advisory Committee.
St. Paul (MN): Minnesota Department of Health; 1995-2001.

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