Two serious adverse reactions reported in patients treated with Flagyl (metronidazole) have been convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of Flagyl, patients should be specifically warned about these reactions and should be told to stop the drug and report immediately to their physicians if any neurologic symptoms occur.
The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea reported by about 12% of patients, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping. Constipation has also been reported.
The following reactions have also been reported during treatment with Metronidazole:
Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during effective therapy.
Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.
Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings.
Central Nervous System: Convulsive seizures, peripheral neuropathy, dizziness, vertigo, incoordination, ataxia, confusion, irritability, depression, weakness, and insomnia.
Hypersensitivity: Urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever.
Renal: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance.
Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling "serum sickness." If patients receiving Metronidazole drink alcoholic beverages, they may experience abdominal distress, nausea, vomiting, flushing, or headache. A modification of the taste of alcoholic beverages has also been reported. Rare cases of pancreatitis, which abated on withdrawal of the drug, have been reported.
Crohn's disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn,s disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established. Crohn's disease is not an approved indication for Metronidazole.
Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when Metronidazole is prescribed for patients on this type of anticoagulant, therapy.
The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.
The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. In patients stabilized on relatively high doses of lithium, short-term Metronidazole therapy has been associated with elevation of serum lithium and in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.
Alcoholic beverages should not be consumed during Metronidazole therapy and for at least one day afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur.
Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks.
Heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea have been noted in some patients. Although Clostridium difficile has been shown in vitro to be sensitive to rifampin, pseudomembranous colitis has been reported with the use of rifampin (and other broad spectrum antibiotics). Therefore, it is important to consider this diagnosis in patients who develop diarrhea in association with antibiotic use. Rarely, hepatitis or a shock-like syndrome with hepatic involvement and abnormal liver function tests has been reported.
Thrombocytopenia has occurred primarily with high dose intermittent therapy, but has also been noted after resumption of interrupted treatment. It rarely occurs during well supervised daily therapy. This effect is reversible if the drug is discontinued as soon as purpura occurs. Cerebral hemorrhage and fatalities have been reported when rifampin administration has been continued or resumed after the appearance of purpura.
Rare reports of disseminated intravascular coagulation have been observed.
Transient leukopenia, hemolytic anemia, and decreased hemoglobin have been observed.
Central Nervous System
Headache, fever, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, behavioral changes, pain in extremities, and generalized numbness have been observed.
Psychoses has been rarely reported.
Visual disturbances have been observed.
Menstrual disturbances have been observed.
Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.
Elevations in BUN and serum uric acid have been reported. Rarely, hemolysis, hemoglobinuria, hematuria, interstitial nephritis, acute tubular necrosis, renal insufficiency, and acute renal failure have been noted. These are generally considered to be hypersensitivity reactions. They usually occur during intermittent therapy or when treatment is resumed following intentional or accidental interruption of a daily dosage regimen, and are reversible when rifampin is discontinued and appropriate therapy instituted.
Cutaneous reactions are mild and self-limiting and do not appear to be hypersensitivity reactions. Typically, they consist of flushing and itching with or without a rash. More serious cutaneous reactions which may be due to hypersensitivity occur but are uncommon.
Occasionally, pruritus, urticaria, rash, pemphigoid reaction, erythema multiforme including Stevens-Johnson Syndrome, toxic epidermal necrolysis, vasculitis, eosinophilia, sore mouth, sore tongue, and conjunctivitis have been observed.
Anaphylaxis has been reported rarely.
Rare reports of myopathy and muscular weakness have also been observed.
Edema of the face and extremities has been reported. Other reactions reported to have occurred with intermittent dosage regimens include "flu syndrome" (such as episodes of fever, chills, headache, dizziness, and bone pain), shortness of breath, wheezing, decrease in blood pressure and shock. The "flu syndrome" may also appear if rifampin is taken irregularly by the patient or if daily administration is resumed after a drug free interval.
ENZYME INDUCTION: Rifampin is known to induce certain cytochrome P-450 enzymes. Administration of rifampin with drugs that undergo biotransformation through these metabolic pathways may accelerate elimination of coadministered drugs. To maintain optimum therapeutic blood levels, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered rifampin.
Rifampin has been reported to accelerate the metabolism of the following drugs: anticonvulsants (eg, phenytoin), antiarrhythmics (eg, disopyramide, mexiletine, quinidine, tocainide), oral anticoagulants, antifungals (eg, fluconazole, itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel blockers (eg, diltiazem, nifedipine, verapamil), chloramphenicol, clarithromycin, corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral or other systemic hormone contraceptives, dapsone, diazepam, doxycycline, fluoroquinolones (eg ciprofloxacin), haloperidol, oral hypoglycemic agents (sulfonylureas), levothyroxine, methadone, narcotic analgesics, nortriptyline, progestins, quinine, tacrolimus, theophylline tricyclic antidepressants (eg, amitriptyline, nortriptyline), and zidovudine. It may be necessary to adjust the dosages of these drugs if they are given concurrently with rifampin.
Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control during rifampin therapy.
Rifampin has been observed to increase the requirements for anticoagulant drugs of the coumarin type. In patients receiving anticoagulants and rifampin concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant.
Diabetes may become more difficult to control.
OTHER INTERACTIONS: When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampin were observed.
Concurrent use of ketoconazole and rifampin has resulted in decreased serum concentrations of both drugs. Concurrent use of rifampin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient's clinical condition.
Concomitant antacid administration may reduce the absorption of rifampin. Daily doses of rifampin should be given at least 1 hour before the ingestion of antacids.
Probenecid and cotrimoxazole have been reported to increase the blood level of rifampin.
When rifampin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of rifampin and halothane should be avoided. Patients receiving both rifampin and isoniazid should be monitored close for hepatotoxicity.
Plasma concentrations of sulfapyridine may be reduced following the concomitant administration of sulfasalazine and rifampin. This finding may be the result of alteration in the colonic bacteria responsible for the reduction of sulfasalazine to sulfapyridine and mesalamine.
Doxycycline can be stored at room temperature. Protect from light and excessive heat.
What side effects may occur?
Side effects cannot be anticipated. If any develop or change in intensity, inform your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking doxycycline.
More common side effects may include:
Angioedema (chest pain; swelling of face, around lips, tongue and throat, arms and legs; difficulty swallowing), bulging foreheads in infants, diarrhea, difficulty swallowing, discolored teeth in infants and children (more common during long-term use of tetracycline), inflammation of the tongue, loss of appetite, nausea, rash, rectal or genital itching, severe allergic reaction (hives, itching, and swelling), skin sensitivity to light, vomiting
Less common or rare side effects may include:
Aggravation of lupus erythematosus (disease of the connective tissue), skin inflammation and peeling, throat inflammation and ulcerations
Why should this drug not be prescribed?
If you are sensitive to or have ever had an allergic reaction to doxycycline or drugs of this type, you should not take this medication. Make sure your doctor is aware of any drug reactions that you have experienced.
Special warnings about this medication
As with other antibiotics, treatment with doxycycline may result in a growth of bacteria that do not respond to this medication and can cause a secondary infection.
Bulging foreheads in infants and headaches in adults have occurred. These symptoms disappeared when doxycycline was discontinued.
You may become more sensitive to sunlight while taking doxycycline. Be careful if you are going out in the sun or using a sunlamp. If you develop a skin rash, notify your doctor immediately.
Birth control pills that contain estrogen may not be as effective while you are taking tetracycline drugs. Ask your doctor or pharmacist if you should use another form of birth control while taking doxycycline.
Doxycycline syrup (Vibramycin) contains a sulfite that may cause allergic reactions in certain people. This reaction happens more frequently to people with asthma.
Possible food and drug interactions when taking this medication
If doxycycline is taken with certain other drugs, the effects of either could be increased, decreased, or altered. It is especially important to check with your doctor before combining doxycycline with the following:
Antacids containing aluminum, calcium, or magnesium, and iron-containing preparations such as Maalox, Mylanta, and others
Barbiturates such as phenobarbital
Bismuth subsalicylate (Pepto-Bismol)
Blood-thinning medications such as Coumadin
Penicillin (V-Cillin K, Pen-vee K, others)
Special information if you are pregnant or breastfeeding
Doxycycline should not be used during pregnancy. Tetracycline can damage developing teeth during the last half of pregnancy. If you are pregnant or plan to become pregnant, inform your doctor immediately. Tetracyclines such as doxycycline appear in breast milk and can affect a nursing infant. If this medication is essential to your health, your doctor may advise you to discontinue breastfeeding until your treatment is finished.
The usual dose of oral doxycycline is 200 milligrams on the first day of treatment (100 milligrams every 12 hours) followed by a maintenance dose of 100 milligrams per day. The maintenance dose may be taken as a single dose or as 50 milligrams every 12 hours.
Your doctor may prescribe 100 milligrams every 12 hours for severe infections such as chronic urinary tract infection.
For Uncomplicated Gonorrhea (Except Anorectal Infections in Men)
The usual dose is 100 milligrams by mouth, twice a day for 7 days. An alternate, single-day treatment is 300 milligrams, followed in 1 hour by a second 300-milligram dose.
For Primary and Secondary Syphilis
The usual dose is 200 milligrams a day, divided into smaller, equal doses for 14 days.
For Inhalational Anthrax
To prevent or combat infection after exposure, the usual dose is 100 milligrams taken by mouth twice a day for 60 days. Treatment can be started intravenously, but should be switched to oral doses as soon as possible.
For Prevention of Malaria
The usual dose is 100 milligrams a day. Treatment should begin 1 to 2 days before travel to the area where malaria is found, then continue daily during travel in the area and 4 weeks after leaving.
For children above 8 years of age, the recommended dosage schedule for those weighing 100 pounds or less is 2 milligrams per pound of body weight, divided into 2 doses, on the first day of treatment, followed by 1 milligram per pound of body weight given as a single daily dose or divided into 2 doses on subsequent days.
For more severe infections, up to 2 milligrams per pound of body weight may be used.
For inhalational anthrax in children weighing less than 100 pounds, the usual dose is 1 milligram per pound of body weight twice daily for 60 days.
For prevention of malaria, the recommended dose is 2 milligrams per 2.2 pounds of body weight up to 100 milligrams.
For children over 100 pounds, the usual adult dose should be used.
Any medication taken in excess can have serious consequences. If you suspect an overdose, seek medical treatment immediately.