Topiramate Teva may be available in the countries listed below.
Ingredient matches for Topiramate Teva
Topiramate
Topiramate is reported as an ingredient of Topiramate Teva in the following countries:
- Bulgaria
International Drug Name Search
Sunday 26 April 2009
Wednesday 22 April 2009
D 1000 IU
Generic Name: cholecalciferol (vitamin D3) (KOE le kal SIF e role)
Brand Names: D 1000 IU, D3-5, D3-50, Delta D3, Vitamin D3
What is cholecalciferol?
Cholecalciferol is a vitamin D3. Vitamin D is important for the absorption of calcium from the stomach and for the functioning of calcium in the body.
Cholecalciferol is used to treat or prevent many conditions caused by a lack of vitamin D, especially conditions of the skin or bones.
Cholecalciferol may also be used for other purposes not listed in this medication guide.
What is the most important information I should know about cholecalciferol?
Do not use this medication if you have ever had an allergic reaction to vitamin D, or if you have high levels of calcium or vitamin D in your blood, or if you have any condition that makes it hard for your body to absorb nutrients from food (malabsorption).
Before taking cholecalciferol, tell your doctor if you are allergic to any drugs, or if you have heart disease, kidney disease, or an electrolyte imbalance.
Do not take other vitamin or mineral supplements unless your doctor has told you to.
Avoid using calcium supplements or antacids without your doctor's advice. Use only the specific type of supplement or antacid your doctor recommends. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.
Seek emergency medical attention if you think you have used too much of this medicine. An overdose of vitamin D can cause serious or life-threatening side effects.
Overdose symptoms may include headache, weakness, drowsiness, dry mouth, nausea, vomiting, constipation, muscle or bone pain, metallic taste in the mouth, weight loss, itchy skin, changes in heart rate, loss of interest in sex, confusion, unusual thoughts or behavior, severe pain in your upper stomach spreading to your back, or fainting.
What should I discuss with my healthcare provider before taking cholecalciferol?
Do not use this medication if you have ever had an allergic reaction to vitamin D, or if you have:
high levels of calcium in your blood (hypercalcemia);
high levels of vitamin D in your body (hypervitaminosis D); or
any condition that makes it hard for your body to absorb nutrients from food (malabsorption).
If you have any of these other conditions, you may need a dose adjustment or special tests to safely use cholecalciferol:
heart disease;
kidney disease; or
an electrolyte imbalance.
Your cholecalciferol dose needs may change if you are pregnant or breast-feeding. Tell your doctor if you are pregnant or plan to become pregnant during treatment, or if you are breast-feeding a baby.
How should I take cholecalciferol?
Take this medication exactly as directed on the label, or as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended.
Your doctor may occasionally change your dose to make sure you get the best results from this medication.
Measure liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
Cholecalciferol is only part of a complete program of treatment that may also include a special diet. It is very important to follow the diet plan created for you by your doctor or nutrition counselor. You should become very familiar with the list of foods you must eat or avoid to help control your condition.
Store this medication at room temperature away from moisture, light, and heat.
What happens if I miss a dose?
Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.
What happens if I overdose?
Seek emergency medical attention if you think you have used too much of this medicine. An overdose of vitamin D can cause serious or life-threatening side effects.
Overdose symptoms may include headache, weakness, drowsiness, dry mouth, nausea, vomiting, constipation, muscle or bone pain, metallic taste in the mouth, weight loss, itchy skin, changes in heart rate, loss of interest in sex, confusion, unusual thoughts or behavior, severe pain in your upper stomach spreading to your back, or fainting.
What should I avoid while taking cholecalciferol?
Do not take other vitamin or mineral supplements unless your doctor has told you to.
Avoid using calcium supplements or antacids without your doctor's advice. Use only the specific type of supplement or antacid your doctor recommends.
Cholecalciferol side effects
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop taking cholecalciferol and call your doctor at once if you have a serious side effect such as:
thinking problems, changes in behavior, feeling irritable;
urinating more than usual;
chest pain, feeling short of breath; or
early signs of vitamin D overdose (weakness, metallic taste in your mouth, weight loss, muscle or bone pain, constipation, nausea, and vomiting).
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What other drugs will affect cholecalciferol?
Before taking cholecalciferol, tell your doctor if you are taking any of the following medicines:
seizure medication;
cholestyramine (Prevalite, Questran);
colestipol (Colestid);
steroids (prednisone and others);
digoxin (digitalis, Lanoxin); or
a diuretic (water pill) such as chlorothiazide (Diuril), hydrochlorothiazide (HCTZ, HydroDiuril, Hyzaar, Lopressor, Vasoretic, Zestoretic), chlorthalidone (Hygroton, Thalitone), indapamide (Lozol), metolazone (Mykrox, Zaroxolyn), and others.
This list is not complete and there may be other drugs that can interact with cholecalciferol. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.
More D 1000 IU resources
- D 1000 IU Side Effects (in more detail)
- D 1000 IU Use in Pregnancy & Breastfeeding
- D 1000 IU Drug Interactions
- D 1000 IU Support Group
- 0 Reviews for D000 IU - Add your own review/rating
- Delta D3 Advanced Consumer (Micromedex) - Includes Dosage Information
Compare D 1000 IU with other medications
- Prevention of Falls
- Prevention of Fractures
- Vitamin D Deficiency
- Vitamin D Insufficiency
Where can I get more information?
- Your pharmacist can provide more information about cholecalciferol.
See also: D000 IU side effects (in more detail)
Saturday 18 April 2009
Tribonat
Tribonat may be available in the countries listed below.
Ingredient matches for Tribonat
Trometamol
Trometamol is reported as an ingredient of Tribonat in the following countries:
- Norway
International Drug Name Search
Thursday 16 April 2009
Hascosept
Hascosept may be available in the countries listed below.
Ingredient matches for Hascosept
Benzydamine
Benzydamine hydrochloride (a derivative of Benzydamine) is reported as an ingredient of Hascosept in the following countries:
- Poland
International Drug Name Search
Dicymine
Dicymine may be available in the countries listed below.
Ingredient matches for Dicymine
Dicycloverine
Dicycloverine is reported as an ingredient of Dicymine in the following countries:
- Hong Kong
- Thailand
International Drug Name Search
Tuesday 14 April 2009
Duramorph
morphine sulfate
Dosage Form: injection, solution
Duramorph (morphine sulfate injection, USP)
PRESERVATIVE-FREE
CII
Rx only
Not For Use in Continuous Microinfusion Devices
Duramorph Description
Morphine is the most important alkaloid of opium and is a phenanthrene derivative. It is available as the sulfate salt, having the following structural formula:
7,8-Didehydro-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3,6-diol sulfate (2:1) (salt), pentahydrate
(C17H19NO3)2• H2SO4• 5H2Molecular Weight is 758.83
Preservative-free Duramorph (morphine sulfate injection, USP) is a sterile, nonpyrogenic, isobaric solution of morphine sulfate, free of antioxidants, preservatives or other potentially neurotoxic additives and is intended for intravenous, epidural or intrathecal administration as a narcotic analgesic. Each milliliter contains morphine sulfate 0.5 mg or 1 mg and sodium chloride 9 mg in Water for Injection. pH range is 2.5‑6.5. Each 10 mL DOSETTE ampul of Duramorph is intended for SINGLE USE ONLY. Discard any unused portion. DO NOT HEAT-STERILIZE.
Duramorph - Clinical Pharmacology
Morphine produces a wide spectrum of pharmacologic effects including analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility and physical dependence. Opiate analgesia involves at least three anatomical areas of the central nervous system: the periaqueductal-periventricular gray matter, the ventromedial medulla and the spinal cord. A systematically administered opiate may produce analgesia by acting at any, all or some combination of these distinct regions. Morphine interacts predominantly with the μ-receptor. The μ-binding sites of opioids are very discretely distributed in the human brain, with high densities of sites found in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve.
Morphine has an apparent volume of distribution ranging from 1.0 to 4.7 L/kg after intravenous dosage. Protein binding is low, about 36%, and muscle tissue binding is reported as 54%. A blood-brain barrier exists, and when morphine is introduced outside of the CNS (e.g.,intravenously), plasma concentrations of morphine remain higher than the corresponding CSF morphine levels. Conversely, when morphine is injected into the intrathecal space, it diffuses out into the systemic circulation slowly, accounting for the long duration of action of morphine administered by this route.
Morphine has a total plasma clearance which ranges from 0.9 to 1.2 L/kg/h (liters/kilogram/hour) in postoperative patients, but shows considerable interindividual variation. The major pathway of clearance is hepatic glucuronidation to morphine‑3‑glucuronide, which is pharmacologically inactive. The major excretion path of the conjugate is through the kidneys, with about 10% in the feces. Morphine is also eliminated by the kidneys, 2 to 12% being excreted unchanged in the urine. Terminal half-life is commonly reported to vary from 1.5 to 4.5 hours, although the longer half‑lives were obtained when morphine levels were monitored over protracted periods with very sensitive radioimmunoassay methods. The accepted elimination half-life in normal subjects is 1.5 to 2 hours.
“Selective” blockade of pain sensation is possible by neuraxial application of morphine. In addition, duration of analgesia may be much longer by this route compared to systemic administration. However, CNS effects, associated with systemic administration, are still seen. These include respiratory depression, sedation, nausea and vomiting, pruritus and urinary retention. In particular, both early and late respiratory depression (up to 24 hours post dosing) have been reported following neuraxial administration. Circulation of the spinal fluid may also result in high concentrations of morphine reaching the brain stem directly.
The incidence of unwanted CNS effects, including delayed respiratory depression, associated with neuraxial application of morphine, is related to the circulatory dynamics of the epidural venous plexus and the spinal fluid. The lipid solubility and degree of ionization of morphine plays an important part in both the onset and duration of analgesia and the CNS effects. Morphine has a pKa 7.9, with an octanol/water partition coefficient of 1.42 at pH 7.4. At this pH, the tertiary amino group in each of the opioids is mostly ionized, making the molecule water soluble. Morphine, with additional hydroxyl groups on the molecule, is significantly more water soluble than any other opioid in clinical use.
Morphine, injected into the epidural space, is rapidly absorbed into the general circulation. Absorption is so rapid that the plasma concentration-time profiles closely resemble those obtained after intravenous or intramuscular administration. Peak plasma concentrations averaging 33–40 ng/mL (range 5–62 ng/mL) are achieved within 10 to 15 minutes after administration of 3 mg of morphine. Plasma concentrations decline in a multiexponential fashion. The terminal half-life is reported to range from 39 to 249 minutes (mean of 90±34.3 min) and, though somewhat shorter, is similar in magnitude as values reported after intravenous and intramuscular administration (1.5–4.5 h). CSF concentrations of morphine, after epidural doses of 2 to 6 mg in postoperative patients, have been reported to be 50 to 250 times higher than corresponding plasma concentrations. The CSF levels of morphine exceed those in plasma after only 15 minutes and are detectable for as long as 20 hours after the injection of 2 mg of epidural morphine. Approximately 4% of the dose injected epidurally reaches the CSF. This corresponds to the relative minimum effective epidural and intrathecal doses of 5 mg and 0.25 mg, respectively. The disposition of morphine in the CSF follows a biphasic pattern, with an early half-life of 1.5 h and a late phase half-life of about 6 h. Morphine crosses the dura slowly, with an absorption half-life across the dura averaging 22 minutes. Maximum CSF concentrations are seen 60–90 minutes after injection. Minimum effective CSF concentrations for postoperative analgesia average 150 ng/mL (range < 1‑380 ng/mL).
The intrathecal route of administration circumvents meningeal diffusion barriers and, therefore, lower doses of morphine produce comparable analgesia to that induced by the epidural route. After intrathecal bolus injection of morphine, there is a rapid initial distribution phase lasting 15–30 minutes and a half-life in the CSF of 42–136 min (mean 90±16 min). Derived from limited data, it appears that the disposition of morphine in the CSF, from 15 minutes postintrathecal administration to the end of a six-hour observation period, represents a combination of the distribution and elimination phases. Morphine concentrations in the CSF averaged 332±137 ng/mL at 6 hours, following a bolus dose of 0.3 mg of morphine. The apparent volume of distribution of morphine in the intrathecal space is about 22±8 mL.
Time-to-peak plasma concentrations, however, are similar (5-10 min) after either epidural or intrathecal bolus administration of morphine. Maximum plasma morphine concentrations after 0.3 mg intrathecal morphine have been reported from < 1 to 7.8 ng/mL. The minimum analgesic morphine plasma concentration during Patient‑Controlled Analgesia (PCA) has been reported as 20–40 ng/mL, suggesting that any analgesic contribution from systemic redistribution would be minimal after the first 30–60 minutes with epidural administration and virtually absent with intrathecal administration of morphine.
Indications and Usage for Duramorph
Duramorph is a systemic narcotic analgesic for administration by the intravenous, epidural or intrathecal routes. It is used for the management of pain not responsive to non-narcotic analgesics. Duramorph administered epidurally or intrathecally, provides pain relief for extended periods without attendant loss of motor, sensory or sympathetic function.
Not For Use in Continuous Microinfusion Devices
Contraindications
Duramorph is contraindicated in those medical conditions which would preclude the administration of opioids by the intravenous route—allergy to morphine or other opiates, acute bronchial asthma, upper airway obstruction.
Duramorph, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by a depleted blood volume or a concurrent administration of drugs, such as phenothiazines or general anesthetics. (See also PRECAUTIONS: Use with Other Central Nervous System Depressants.)
Warnings
Morphine sulfate may be habit forming. (See DRUG ABUSE AND DEPENDENCE.) Overdoses may cause respiratory depression, coma and death.
Duramorph administration should be limited to use by those familiar with the management of respiratory depression. Rapid intravenous administration may result in chest wall rigidity.
Prior to any epidural or intrathecal drug administration, the physician should be familiar with patient conditions (such as infection at the injection site, bleeding diathesis, anticoagulant therapy, etc.) which call for special evaluation of the benefit versus risk potential.
In the case of epidural or intrathecal administration, Duramorph should be administered by or under the direction of a physician experienced in the techniques and familiar with the patient management problems associated with epidural or intrathecal drug administration. Because epidural administration has been associated with less potential for immediate or late adverse effects than intrathecal administration, the epidural route should be used whenever possible.
SEVERE RESPIRATORY DEPRESSION UP TO 24 HOURS FOLLOWING EPIDURAL OR INTRATHECAL ADMINISTRATION HAS BEEN REPORTED.
BECAUSE OF THE RISK OF SEVERE ADVERSE EFFECTS WHEN THE EPIDURAL OR INTRATHECAL ROUTE OF ADMINISTRATION IS EMPLOYED, PATIENTS MUST BE OBSERVED IN A FULLY EQUIPPED AND STAFFED ENVIRONMENT FOR AT LEAST 24 HOURS AFTER THE INITIAL DOSE. |
THE FACILITY MUST BE EQUIPPED TO RESUSCITATE PATIENTS WITH SEVERE OPIATE OVERDOSAGE, AND THE PERSONNEL MUST BE FAMILIAR WITH THE USE AND LIMITATIONS OF SPECIFIC NARCOTIC ANTAGONISTS (NALOXONE, NALTREXONE) IN SUCH CASES.
Tolerance and Myoclonic Activity
PATIENTS SOMETIMES MANIFEST UNUSUAL ACCELERATION OF NEURAXIAL MORPHINE REQUIREMENTS, WHICH MAY CAUSE CONCERN REGARDING SYSTEMIC ABSORPTION AND THE HAZARDS OF LARGE DOSES; THESE PATIENTS MAY BENEFIT FROM HOSPITALIZATION AND DETOXIFICATION. TWO CASES OF MYOCLONIC-LIKE SPASM OF THE LOWER EXTREMITIES HAVE BEEN REPORTED IN PATIENTS RECEIVING MORE THAN 20 MG/DAY OF INTRATHECAL MORPHINE. AFTER DETOXIFICATION, IT MIGHT BE POSSIBLE TO RESUME TREATMENT AT LOWER DOSES, AND SOME PATIENTS HAVE BEEN SUCCESSFULLY CHANGED FROM CONTINUOUS EPIDURAL MORPHINE TO CONTINUOUS INTRATHECAL MORPHINE. REPEAT DETOXIFICATION MAY BE INDICATED AT A LATER DATE. THE UPPER DAILY DOSAGE LIMIT FOR EACH PATIENT DURING CONTINUING TREATMENT MUST BE INDIVIDUALIZED.
Precautions
General
Control of pain by neuraxial opiate delivery is always accompanied by considerable risk to the patients and requires a high level of skill to be successfully accomplished. The task of treating these patients must be undertaken by experienced clinical teams, well-versed in patient selection, evolving technology and emerging standards of care. For safety reasons, it is recommended that administration of Duramorph by the epidural or intrathecal routes be limited to the lumbar area. Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use.
Seizures may result from high doses. Patients with known seizure disorders should be carefully observed for evidence of morphine-induced seizure activity.
Use in Patients with Increased Intracranial Pressure or Head Injury
Duramorph should be used with extreme caution in patients with head injury or increased intracranial pressure. Pupillary changes (miosis) from morphine may obscure the existence, extent and course of intracranial pathology. High doses of neuraxial morphine may produce myoclonic events (see WARNINGS and ADVERSE REACTIONS). Clinicians should maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status or movement abnormalities in patients receiving this modality of treatment.
Use in Chronic Pulmonary Disease
Care is urged in using this drug in patients who have a decreased respiratory reserve (e.g., emphysema, severe obesity, kyphoscoliosis or paralysis of the phrenic nerve). Duramorph should not be given in cases of chronic asthma, upper airway obstruction or in any other chronic pulmonary disorder without due consideration of the known risk of acute respiratory failure following morphine administration in such patients.
Use in Hepatic or Renal Disease
The elimination half-life of morphine may be prolonged in patients with reduced metabolic rates and with hepatic and/or renal dysfunction. Hence, care should be exercised in administering Duramorph epidurally to patients with these conditions, since high blood morphine levels, due to reduced clearance, may take several days to develop.
Use in Biliary Surgery or Disorders of the Biliary Tract
As significant morphine is released into the systemic circulation from neuraxial administration, the ensuing smooth muscle hypertonicity may result in biliary colic.
Use with Disorders of the Urinary System
Initiation of neuraxial opiate analgesia is frequently associated with disturbances of micturition, especially in males with prostatic enlargement. Early recognition of difficulty in urination and prompt intervention in cases of urinary retention is indicated.
Use in Ambulatory Patients
Patients with reduced circulating blood volume, impaired myocardial function or on sympatholytic drugs should be monitored for the possible occurrence of orthostatic hypotension, a frequent complication in single-dose neuraxial morphine analgesia.
Use with Other Central Nervous System Depressants
The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics or psychotropic drugs. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Morphine is without known carcinogenic or mutagenic effects and is not known to impair fertility at non-narcotic doses in animals, but studies of the carcinogenic and mutagenic potential or the effect on fertility of Duramorph have not been conducted.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Morphine sulfate is not teratogenic in rats at 35 mg/kg/day (thirty-five times the usual human dose) but does result in increased pup mortality and growth retardation at doses that narcotize the animal (> 10 mg/kg/day, ten times the usual human dose). Duramorph should only be given to pregnant women when no other method of controlling pain is available and means are at hand to manage the delivery and perinatal care of the opiate-dependent infant.
Nonteratogenic Effects
Infants born to mothers who have been taking morphine chronically may exhibit withdrawal symptoms.
Labor and Delivery
Intravenous morphine readily passes into the fetal circulation and may result in respiratory depression in the neonate. Naloxone and resuscitative equipment should be available for reversal of narcotic-induced respiratory depression in the neonate. In addition, intravenous morphine may reduce the strength, duration and frequency of uterine contraction resulting in prolonged labor.
Epidurally and intrathecally administered morphine readily passes into the fetal circulation and may result in respiratory depression of the neonate. Controlled clinical studies have shown that epidural administration has little or no effect on the relief of labor pain.
Nursing Mothers
Morphine is excreted in maternal milk. Effects on the nursing infant are not known.
Pediatric Use
Adequate studies, to establish the safety and effectiveness of spinal morphine in pediatric patients, have not been performed, and usage in this population is not recommended.
Geriatric Use
The pharmacodynamic effects of neuraxial morphine in the elderly are more variable than in the younger population. Patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. Initial doses should be based on careful clinical observation following “test doses”, after making due allowances for the effects of the patient’s age and infirmity on his/her ability to clear the drug, particularly in patients receiving epidural morphine.
Elderly patients may be more susceptible to respiratory depression and/or respiratory arrest following administration of morphine.
Adverse Reactions
The most serious adverse experience encountered during administration of Duramorph is respiratory depression and/or respiratory arrest. This depression and/or respiratory arrest may be severe and could require intervention. (See WARNINGS and OVERDOSAGE.) Because of delay in maximum CNS effect with intravenously administered drug (30 min), rapid administration may result in overdosing. Single-dose neuraxial administration may result in acute or delayed respiratory depression for periods at least as long as 24 hours.
Tolerance and Myoclonus
See WARNINGS for discussion of these and related hazards.
While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulating catecholamines. Excitation of the central nervous system, resulting in convulsions, may accompany high doses of morphine given intravenously. Dysphoric reactions may occur after any size dose and toxic psychoses have been reported.
Pruritus
Single-dose epidural or intrathecal administration is accompanied by a high incidence of pruritus that is dose-related but not confined to the site of administration. Pruritus, following continuous infusion of epidural or intrathecal morphine, is occasionally reported in the literature; these reactions are poorly understood as to their cause.
Urinary Retention
Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal administration, is a frequent side effect and must be anticipated primarily in male patients, with a somewhat lower incidence in females. Also frequently reported in the literature is the occurrence of urinary retention during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy. Patients who develop urinary retention have responded to cholinomimetic treatment and/or judicious use of catheters (see PRECAUTIONS).
Constipation
Constipation is frequently encountered during continuous infusion of morphine; this can usually be managed by conventional therapy.
Headache
Lumbar puncture-type headache is encountered in a significant minority of cases for several days following intrathecal catheter implantation; this, generally, responds to bed rest and/or other conventional therapy.
Other
Other adverse experiences reported following morphine therapy include—Dizziness, euphoria, anxiety, hypotension, confusion, reduced male potency, decreased libido in men and women, and menstrual irregularities including amenorrhea, depression of cough reflex, interference with thermal regulation and oliguria. Evidence of histamine release such as urticaria, wheals and/or local tissue irritation may occur. Nausea and vomiting are frequently seen in patients following morphine administration.
Pruritus, nausea/vomiting and urinary retention, if associated with continuous infusion therapy, may respond to intravenous administration of a low dose of naloxone (0.2 mg). The risks of using narcotic antagonists in patients chronically receiving narcotic therapy should be considered.
In general, side effects are amenable to reversal by narcotic antagonists.
NALOXONE INJECTION AND RESUSCITATIVE EQUIPMENT SHOULD BE IMMEDIATELY AVAILABLE FOR ADMINISTRATION IN CASE OF LIFE-THREATENING OR INTOLERABLE SIDE EFFECTS AND WHENEVER Duramorph THERAPY IS BEING INITIATED. |
Drug Abuse and Dependence
Controlled Substance
Morphine sulfate is a Schedule II narcotic under the United States Controlled Substance Act (21 U.S.C. 801-886).
Morphine is the most commonly cited prototype for narcotic substances that possess an addiction-forming or addiction-sustaining liability. A patient may be at risk for developing a dependence to morphine if used improperly or for overly long periods of time. As with all potent opioids which are μ-agonists, tolerance as well as psychological and physical dependence to morphine may develop irrespective of the route of administration (intravenous, intramuscular, intrathecal, epidural or oral). Individuals with a prior history of opioid or other substance abuse or dependence, being more apt to respond to the euphorogenic and reinforcing properties of morphine, would be considered to be at greater risk.
Care must be taken to avert withdrawal in patients who have been maintained on parenteral/oral narcotics when epidural or intrathecal administration is considered. Withdrawal symptoms may occur when morphine is discontinued abruptly or upon administration of a narcotic antagonist.
Overdosage
PARENTERAL ADMINISTRATION OF NARCOTICS IN PATIENTS RECEIVING EPIDURAL OR INTRATHECAL MORPHINE MAY RESULT IN OVERDOSAGE.
Overdosage of morphine is characterized by respiratory depression, with or without concomitant CNS depression. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. Since respiratory arrest may result either through direct depression of the respiratory center or as the result of hypoxia, primary attention should be given to the establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted, or controlled, ventilation. The narcotic antagonist, naloxone, is a specific antidote. An initial dose of 0.4 to 2 mg of naloxone should be administered intravenously, simultaneously with respiratory resuscitation. If the desired degree of counteraction and improvement in respiratory function is not obtained, naloxone may be repeated at 2- to 3-minute intervals. If no response is observed after 10 mg of naloxone has been administered, the diagnosis of narcotic-induced, or partial narcotic-induced, toxicity should be questioned. Intramuscular or subcutaneous administration may be used if the intravenous route is not available.
As the duration of effect of naloxone is considerably shorter than that of epidural or intrathecal morphine, repeated administration may be necessary. Patients should be closely observed for evidence of renarcotization.
Duramorph Dosage and Administration
Duramorph is intended for intravenous, epidural or intrathecal administration.
Not For Use in Continuous Microinfusion Devices
Intravenous Administration
Dosage
The initial dose of morphine should be 2 mg to 10 mg/70 kg of body weight. No information is available regarding the use of Duramorph in patients under the age of 18.
Geriatric Use
Administer with extreme caution. (See PRECAUTIONS.)
Epidural Administration
Duramorph SHOULD BE ADMINISTERED EPIDURALLY BY OR UNDER THE DIRECTION OF A PHYSICIAN EXPERIENCED IN THE TECHNIQUE OF EPIDURAL ADMINISTRATION AND WHO IS THOROUGHLY FAMILIAR WITH THE LABELING. IT SHOULD BE ADMINISTERED ONLY IN SETTINGS WHERE ADEQUATE PATIENT MONITORING IS POSSIBLE. RESUSCITATIVE EQUIPMENT AND A SPECIFIC ANTAGONIST (NALOXONE INJECTION) SHOULD BE IMMEDIATELY AVAILABLE FOR THE MANAGEMENT OF RESPIRATORY DEPRESSION AS WELL AS COMPLICATIONS WHICH MIGHT RESULT FROM INADVERTENT INTRATHECAL OR INTRAVASCULAR INJECTION. (NOTE: INTRATHECAL DOSAGE IS USUALLY 1/10 THAT OF EPIDURAL DOSAGE.) PATIENT MONITORING SHOULD BE CONTINUED FOR AT LEAST 24 HOURS AFTER EACH DOSE, SINCE DELAYED RESPIRATORY DEPRESSION MAY OCCUR.
Proper placement of a needle or catheter in the epidural space should be verified before Duramorph is injected.
Acceptable techniques for verifying proper placement include: a) aspiration to check for absence of blood or cerebrospinal fluid, or b) administration of 5 mL (3 mL in obstetric patients) of 1.5% PRESERVATIVE-FREE Lidocaine and Epinephrine (1:200,000) Injection and then observe the patient for lack of tachycardia (this indicates that vascular injection has not been made) and lack of sudden onset of segmental anesthesia (this indicates that intrathecal injection has not been made).
Epidural Adult Dosage
Initial injection of 5 mg in the lumbar region may provide satisfactory pain relief for up to 24 hours. If adequate pain relief is not achieved within one hour, careful administration of incremental doses of 1 to 2 mg at intervals sufficient to assess effectiveness may be given. No more than 10 mg/24 hr should be administered.
Thoracic administration has been shown to dramatically increase the incidence of early and late respiratory depression even at doses of 1 to 2 mg.
Geriatric Use
Administer with extreme caution. (See PRECAUTIONS.)
Epidural Pediatric Use
No information on use in pediatric patients is available. (See PRECAUTIONS.)
Intrathecal Administration
NOTE: INTRATHECAL DOSAGE IS USUALLY 1/10 THAT OF EPIDURAL DOSAGE. |
Duramorph SHOULD BE ADMINISTERED INTRATHECALLY BY OR UNDER THE DIRECTION OF A PHYSICIAN EXPERIENCED IN THE TECHNIQUE OF INTRATHECAL ADMINISTRATION AND WHO IS THOROUGHLY FAMILIAR WITH THE LABELING. IT SHOULD BE ADMINISTERED ONLY IN SETTINGS WHERE ADEQUATE PATIENT MONITORING IS POSSIBLE. RESUSCITATIVE EQUIPMENT AND A SPECIFIC ANTAGONIST (NALOXONE INJECTION) SHOULD BE IMMEDIATELY AVAILABLE FOR THE MANAGEMENT OF RESPIRATORY DEPRESSION AS WELL AS COMPLICATIONS WHICH MIGHT RESULT FROM INADVERTENT INTRAVASCULAR INJECTION. PATIENT MONITORING SHOULD BE CONTINUED FOR AT LEAST 24 HOURS AFTER EACH DOSE, SINCE DELAYED RESPIRATORY DEPRESSION MAY OCCUR. RESPIRATORY DEPRESSION (BOTH EARLY AND LATE ONSET) HAS OCCURRED MORE FREQUENTLY FOLLOWING INTRATHECAL ADMINISTRATION THAN EPIDURAL ADMINISTRATION.
Intrathecal Adult Dosage
A single injection of 0.2 to 1 mg may provide satisfactory pain relief for up to 24 hours. (CAUTION: THIS IS ONLY 0.4 TO 2 ML OF THE 5 MG/10 ML AMPUL OR 0.2 TO 1 ML OF THE 10 MG/10 ML AMPUL OF Duramorph). DO NOT INJECT INTRATHECALLY MORE THAN 2 ML OF THE 5 MG/10 ML AMPUL OR 1 ML OF THE 10 MG/10 ML AMPUL. USE IN THE LUMBAR AREA ONLY IS RECOMMENDED. Repeated intrathecal injections of Duramorph are not recommended. A constant intravenous infusion of naloxone, 0.6 mg/hr, for 24 hours after intrathecal injection may be used to reduce the incidence of potential side effects.
Geriatric Use
Administer with extreme caution. (See PRECAUTIONS.)
Repeat Dosage
If pain recurs, alternative routes of administration should be considered, since experience with repeated doses of morphine by the intrathecal route is limited.
Intrathecal Pediatric Use
No information on use in pediatric patients is available. (See PRECAUTIONS.)
SAFETY AND HANDLING INSTRUCTIONS
Duramorph is supplied in sealed ampuls. Accidental dermal exposure should be treated by the removal of any contaminated clothing and rinsing the affected area with water. |
How is Duramorph Supplied
Preservative-Free Duramorph (morphine sulfate injection, USP) is available in amber DOSETTE ampuls for intravenous, epidural and intrathecal administration:
5 mg/10 mL (0.5 mg/mL) packaged in 10s (NDC 60977-016-02)
10 mg/10 mL (1 mg/mL) packaged in 10s (NDC 60977-017-01)
Also available from Baxter: INFUMORPH (Preservative-free Morphine Sulfate Sterile Solution) 200 mg/20 mL (10 mg/mL) and 500 mg/20 mL (25 mg/mL) for epidural and intrathecal administration via a continuous microinfusion device.
Storage
PROTECT FROM LIGHT. Store in carton at 20°- 25°C (68°- 77°F), excursions permitted to 15°- 30°C (59°- 86°F) [see USP Controlled Room Temperature] until ready to use. DO NOT FREEZE. Duramorph contains no preservative or antioxidant. DISCARD ANY UNUSED PORTION. DO NOT HEAT-STERILIZE.
Baxter, Dosette, Duramorph, and Infumorph are trademarks of Baxter International, Inc., or its subsidiaries.
Manufactured by
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)
MLT 01070,B
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL
Container Label
NDC 60977-016-73
PRESERVATIVE-FREE
Duramorph
(morphine sulfate injection, USP)
CII
5 mg/10 mL (0.5 mg/mL)
10 mL DOSETTE Ampul
Rx only
FOR INTRAVENOUS, EPIDURAL OR INTRATHECAL
ADMINISTRATION-Read Package Insert Carefully
Each mL contains morphine sulfate 0.5 mg and sodium
chloride 9 mg in Water for Injection. pH 2.5-6.5.
PROTECT FROM LIGHT. Do not use if color is darker
than pale yellow, if it is discolored in any other way or
if it contains a precipitate. DO NOT HEAT-STERILIZE.
Baxter
Baxter Healthcare Corp.
Deerfield, IL 60015 USA
462-208-00
(01)00360977016733
LOT:
EXP.:
Carton Label
NDC 60977-016-02
PRESERVATIVE-FREE
Duramorph (morphine sulfate injection, USP)
CII
5 mg/10 mL (0.5 mg/mL)
Rx only
FOR INTRAVENOUS, EPIDURAL OR
INTRATHECALADMINISTRATION
10 x 10 mL DOSETTE Ampuls
Baxter
Manufactured by
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Each mL contains morphine sulfate 0.5 mg and sodium chloride 9 mg in
Water for Injection. pH 2.5-6.5.
Usual Dosage and Administration: Read Package Insert.
PROTECT FROM LIGHT: Keep covered in carton until time of use.
Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C
(59°-86°F) [see USP Controlled Room Temperature].
Do not use if color is darker than pale yellow, if it is discolored in any
other way or if it contains a precipitate.
CONTAINS NO PRESERVATIVE. Discard any unused portion. DO NOT
HEAT-STERILIZE.
To open ampuls, ignore color line; break at constriction.
Baxter, Duramorph and Dosette are registered trademarks of Baxter International, Inc., or its subsidiaries.
NDC 60977-016-02
PRESERVATIVE-FREE
Duramorph (morphine sulfate injection, USP)
CII
5 mg/10 mL (0.5 mg/mL)
10 x 10 mL DOSETTE Ampuls
FOR YOUR CONVENIENCE IN RECORDING NARCOTIC USE
PATIENT NAME / INITIAL / DATE
1.__________________________________________________
2.__________________________________________________
3.__________________________________________________
4.__________________________________________________
5.__________________________________________________
6.__________________________________________________
7.__________________________________________________
8.__________________________________________________
9.__________________________________________________
10.__________________________________________________
Baxter
462-209-00
N 3 60977 01602 3
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| NDA | NDA018565 | 05/31/2010 | |
| Duramorph morphine sulfate injection, solution | ||||||||||||||||||||
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| NDA | NDA018565 | 05/31/2010 | |
| Labeler - Baxter Healthcare Corporation (005083209) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Baxter Healthcare Corporation | 946499746 | MANUFACTURE | |
More Duramorph resources
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- Pain
Sunday 12 April 2009
Oxcarbazepine Suspension
Dosage Form: oral suspension
Oxcarbazepine OS
Oxcarbazepine
Oral Suspension
Rx only
Prescribing Information
DESCRIPTION
Oxcarbazepine is an antiepileptic drug available as 150 mg, 300 mg and 600 mg film-coated tablets for oral administration. Oxcarbazepine is also available as a 300 mg/5 mL (60 mg/mL) oral suspension. Oxcarbazepine is 10,11-Dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide, and its structural formula is
Oxcarbazepine is a white to faintly orange crystalline powder. It is slightly soluble in chloroform, dichloromethane, acetone, and methanol and practically insoluble in ethanol, ether and water. Its molecular weight is 252.27.
Oxcarbazepine oral suspension contains the following inactive ingredients: ascorbic acid; dispersible cellulose; ethanol; macrogol stearate; methyl parahydroxybenzoate; propylene glycol; propyl parahydroxybenzoate; purified water; sodium saccharin; sorbic acid; sorbitol; yellow-plum-lemon aroma.
CLINICAL PHARMACOLOGY
Mechanism of Action
The pharmacological activity of oxcarbazepine is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine (see Metabolism and Excretion subsection). The precise mechanism by which oxcarbazepine and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects of the drug. No significant interactions of oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated.
Pharmacodynamics
Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for five days and four weeks, respectively, with oxcarbazepine or MHD.
Pharmacokinetics
Following oral administration of oxcarbazepine tablets, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). The half-life of the parent is about two hours, while the half-life of MHD is about nine hours, so that MHD is responsible for most antiepileptic activity.
Based on MHD concentrations, oxcarbazepine tablets and suspension were shown to have similar bioavailability.
After single-dose administration of oxcarbazepine tablets to healthy male volunteers under fasted conditions, the median tmax was 4.5 (range 3 to 13) hours. After single-dose administration of oxcarbazepine oral suspension to healthy male volunteers under fasted conditions, the median tmax was six hours.
In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites.
Effect of Food: Food has no effect on the rate and extent of absorption of oxcarbazepine from oxcarbazepine tablets. Although not directly studied, the oral bioavailability of oxcarbazepine oral suspension is unlikely to be affected under fed conditions. Therefore, oxcarbazepine tablets and oral suspension can be taken with or without food.
Steady-state plasma concentrations of MHD are reached within 2-3 days in patients when oxcarbazepine is given twice a day. At steady state the pharmacokinetics of MHD are linear and show dose proportionality over the dose range of 300 to 2400 mg/day.
Distribution
The apparent volume of distribution of MHD is 49L.
Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.
Metabolism and Excretion
Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of oxcarbazepine. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD).
Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose.
Special Populations
Hepatic Impairment
The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900-mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD. No dose adjustment for oxcarbazepine is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of oxcarbazepine and MHD have not been evaluated in severe hepatic impairment and, therefore, caution should be exercised when dosing severely impaired patients.
Renal Impairment
There is a linear correlation between creatinine clearance and the renal clearance of MHD. When oxcarbazepine is administered as a single 300-mg dose in renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a two-fold increase in AUC. Dose adjustment for oxcarbazepine is recommended in these patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).
Pediatric Use
Weight-adjusted MHD clearance decreases as age and weight increases, approaching that of adults. The mean weight-adjusted clearance in children 2 years-<4 years of age is approximately 80% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about one-half that of adults when treated with a similar weight-adjusted dose. The mean weight-adjusted clearance in children 4–12 years of age is approximately 40% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about three-quarters that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, the weight-adjusted MHD clearance is expected to reach that of adults.
Geriatric Use
Following administration of single (300 mg) and multiple (600 mg/day) doses of oxcarbazepine to elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance.
Gender
No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly.
Race
No specific studies have been conducted to assess what effect, if any, race may have on the disposition of oxcarbazepine.
CLINICAL STUDIES
The effectiveness of oxcarbazepine as adjunctive and monotherapy for partial seizures in adults, and as adjunctive therapy in children aged 2-16 years was established in seven multicenter, randomized, controlled trials.
The effectiveness of oxcarbazepine as monotherapy for partial seizures in children aged 4-16 years was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations.
Oxcarbazepine Monotherapy Trials
Four randomized, controlled, double-blind, multicenter trials, conducted in a predominately adult population, demonstrated the efficacy of oxcarbazepine as monotherapy. Two trials compared oxcarbazepine to placebo and two trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of oxcarbazepine, after substituting oxcarbazepine 2400 mg/day for one or more antiepileptic drugs (AEDs). All doses were administered on a BID schedule. A fifth randomized, controlled, rater-blind, multicenter study, conducted in a pediatric population, failed to demonstrate a statistically significant difference between low and high dose oxcarbazepine treatment groups.
One placebo-controlled trial was conducted in 102 patients (11-62 years of age) with refractory partial seizures who had completed an inpatient evaluation for epilepsy surgery. Patients had been withdrawn from all AEDs and were required to have 2-10 partial seizures within 48 hours prior to randomization. Patients were randomized to receive either placebo or oxcarbazepine given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional nine days, or until one of the following three exit criteria occurred: 1) the occurrence of a fourth partial seizure, excluding Day 1, 2) two new-onset secondarily generalized seizures, where such seizures were not seen in the one-year period prior to randomization, or 3) occurrence of serial seizures or status epilepticus. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. There was a statistically significant difference in favor of oxcarbazepine (see Figure 1), p=0.0001.
Figure 1: Kaplan-Meier Estimates of Exit Rate by Treatment Group
The second placebo-controlled trial was conducted in 67 untreated patients (8-69 years of age) with newly-diagnosed and recent-onset partial seizures. Patients were randomized to placebo or oxcarbazepine, initiated at 300 mg BID and titrated to 1200 mg/day (given as 600 mg BID) in six days, followed by maintenance treatment for 84 days. The primary measure of effectiveness was a between-group comparison of the time to first seizure. The difference between the two treatments was statistically significant in favor of oxcarbazepine (see Figure 2), p=0.046.
Figure 2: Kaplan-Meier Estimates of First Seizure Event Rate by Treatment Group
A third trial substituted oxcarbazepine monotherapy at 2400 mg/day for carbamazepine in 143 patients (12-65 years of age) whose partial seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at a stable dose of 800 to 1600 mg/day, and maintained this oxcarbazepine dose for 56 days (baseline phase). Patients who were able to tolerate titration of oxcarbazepine to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of oxcarbazepine or 2400 mg/day oxcarbazepine. Patients were observed for 126 days or until one of the following four exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a two-fold increase in the highest consecutive two-day seizure frequency during baseline, 3) a single generalized seizure if none had occurred during baseline, or 4) a prolonged generalized seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. The difference between the curves was statistically significant in favor of the oxcarbazepine 2400 mg/day group (see Figure 3), p=0.0001.
Figure 3: Kaplan-Meier Estimates of Exit Rate by Treatment Group
Another monotherapy substitution trial was conducted in 87 patients (11-66 years of age) whose seizures were inadequately controlled on one or two AEDs. Patients were randomized to either oxcarbazepine 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first six weeks of double-blind therapy. Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until one of the four exit criteria described for the previous study occurred. The primary measure of effectiveness was a between-group comparison of the percentage of patients meeting exit criteria. The results were statistically significant in favor of the oxcarbazepine 2400 mg/day group (14/34; 41.2%) compared to the oxcarbazepine 300 mg/day group (42/45; 93.3%) (p<0.0001). The time to meeting one of the exit criteria was also statistically significant in favor of the oxcarbazepine 2400 mg/day group (see Figure 4), p=0.0001.
Figure 4: Kaplan-Meier Estimates of Exit Rate by Treatment Group
A monotherapy trial was conducted in 92 pediatric patients (1 month to 16 years of age) with inadequately-controlled or new-onset partial seizures. Patients were hospitalized and randomized to either oxcarbazepine 10 mg/kg/day or were titrated up to 40-60 mg/kg/day within three days while withdrawing the previous AED on the second day of oxcarbazepine therapy. Seizures were recorded through continuous video-EEG monitoring from Day 3 to Day 5. Patients either completed the 5-day treatment or met one of the two exit criteria: 1) three study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate), 2) a prolonged study-specific seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria in which the difference between the curves was not statistically significant (p=0.904). The majority of patients from both dose groups completed the 5-day study without exiting.
Although this study failed to demonstrate an effect of oxcarbazepine as monotherapy in pediatric patients, several design elements, including the short treatment and assessment period, the absence of a true placebo, and the likely persistence of plasma levels of previously administered AEDs during the treatment period, make the results uninterpretable. For this reason, the results do not undermine the conclusion, based on pharmacokinetic/pharmacodynamic considerations, that oxcarbazepine is effective as monotherapy in pediatric patients 4 years old and older.
Oxcarbazepine Adjunctive Therapy Trials
The effectiveness of oxcarbazepine as an adjunctive therapy for partial seizures was established in two multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15-66 years of age) and one in 264 pediatric patients (3-17 years of age), and in one multicenter, rater-blind, randomized, age-stratified, parallel-group study comparing two doses of oxcarbazepine in 128 pediatric patients (1 month to < 4 years of age).
Patients in the two placebo-controlled trials were on 1-3 concomitant AEDs. In both of the trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least 8 (minimum of 1-4 per month) partial seizures during the baseline phase were randomly assigned to placebo or to a specific dose of oxcarbazepine in addition to their other AEDs.
In these studies, the dose was increased over a two-week period until either the assigned dose was reached, or intolerance prevented increases. Patients then entered a 14- (pediatrics) or 24-week (adults) maintenance period.
In the adult trial, patients received fixed doses of 600, 1200 or 2400 mg/day. In the pediatric trial, patients received maintenance doses in the range of 30-46 mg/kg/day, depending on baseline weight. The primary measure of effectiveness in both trials was a between-group comparison of the percentage change in partial seizure frequency in the double-blind treatment phase relative to baseline phase. This comparison was statistically significant in favor of oxcarbazepine at all doses tested in both trials (p=0.0001 for all doses for both trials). The number of patients randomized to each dose, the median baseline seizure rate, and the median percentage seizure rate reduction for each trial are shown in Table 1. It is important to note that in the high-dose group in the study in adults, over 65% of patients discontinued treatment because of adverse events; only 46 (27%) of the patients in this group completed the 28-week study (see ADVERSE REACTIONS section), an outcome not seen in the monotherapy studies.
| Trial | Treatment Group | |||
| N | Baseline Median Seizure Rate* | Median % Reduction | ||
| 1 (pediatrics) | Oxcarbazepine | 136 | 12.5 | 34.81 |
| Placebo | 128 | 13.1 | 9.4 | |
| 2 (adults) | Oxcarbazepine 2400 mg/day | 174 | 10.0 | 49.91 |
| Oxcarbazepine 1200 mg/day | 177 | 9.8 | 40.21 | |
| Oxcarbazepine 600 mg/day | 168 | 9.6 | 26.41 | |
| Placebo | 173 | 8.6 | 7.6 |
1 p=0.0001; * = # per 28 days
Subset analyses of the antiepileptic efficacy of oxcarbazepine with regard to gender in these trials revealed no important differences in response between men and women. Because there were very few patients over the age of 65 in controlled trials, the effect of the drug in the elderly has not been adequately assessed.
The third adjunctive therapy trial enrolled 128 pediatric patients (1 month to <4 years of age) with inadequately-controlled partial seizures on 1-2 concomitant AEDs. Patients who experienced at least 2 study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate) during the 72-hour baseline period were randomly assigned to either oxcarbazepine 10 mg/kg/day or were titrated up to 60 mg/kg/day within 26 days. Patients were maintained on their randomized target dose for 9 days and seizures were recorded through continuous video-EEG monitoring during the last 72 hours of the maintenance period. The primary measure of effectiveness in this trial was a between-group comparison of the change in seizure frequency per 24 hours compared to the seizure frequency at baseline. For the entire group of patients enrolled, this comparison was statistically significant in favor of oxcarbazepine 60 mg/kg/day. In this study, there was no evidence that oxcarbazepine was effective in patients below the age of 2 years (N=75).
INDICATIONS AND USAGE
Oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as monotherapy in the treatment of partial seizures in children aged 4 years and above with epilepsy, and as adjunctive therapy in children aged 2 years and above with epilepsy.
CONTRAINDICATIONS
Oxcarbazepine should not be used in patients with a known hypersensitivity to oxcarbazepine or to any of its components.
WARNINGS
Hyponatremia
Clinically significant hyponatremia (sodium <125 mmol/L) can develop during oxcarbazepine use. In the 14 controlled epilepsy studies 2.5% of oxcarbazepine-treated patients (38/1,524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first three months of treatment with oxcarbazepine, although there were patients who first developed a serum sodium <125 mmol/L more than one year after initiation of therapy. Most patients who developed hyponatremia were asymptomatic but patients in the clinical trials were frequently monitored and some had their oxcarbazepine dose reduced, discontinued, or had their fluid intake restricted for hyponatremia. Whether or not these maneuvers prevented the occurrence of more severe events is unknown. Cases of symptomatic hyponatremia have been reported during post-marketing use. In clinical trials, patients whose treatment with oxcarbazepine was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment.
Measurement of serum sodium levels should be considered for patients during maintenance treatment with oxcarbazepine, particularly if the patient is receiving other medications known to decrease serum sodium levels (for example, drugs associated with inappropriate ADH secretion) or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity).
Anaphylactic Reactions and Angioedema
Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of oxcarbazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with oxcarbazepine, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug (see WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine subsection).
Patients with a Past History of Hypersensitivity Reaction to Carbamazepine
Patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of them will experience hypersensitivity reactions with oxcarbazepine. For this reason patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with oxcarbazepine only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, oxcarbazepine should be discontinued immediately (see WARNINGS, Anaphylactic Reactions and Angioedema subsection; see PRECAUTIONS, Multi-Organ Hypersensitivity subsection).
Serious Dermatological Reactions
Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with oxcarbazepine use. The median time of onset for reported cases was 19 days. Such serious skin reactions may be life threatening, and some patients have required hospitalization with very rare reports of fatal outcome. Recurrence of the serious skin reactions following rechallenge with oxcarbazepine has also been reported.
The reporting rate of TEN and SJS associated with oxcarbazepine use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3- to 10-fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to 6 cases per million-person years. Therefore, if a patient develops a skin reaction while taking oxcarbazepine, consideration should be given to discontinuing oxcarbazepine use and prescribing another antiepileptic medication.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including oxcarbazepine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
| Indication | Placebo Patients with Events Per 1,000 Patients | Drug Patients with Events Per 1,000 Patients | Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients | Risk Difference: Additional Drug Patients with Events Per 1,000 Patients |
| Epilepsy | 1.0 | 3.4 | 3.5 | 2.4 |
| Psychiatric | 5.7 | 8.5 | 1.5 | 2.9 |
| Other | 1.0 | 1.8 | 1.9 | 0.9 |
| Total | 2.4 | 4.3 | 1.8 | 1.9 |
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing oxcarbazepine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Withdrawal of AEDs
As with all antiepileptic drugs, oxcarbazepine should be withdrawn gradually to minimize the potential of increased seizure frequency.
PRECAUTIONS
Cognitive/Neuropsychiatric Adverse Events
Use of oxcarbazepine has been associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances.
Adult Patients
In one large, fixed-dose study, oxcarbazepine was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as oxcarbazepine was added, reduction in oxcarbazepine dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of oxcarbazepine on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related.
In this trial, 7.1% of oxcarbazepine-treated patients and 4% of placebo-treated patients experienced a cognitive adverse event. The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo. In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo. Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about seven times greater on oxcarbazepine than on placebo.
In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of oxcarbazepine, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance.
In the two dose-controlled conversion to monotherapy trials comparing 2400 mg/day and 300 mg/day oxcarbazepine, 1.1% of patients in the 2400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse events compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group.
Pediatric Patients
A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial seizures in which oxcarbazepine was added to existing AED therapy (up to two concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as oxcarbazepine was added. Oxcarbazepine was titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient’s body weight with fixed doses for predefined weight ranges).
Cognitive adverse events occurred in 5.8% of oxcarbazepine-treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo. In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (No patient discontinued due to a cognitive adverse event or somnolence.) Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances.
Multi-Organ Hypersensitivity
Multi-organ hypersensitivity reactions have occurred in close temporal association (median time to detection 13 days: range 4-60) to the initiation of oxcarbazepine therapy in adult and pediatric patients. Although there have been a limited number of reports, many of these cases resulted in hospitalization and some were considered life threatening. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other organ systems and manifestations included hemic and lymphatic (e.g., eosinophilia, thrombocytopenia, lymphadenopathy, leukopenia, neutropenia, splenomegaly), hepatobiliary (e.g., hepatitis, liver function test abnormalities), renal (e.g., proteinuria, nephritis, oliguria, renal failure), muscles and joints (e.g., joint swelling, myalgia, arthralgia, asthenia), nervous system (e.g., hepatic encephalopathy), respiratory (e.g., dyspnea, pulmonary edema, asthma, bronchospasm, interstitial lung disease), hepatorenal syndrome, pruritus, and angioedema. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, oxcarbazepine should be discontinued and an alternative treatment started. Although there are no case reports to indicate cross sensitivity with other drugs that produce this syndrome, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility (see WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine subsection).
Hematologic Events
Very rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients treated with oxcarbazepine during post-marketing experience. Discontinuation of the drug should be considered if any evidence of these hematologic events develop.
Information for Patients
Anaphylactic reactions and angioedema may occur during treatment with oxcarbazepine. Patients should be advised to report immediately signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, tongue or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician (see WARNINGS, Anaphylactic Reactions and Angioedema subsection).
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of these patients may experience hypersensitivity reactions with oxcarbazepine. Patients should be advised that if they experience a hypersensitivity reaction while taking oxcarbazepine they should consult with their physician immediately (see WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine subsection).
Patients should be advised that serious skin reactions have been reported in association with oxcarbazepine. In the event a skin reaction should occur while taking oxcarbazepine, patients should consult with their physician immediately (see WARNINGS, Serious Dermatological Reactions subsection).
Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug related and should be reported to the physician immediately (see PRECAUTIONS, Multi-Organ Hypersensitivity subsection).
Patients should be advised that there have been very rare reports of blood disorders reported in patients treated with oxcarbazepine. Patients should be instructed to immediately consult with their physician if they experience symptoms suggestive of blood disorders (see PRECAUTIONS, Hematologic Events subsection).
Female patients of childbearing age should be warned that the concurrent use of oxcarbazepine with hormonal contraceptives may render this method of contraception less effective (see Drug Interactions subsection). Additional non-hormonal forms of contraception are recommended when using oxcarbazepine.
Patients, their caregivers, and families should be counseled that AEDs, including oxcarbazepine, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Caution should be exercised if alcohol is taken in combination with oxcarbazepine therapy, due to a possible additive sedative effect.
Patients should be advised that oxcarbazepine may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on oxcarbazepine to gauge whether it adversely affects their ability to drive or operate machinery.
Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS, Pregnancy Category C subsection).
Laboratory Tests
Serum sodium levels below 125 mmol/L have been observed in patients treated with oxcarbazepine (see WARNINGS section). Experience from clinical trials indicates that serum sodium levels return toward normal when the oxcarbazepine dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction).
Laboratory data from clinical trials suggest that oxcarbazepine use was associated with decreases in T4, without changes in T3 or TSH.
Drug Interactions
Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD.
Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP3A4/5 by oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by oxcarbazepine and MHD, however, is clinically relevant (see below).
In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine).
In addition, oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in a lower plasma concentration of these drugs.
As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely.
Antiepileptic Drugs
Potential interactions between oxcarbazepine and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarized in Table 3.
| AED Coadministered | Dose of AED (mg/day) | Oxcarbazepine Dose (mg/day) | Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) | Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400-2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] | 25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 | nc1,2 up to 40% increase3 [CI: 12% increase, 60% increase] | 30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
1 nc denotes a mean change of less than 10%
2 Pediatrics
3 Mean increase in adults at high oxcarbazepine doses
In vivo, the plasma levels of phenytoin increased by up to 40% when oxcarbazepine was given at doses above 1200 mg/day. Therefore, when using doses of oxcarbazepine greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required. The increase of phenobarbital level, however, is small (15%) when given with oxcarbazepine.
Strong inducers of cytochrome P450 enzymes (i.e., carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma levels of MHD (29%-40%).
No autoinduction has been observed with oxcarbazepine.
Hormonal Contraceptives
Coadministration of oxcarbazepine with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components, ethinylestradiol (EE) and levonorgestrel (LNG). The mean AUC values of EE were decreased by 48% [90% CI: 22-65] in one study and 52% [90% CI: 38-52] in another study. The mean AUC values of LNG were decreased by 32% [90% CI: 20-45] in one study and 52% [90% CI: 42-52] in another study. Therefore, concurrent use of oxcarbazepine with hormonal contraceptives may render these contraceptives less effective (see Drug Interactions subsection). Studies with other oral or implant contraceptives have not been conducted.
Calcium Antagonists
After repeated coadministration of oxcarbazepine, the AUC of felodipine was lowered by 28% [90% CI: 20-33].
Verapamil produced a decrease of 20% [90% CI: 18-27] of the plasma levels of MHD.
Other Drug Interactions
Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of oxcarbazepine.
Drug/Laboratory Test Interactions
There are no known interactions of oxcarbazepine with commonly used laboratory tests.
Carcinogenesis/Mutagenesis/Impairment of Fertility
In two-year carcinogenicity studies, oxcarbazepine was administered in the diet at doses of up to 100 mg/kg/day to mice and by gavage at doses of up to 250 mg/kg to rats, and the pharmacologically active 10-hydroxy metabolite (MHD) was administered orally at doses of up to 600 mg/kg/day to rats. In mice, a dose-related increase in the incidence of hepatocellular adenomas was observed at oxcarbazepine doses ≥70 mg/kg/day or approximately 0.1 times the maximum recommended human dose (MRHD) on a mg/m2 basis. In rats, the incidence of hepatocellular carcinomas was increased in females treated with oxcarbazepine at doses ≥25 mg/kg/day (0.1 times the MRHD on a mg/m2 basis), and incidences of hepatocellular adenomas and/or carcinomas were increased in males and females treated with MHD at doses of 600 mg/kg/day (2.4 times the MRHD on a mg/m2 basis) and ≥250 mg/kg/day (equivalent to the MRHD on a mg/m2 basis), respectively. There was an increase in the incidence of benign testicular interstitial cell tumors in rats at 250 mg oxcarbazepine/kg/day and at ≥250 mg MHD/kg/day, and an increase in the incidence of granular cell tumors in the cervix and vagina in rats at 600 mg MHD/kg/day.
Oxcarbazepine increased mutation frequencies in the Ames test in vitro in the absence of metabolic activation in one of five bacterial strains. Both oxcarbazepine and MHD produced increases in chromosomal aberrations and polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro. Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay.
In a fertility study in which rats were administered MHD (50, 150, or 450 mg/kg) orally prior to and during mating and early gestation, estrous cyclicity was disrupted and numbers of corpora lutea, implantations, and live embryos were reduced in females receiving the highest dose (approximately two times the MRHD on a mg/m2 basis).
Pregnancy Category C
Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose.
When pregnant rats were given oxcarbazepine (30, 300, o
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