Glimépiride Actavis may be available in the countries listed below.
Glimepiride is reported as an ingredient of Glimépiride Actavis in the following countries:
International Drug Name Search
Xymel may be available in the countries listed below.
Tramadol hydrochloride (a derivative of Tramadol) is reported as an ingredient of Xymel in the following countries:
International Drug Name Search
In the US, Oxymetholone (oxymetholone systemic) is a member of the drug class androgens and anabolic steroids and is used to treat Anemia.
US matches:
Rec.INN
A14AA05
0000434-07-1
C21-H32-O3
332
Anabolic
Androgen
Androstan-3-one, 17-hydroxy-2-(hydroxymethylene)-17-methyl-, (5α,17ß)-
International Drug Name Search
Glossary
| BAN | British Approved Name |
| DCF | Dénomination Commune Française |
| IS | Inofficial Synonym |
| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| PH | Pharmacopoeia Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
Neozalocaine may be available in the countries listed below.
Benzocaine is reported as an ingredient of Neozalocaine in the following countries:
Farmocaine hydrochloride (a derivative of Farmocaine) is reported as an ingredient of Neozalocaine in the following countries:
International Drug Name Search
Generic Name: brompheniramine (brome feh NEER a meen)
Brand Names: BroveX, BroveX CT, Dimetane, Dimetane Extentab, Dimetapp Allergy, Dimetapp Allergy Liquigel, Lodrane 12 Hour
Brompheniramine is an antihistamine. Brompheniramine blocks the effects of the naturally occurring chemical histamine in the body.
Brompheniramine is used to sneezing; runny nose; itching, watery eyes; hives; rashes; itching; and other symptoms of allergies and the common cold.
Brompheniramine may also be used for purposes other than those listed in this medication guide.
Before taking brompheniramine, talk to your doctor if you have
glaucoma or increased pressure in the eye;
a stomach ulcer;
an enlarged prostate, bladder problems or difficulty urinating;
an overactive thyroid (hyperthyroidism);
hypertension or any type of heart problems; or
asthma.
You may not be able to take brompheniramine, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.
Take brompheniramine exactly as directed on the package or as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.
Brompheniramine can be taken with or without food.
To ensure that you get a correct dose, measure the liquid form of brompheniramine with a special dose-measuring spoon or cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.
Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication unless otherwise directed by your doctor.
Symptoms of a brompheniramine overdose may include extreme sleepiness, confusion, weakness, ringing in the ears, blurred vision, large pupils, dry mouth, flushing, fever, shaking, insomnia, hallucinations, and possibly seizures.
Do not take other over-the-counter cough, cold, allergy, diet, pain, or sleep medications while taking brompheniramine without first talking to your pharmacist or doctor. Other medications may also contain brompheniramine or other similar drugs, and you may accidentally take too much of these medicines.
Brompheniramine may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, other antihistamines, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Dangerous sedation, dizziness, or drowsiness may occur if brompheniramine is taken with any of these medications.
Other, less serious side effects may be more likely to occur. Continue to take brompheniramine and talk to your doctor if you experience
sleepiness, fatigue, or dizziness;
headache;
dry mouth; or
difficulty urinating or an enlarged prostate.
Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.
Do not take other over-the-counter cough, cold, allergy, diet, pain, or sleep medications while taking brompheniramine without first talking to your pharmacist or doctor. Other medications may also contain brompheniramine or other similar drugs, and you may accidentally take too much of these medicines.
Brompheniramine may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, other antihistamines, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Dangerous sedation, dizziness, or drowsiness may occur if brompheniramine is taken with any of these medications.
Drugs other than those listed here may also interact with brompheniramine. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including vitamins, minerals, and herbal products.
See also: BroveX CT side effects (in more detail)
Winkol may be available in the countries listed below.
Chlorphenamine maleate (a derivative of Chlorphenamine) is reported as an ingredient of Winkol in the following countries:
International Drug Name Search
Acébutolol Ranbaxy may be available in the countries listed below.
Acebutolol hydrochloride (a derivative of Acebutolol) is reported as an ingredient of Acébutolol Ranbaxy in the following countries:
International Drug Name Search
Generic Name: Cytarabine
Class: Antineoplastic Agents
VA Class: AN300
CAS Number: 147-94-4
Conventional cytarabine: Use only under supervision of qualified clinicians experienced in therapy with antineoplastic agents.a b c c j Consider possible benefits vs known risks of cytarabine treatment.a b c j
Liposomal cytarabine: Use only under supervision of qualified clinicians experienced in intrathecal therapy with antineoplastic agents; adequate diagnostic and treatment facilities must be readily available for management of complications.d
Patients should be treated in a facility with laboratory and supportive resources sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity.a b c j
Risk of serious adverse effects, including myelosuppression with leukopenia, thrombocytopenia, and anemia.a b c j Less serious adverse effects include nausea, vomiting, diarrhea, abdominal pain, oral ulceration, and hepatic dysfunction.a b c j (See Cautions.)
Chemical arachnoiditis, a syndrome manifested principally by nausea, vomiting, headache, and fever, commonly occurs.d If left untreated, may be fatal.d (See Chemical Arachnoiditis Related to Liposomal Cytarabine under Cautions.)
Administer dexamethasone to ameliorate symptoms and reduce incidence.d (See Liposomal Cytarabine under Dosage and Administration.)
Antimetabolite antineoplastic agent; synthetic pyrimidine antagonist.d f i
Conventional cytarabine: Remission induction (in combination with other antineoplastic agents) in AML (acute nonlymphocytic leukemia) in children and adults.237 a b c j
Conventional cytarabine and either idarubicin or daunorubicin (with or without thioguanine) are currently preferred components of induction regimens.g h However, various regimens have been used in combination therapy, and comparative efficacy is continually being evaluated.g
Conventional cytarabine: Has been used with other antineoplastic agents in regimens of consolidation following induction of a complete remission†; 239 242 243 f g role of such therapy in prolonging remissions and optimal dosage, schedules, and duration of consolidation chemotherapy regimens not established.g
Conventional cytarabine: Has been used with other antineoplastic agents in the treatment of erythroleukemia.f
Conventional cytarabine: Also has been used alone in high-dose† regimens to induce remissions in some patients with refractory AML or with secondary AML.f
Conventional cytarabine: Has been used alone or with other antineoplastic agents for remission induction in ALL;237 a b c j however, combinations containing other antineoplastic agents are more effective.f h
Conventional cytarabine: Generally has been limited to use with other antineoplastics for remission induction in some patients who do not achieve a complete remission with combinations containing other agents or who relapse during maintenance therapy.f
Conventional cytarabine: Also has been used occasionally in regimens of consolidation and/or maintenance therapy following induction of a complete remission by combinations containing other agents.f h
Conventional cytarabine: Has been used alone in high-dose† regimens to induce remissions in some patients with refractory ALL.f
Conventional cytarabine: Has been used effectively alone or with other chemotherapeutic agents in treatment, maintenance, and prophylactic therapy of meningeal leukemia and other meningeal neoplasms (e.g., lymphoma).a c f j
Many clinicians consider intrathecal conventional cytarabine and intrathecal methotrexate to have similar efficacy in the treatment of these conditions; however, intrathecal conventional cytarabine produces less systemic toxicity than intrathecal methotrexate.f
Liposomal cytarabine: Treatment of lymphomatous meningitis.d
Intrathecal liposomal cytarabine appears to have greater efficacy in the treatment of neoplastic meningitis and less systemic toxicity compared with intrathecal conventional cytarabine;i however, further study is needed.d i
Conventional cytarabine: Used with other antineoplastic agents (e.g., daunorubicin) in the treatment of accelerated or blast phase of CML;a b c f j however, various regimens have been used in combination therapy, and comparative efficacy is continually being evaluated.237 246 247 253 254
Conventional cytarabine: Has been used with other antineoplastic agents for maintenance therapy of non-Hodgkin’s lymphoma in children†.f
Conventional cytarabine: Has been used with other antineoplastic agents for remission induction and/or maintenance therapy in adults with non-Hodgkin’s lymphomas, principally advanced diffuse histiocytic lymphoma†.f
Conventional cytarabine: Has been used alone in high-dose† regimens with some success for the treatment of refractory non-Hodgkin’s lymphomas†.f
Consult specialized references for procedures for proper handling and disposal of antineoplastics.a b c d j
Initiate dexamethasone therapy on the day of the intrathecal administration of liposomal cytarabine to prevent or ameliorate chemical arachnoiditis.d i Administer 4 mg of dexamethasone twice daily orally or IV for 5 days.d
Conventional cytarabine: Administer by rapid IV injection or continuous IV infusion, sub-Q injection, or intrathecal injection; a b c j also has been administered by IM injection† and by continuous sub-Q infusion†.f
Liposomal cytarabine: Administer only by intrathecal injection.d
For solution compatibility information for conventional cytarabine see Compatibility under Stability.
Higher total doses of conventional cytarabine may be given by rapid IV injection compared with continuous IV infusion with no increase in hematologic toxicity; most effective method of administration not established.a b c f j
Cytarabine injection solution containing benzyl alcohol may be used for IV administration but should not be used in high-dose regimens†.251
Cytarabine injection solution containing benzyl alcohol should not be used in neonates.a b c f
Cytarabine injection in pharmacy bulk packages is not intended for direct IV infusion; individual doses can be withdrawn with a sterile dispensing set or transfer device and used undiluted or further diluted in a compatible IV solution.252 f
Add 5, 10, 10, or 20 mL of bacteriostatic water for injection containing 0.945% benzyl alcohol to a vial containing 100, 500, 1000, or 2000 mg cytarabine powder; resultant solutions contain 20, 50, 100, or 100 mg of cytarabine per mL, respectively.j
Diluents containing benzyl alcohol should not be used in neonatesf j or in high-dose† regimens.a b c j (See Benzyl Alcohol under Cautions.)
The desired dose of reconstituted solution may be given by rapid IV injection or may be further diluted with 5% dextrose or 0.9% sodium chloride injection for IV infusion.f j
Cytarabine injection solution (containing 20 or 100 mg/mL) may be diluted with a compatible IV solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection) for direct IV injection, rapid IV injection, or IV infusion.250 b c j
Cytarabine injection in pharmacy bulk package solution (containing 20 mg/mL) should be diluted with a compatible IV solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection) for IV infusion.c
Alternatively, desired dose of the solution reconstituted from powder may be further diluted with 5% dextrose or 0.9% sodium chloride injection for IV infusion.j
Has been given over 1–3 hours when used for treatment of refractory or secondary acute leukemia and refractory non-Hodgkin’s lymphomas.f
Also administered by rapid IV injection or continuous IV infusion.a b c j
For solution compatibility information on conventional cytarabine see Compatibility under Stability. Consult specialized references for information on continuous sub-Q infusion†.
Cytarabine injection solution containing benzyl alcohol may be used for sub-Q administration but should not be used in high-dose regimens†.251
Add 5, 10, 10, or 20 mL of bacteriostatic water for injection containing 0.945% benzyl alcohol to a vial containing 100, 500, 1000, or 2000 mg cytarabine powder; resultant solutions contain 20, 50, 100, or 100 mg of cytarabine per mL, respectively.j
Diluents or drug solutions containing benzyl alcohol should not be used in neonatesa b c f j or in high-dose† regimens.a b c j (See Benzyl Alcohol under Cautions.)
Usually administered in 5–15 mL of solution, after removing an equivalent volume of CSF.f
Only preservative-free injection solutions are suitable for intrathecal administration.250 a b c j
Injection in pharmacy bulk packages should not be used for preparation of solutions for intrathecal administration.252
Do not use diluents containing benzyl alcohol for preparation of solutions.b c j
Reconstitute cytarabine powder with preservative-free 0.9% sodium chloride injection, Elliott’s B solution, other isotonic buffered diluents that do not contain a preservative (e.g., lactated Ringer’s injection), or the patient’s spinal fluid.f j
Only use for intrathecal administration.d
Administer directly into CSF via an intraventricular reservoir or by direct injection into lumbar sac; do not use inline filters.d
Following intrathecal administration by lumbar puncture, patient should lie flat for 1 hour.d
Allow vials to warm to room temperature; immediately prior to withdrawing dose, gently agitate or invert to ensure resuspension of liposomes.d Avoid aggressive agitation.d
Withdraw dose from the vial immediately before administration.d
Do not dilute or mix with any other drugs.d
Inject slowly over a period of 1–5 minutes.d
Conventional cytarabine: Optimize results and minimize adverse effects by basing dose on clinical and hematologic response, patient tolerance, and other therapy being used.f
Consult published protocols for dosages used in combination regimens and method and sequence of administration.
The manufacturers make no specific dosage recommendations for pediatric patients; consult published protocols for dosages used in children.a b c j
Monotherapy: 200 mg/m2 daily by continuous IV infusion for 5 days at approximately 2-week intervals.f
Combination therapy: 2–6 mg/kg daily or 100–200 mg/m2 daily by continuous IV infusion or in 2 or 3 divided doses by rapid IV injection or IV infusion for 5–10 days in a course of therapy or daily until a remission is attained.f
Initiate appropriate maintenance therapy after induction of a complete remission.f
Dosage and schedule vary according to regimen used.f
70–200 mg/m2 daily by rapid IV injection or continuous IV infusion for 2–5 days at monthly intervals.f
1 or 1.5 mg/kg IM at intervals of 1–4 weeks.f
3 g/m2 by IV infusion (usually over 1–3 hours) every 12 hours for up to 12 doses has been used.f
Dosage schedule usually determined by the type and severity of CNS manifestations and prior response to therapy.a b c j
5–75 mg/m2 or 30–100 mg administered at frequencies ranging from once every 2–7 days to once daily for 4 or 5 days.a b c f j
Alternatively, 30 mg/m2 once every 4 days until CSF findings are normal, followed by 1 additional dose.a b c j
50 mg every 14 days for 2 doses (weeks 1 and 3).d
50 mg every 14 days for 3 doses (weeks 5, 7, and 9) followed by 1 additional dose after 28 days (week 13).d
50 mg every 28 days for 4 doses (weeks 17, 21, 25, and 29).d
3 g/m2 by IV infusion (usually over 1–3 hours) every 12 hours for up to 12 doses has been used.f
Consider suspension or modification of therapy if polymorphonuclear granulocyte count <1000/mm3 or platelet count <50,000/mm3;a b c j however, during remission induction therapy in acute leukemia, the drug usually is administered in a short course and therapy is not discontinued or adjusted based on peripheral blood counts.f
When indicated, resume therapy when definite signs of marrow recovery appear (on successive bone marrow studies).a b c j Withholding therapy until peripheral blood values normalize may permit escape from control.a b c j
If drug-related neurotoxicity develops, reduce dose to 25 mg.d If toxicity persists, discontinue therapy.d
Select dosage with caution.a b c j (See Hepatic Impairment under Cautions.)
Select dosage with caution.a b c j (See Renal Impairment under Cautions.)
Liposomal or Conventional Cytarabine: Hypersensitivity to cytarabine or any ingredient in the formulation.a b c d j
Liposomal Cytarabine: Active meningeal infection.d
Conventional cytarabine: Potent myelosuppressant.a b c j Initiate with caution in patients with preexisting drug-induced myelosuppression.a b c j Patients must be under close medical supervision and facilities should be available for management of serious complications, possibly fatal, of myelosuppression (e.g., infection resulting from granulocytopenia, hemorrhage secondary to thrombocytopenia).a b c j (See Boxed Warning.)
Risk of increased frequency of infections (e.g., viral, bacterial, fungal), as well as possible hemorrhagic complications; potentially fatal.a b c j
During induction therapy, perform leukocyte and platelet counts daily.a b c j (See Dosage Modification for Toxicity under Dosage and Administration.)
Perform bone marrow examinations frequently after blasts have disappeared from peripheral blood.a b c f j Counts of formed elements in peripheral blood may continue to fall after drug discontinuance and reach lowest values after drug-free intervals of 12–24 days.a b c j
Liposomal cytarabine: Clinically important systemic exposure to unencapsulated cytarabine unlikely following intrathecal administration.d However, careful hematologic monitoring recommended since myelosuppression cannot be completely ruled out.d
Severe and sometimes fatal CNS, GI, and pulmonary toxicities reported following experimental dosage regimens for refractory or secondary acute leukemia or refractory non-Hodgkin’s lymphomas; differ from reactions seen with regimens employing lower dosages.a b c f j
Cerebral and cerebellar dysfunction (e.g., somnolence, coma, personality changes) reported; usually reversible.a b c j Reversible, acute aseptic meningitis, combined with cerebellar dysfunction, reported in at least 1 patient.205
Peripheral motor and sensory neuropathies have occurred occasionally.202 203 204 a b c j
Patients with renal or hepatic impairment may be at increased risk of CNS toxicity associated with high-dose cytarabine therapy.a b c j
Monitor patients receiving high-dose therapy closely for signs of central or peripheral neurotoxicity.202 203 204 a b c j Dosage schedule adjustment may be necessary to avoid irreversible neurologic toxicity.202 a b c j
Severe GI ulceration (including pneumatosis cystoides intestinalis leading to peritonitis), bowel necrosis, necrotizing colitis, hepatic abscess or hepatic damage with increased hyperbilirubinemia reported.a b c j
Pancreatitis reported in patients previously treated with asparaginase and those receiving high-dose cytarabine therapy.212 218 a b c j
Pulmonary edema reported.a b c j Diffuse interstitial pneumonitis reported occasionally in patients receiving relatively high doses (e.g., 1 g/m2) of cytarabine alone or in combination with other antineoplastic agents.213 214 215 216 217 218 219 220 221 a b c j
A syndrome of acute respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly, which was sometimes fatal, has been reported in patients with refractory acute leukemia receiving high-dose therapy.a b c j
Severe skin rash leading to desquamation has been reported rarely.a b c j Complete alopecia occurs more commonly with high-dose regimens.a b c j
Fatal cardiomyopathy reported in patients receiving high-dose cytarabine in combination with cyclophosphamide in preparation for bone marrow transplantation; this cardiac toxicity may be schedule dependent.a b c j
Hemorrhagic conjunctivitis and reversible corneal toxicity (e.g., keratitis) reported; may be minimized or prevented by prophylaxis with ophthalmic corticosteroid preparations.a b c j
Possible systemic toxicity; carefully monitor hematologic status.a b c j Dosage adjustment of concurrently administered antineoplastic agents may be necessary.a b c j
Concurrent (within a few days) IV chemotherapy or cranial/spinal irradiation and intrathecal treatment with conventional cytarabine may be associated with increased risk of neurotoxicity (e.g., spinal cord toxicity).a b c d j
Progressive ascending paralysis reported.200 a b c j Occurred in 2 children 4–6 months after intrathecal and IV therapy with conventional cytarabine at usual doses in combination with other drugs and CNS irradiation; fatal in one patient.200 a b c j
Permanent neurologic deficits reported rarely.d
Observe closely for acute toxic reactions.d
Neurotoxicity may occur after a single dose or repeated administration; most likely to occur within 5 days of intrathecal administration.d Monitor continuously and reduce subsequent doses if neurotoxicity occurs; discontinue if neurotoxicity persists.d CSF flow obstruction may result in increased CSF concentrations and increased risk of neurotoxicity.d (See Dosage Modification for Toxicity under Dosage and Administration.)
At least 2 fatalities attributed to liposomal cytarabine have occurred.d One patient died after developing encephalopathy 36 hours after receiving intraventricular liposomal cytarabine;d i the other patient developed focal seizures that progressed to status epilepticus and died approximately 8 weeks after the last intraventricular dose of liposomal cytarabine.d
Possible increased risk of adverse events in patients receiving concurrent radiation or chemotherapy.d
Common complication of intrathecal liposomal cytarabine; in clinical studies, generally occurred ≤48 hours after intrathecal administration.d i
Defined in clinical studies as occurrence of any 1 of certain manifestations (i.e., neck rigidity, neck pain, meningism) or any 2 of the following: nausea, vomiting, headache, fever, back pain, or CSF pleocytosis.d i
Administer dexamethasone to ameliorate symptoms and reduce incidence.d i (See Intrathecal Administration under Dosage and Administration and also Chemical Arachnoiditis in Boxed Warning.)
Do not use conventional cytarabine injection solution containing benzyl alcohol in neonates.a b c j f Do not use diluents containing benzyl alcohol to reconstitute or dilute conventional cytarabine for use in neonates.a b c j Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity in neonates.a b c f j
Do not use conventional cytarabine injection solution containing benzyl alcohol for intrathecal administration.a b c Do not use diluents containing benzyl alcohol to reconstitute conventional cytarabine for intrathecal administration.j
Because of potential neurotoxicity, conventional cytarabine injection solution containing benzyl alcohol or cytarabine powder reconstituted or diluted with diluents containing benzyl alcohol should not be used for high-dose regimens.a b c j
May cause fetal harm; upper and lower distal limb defects, extremity and ear deformities, low birth weight, premature delivery, and adverse hematologic effects reported.a b c d j
Avoid pregnancy during therapy with conventional or liposomal cytarabine; especially avoid cytarabine use during first trimester.a b c d j If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.a b c d j Follow-up monitoring of infants exposed to cytarabine in utero is advised.a b c j
At least one case of anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported after IV administration of conventional cytarabine.d
Cytarabine syndrome reported; may manifest as fever, myalgia, bone pain, maculopapular rash, conjunctivitis, malaise, and occasionally chest pain.a b c j Generally occurs 6–12 hours after administration of conventional cytarabine.a b c j
Corticosteroids are beneficial in treatment and prevention.a b c j If symptoms require treatment, consider administration of corticosteroids, as well as continuation of conventional cytarabine therapy.a b c j
Nausea and vomiting are more frequent and severe following rapid IV administration of conventional cytarabine than with continuous IV infusion.a b c j
Pancreatitis reported in patients receiving conventional cytarabine and in those previously treated with asparaginase.a b c j (Also see High-dose Regimens with Conventional Cytarabine under Cautions.)
Hyperuricemia may occur in patients receiving conventional cytarabine because of extensive purine catabolism accompanying rapid cellular destruction.a b c f j
Monitor serum uric acid concentrations in patients receiving conventional cytarabine.a b c j Hyperuricemia may be minimized or prevented by adequate hydration, alkalinization of urine, and/or administration of allopurinol.a b c f j
Transient increases in CSF protein concentration and WBC counts reported in patients following intrathecal administration of liposomal or conventional cytarabine.d
Category D.a b c d j (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Not known whether cytarabine is distributed into milk; discontinue nursing or the drug.a b c d j
Do not use conventional cytarabine injection solution or diluents containing benzyl alcohol in neonates.b 250 (See Benzyl Alcohol under Cautions.)
Safety and efficacy of liposomal cytarabine not established in children.d
Use with caution; increased risk of CNS toxicity after high-dose therapy with conventional cytarabine because of decreased clearance.a b c j Assess hepatic function prior to and periodically during prolonged therapy.a b c j
Use with caution; increased risk of CNS toxicity after high-dose therapy with conventional cytarabine because of decreased clearance.a b c j Assess renal function prior to and periodically during prolonged therapy.a b c j
IV, sub-Q, or IM administration of conventional cytarabine: Myelosuppression, anorexia, nausea, vomiting, diarrhea, oral and anal inflammation or ulceration, hepatic dysfunction, fever, rash, thrombophlebitis, bleeding (all sites).a b c j
Intrathecal administration of conventional cytarabine: Nausea, vomiting, fever, transient headaches.a b c d f j
Intrathecal administration of liposomal cytarabine: Chemical arachnoiditis (neck rigidity, neck pain, meningism, nausea, vomiting, headache, fever, back pain, and/or CSF pleocytosis), asthenia, pain, confusion, somnolence.d i
No formal drug interaction studies conducted with liposomal cytarabine to date.d
Drug or Test | Interaction | Comments |
|---|---|---|
Antineoplastic agents, intrathecally administered | Possible enhanced neurotoxicity when intrathecal conventional cytarabine used concomitantly with other intrathecal cytotoxic agentsd | Concomitant intrathecal use of liposomal cytarabine and other antineoplastic agents not studiedd |
Digoxin | GI absorption of oral digoxin tablets may be substantially reduced when used concomitantly with conventional cytarabine207 208 a b c j | Monitor plasma digoxin concentrations closely; use of digoxin oral elixir or liquid-filled capsules may improve absorption207 208 210 a b c j |
Flucytosine | Possible inhibition of anti-infective activity by competitive inhibition of uptake by fungi when flucytosine was used concomitantly with conventional cytarabinea b c j | |
Gentamicin | In vitro evidence of inhibition of antibacterial activity against Klebsiella pneumoniae with conventional cytarabine211 a b c j | Monitor closely; if therapeutic response is not achieved, reevaluate anti-infective therapy211 a b c j |
Test, for WBC in CSF | Liposomal cytarabine vesicles are similar in size and appearance to WBC d | Interpret CSF analysis with care d |
Conventional cytarabine: <20% of dose is absorbed after oral administration; not effective when administered orally.a b c j
Conventional cytarabine: Continuous IV infusions produce relatively constant plasma concentrations of the drug in 8–24 hours.a b c f j
Following sub-Q or IM injection of radioactively labeled conventional cytarabine, peak plasma concentrations of radioactivity occur within 20–60 minutes and are considerably lower than those attained after IV administration.a b c j
Liposomal cytarabine: Negligible systemic exposure expected after intrathecal administration.d
Liposomal cytarabine: Limited data indicate peak cytarabine concentrations occur within 5 hours in both ventricle and lumbar sac after intrathecal administration into lumbar sac or by intraventricular reservoir.d i
Conventional cytarabine: Rapidly and widely distributed into tissues and fluids, including liver, plasma, and peripheral granulocytes;a b c f j crosses blood-brain barrier to a limited extent.a b c i j
Conventional cytarabine: CSF concentrations are higher during continuous IV or sub-Q infusion than after rapid IV injection and are approximately 40–60% of plasma concentrations.a b c f j
Conventional cytarabine: Apparently crosses placenta;a b
Isosorbidedinitraat ratiopharm may be available in the countries listed below.
Isosorbide Dinitrate is reported as an ingredient of Isosorbidedinitraat ratiopharm in the following countries:
International Drug Name Search
Heart Gold may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Ivermectin is reported as an ingredient of Heart Gold in the following countries:
International Drug Name Search
Insulin Monotard MC may be available in the countries listed below.
Insulin Zinc Suspension (compound) porcine or bovine (a derivative of Insulin Zinc Suspension (compound)) is reported as an ingredient of Insulin Monotard MC in the following countries:
International Drug Name Search
Generic Name: meperidine (Injection route)
me-PER-i-deen
In the U.S.
Available Dosage Forms:
Therapeutic Class: Analgesic
Chemical Class: Opioid
Meperidine injection is used to relieve moderate to severe pain. It belongs to the group of medicines called narcotic analgesics (pain medicines). Meperidine acts on the central nervous system (CNS) to relieve pain.
When a narcotic medicine is used for a long time, it may become habit-forming, causing mental or physical dependence. However, people who have continuing pain should not let the fear of dependence keep them from using narcotics to relieve their pain. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. Physical dependence may lead to withdrawal side effects if treatment is stopped suddenly. However, severe withdrawal side effects can usually be prevented by gradually reducing the dose over a period of time before treatment is stopped completely.
This medicine is available only with your doctor's prescription.
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies have not been performed on the relationship of age to the effects of meperidine injection in children. Safety and efficacy have not been established.
No information is available on the relationship of age to the effects of meperidine injection in geriatric patients. However, elderly patients are more likely to have age-related kidney or liver problems, which may require caution and an adjustment in the dose for patients receiving meperidine injection.
| Pregnancy Category | Explanation | |
|---|---|---|
| All Trimesters | C | Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. |
There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.
Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
A nurse or other trained health professional will give you this medicine in a hospital. This medicine is given through a needle placed in one of your veins, or as a shot under your skin or in a muscle. When the medicine is given in your vein it must be injected slowly, so your IV will need to stay in place for awhile.
It is very important that your doctor check your progress while you are receiving this medicine. This is to make sure that the medicine is working properly, and to allow your doctor to check for any unwanted effects.
Do not use this medicine if you have taken a monoamine oxidase (MAO) inhibitor in the past 2 weeks. MAO inhibitors are used for depression, and some examples are isocarboxazid (Marplan®), phenelzine (Nardil®), selegiline (Eldepryl®), and tranylcypromine (Parnate®). If meperidine injection is used with MAO inhibitors, you may have unwanted effects like confusion, agitation, restlessness, stomach or intestinal symptoms, a sudden high temperature, an extremely high blood pressure, or convulsions.
This medicine will add to the effects of alcohol and other CNS depressants (medicines that can make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers, or sleeping medicine; other prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the medicines listed above while you are using this medicine.
This medicine may be habit-forming. If you feel that the medicine is not working as well, do not use more than your prescribed dose. Call your doctor for instructions.
Using narcotics for a long time can cause severe constipation. To prevent this, your doctor may direct you to take laxatives, drink a lot of fluids, or increase the amount of fiber in the diet. Be sure to follow the directions carefully, because continuing constipation can lead to more serious problems.
Dizziness, lightheadedness, or fainting may occur when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve the dizziness or lightheadedness.
This medicine may make you dizzy, drowsy, confused, or disoriented. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.
Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are using this medicine. Serious unwanted effects can occur if certain medicines are given together with meperidine injection.
If you have been using this medicine regularly for several weeks or longer, do not suddenly stop using it without checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent worsening of your condition and reduce the possibility of withdrawal symptoms, such as abdominal or stomach cramps, anxiety, fever, nausea, runny nose, sweating, tremors, or trouble with sleeping.
Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor or nurse immediately if any of the following side effects occur:
Get emergency help immediately if any of the following symptoms of overdose occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: Demerol Injection side effects (in more detail)
The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.
The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.
Rifatac may be available in the countries listed below.
Isosorbide Dinitrate is reported as an ingredient of Rifatac in the following countries:
International Drug Name Search
Mascote may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Dimpylate is reported as an ingredient of Mascote in the following countries:
Permethrin is reported as an ingredient of Mascote in the following countries:
Piperonyl Butoxide is reported as an ingredient of Mascote in the following countries:
International Drug Name Search
WARNING: LIFE THREATENING ADVERSE REACTIONS
HEPATOTOXICITY
Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote Sprinkle Capsules are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [See Warnings and Precautions (5.1)].
TERATOGENICITY
Valproate can produce teratogenic effects such as neural tube defects (e.g., spina bifida). Accordingly, the use of Depakote Sprinkle Capsules in women of childbearing potential requires that the benefits of its use be weighed against the risk of injury to the fetus. This is especially important when the treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g., migraine) is contemplated. [See Warnings and Precautions (5.2)]
An information sheet describing the teratogenic potential of valproate is available for patients [See Patient Counseling Information (17)].
PANCREATITIS
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.3)].
Depakote Sprinkle Capsules are indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote Sprinkle Capsules are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. [see Warnings and Precautions (5.2), Patient Counseling Information (17.3)].
Depakote Sprinkle Capsules are administered orally. As Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to Depakote, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical studies (14)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures are considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.2)].
As Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote Sprinkle Capsules should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote Sprinkle Capsules, a dosing schedule of two or three times a day may be elected in selected patients.
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.12), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.6)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
Administration of Sprinkle Capsules
Depakote Sprinkle Capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoonful) of soft food such as applesauce or pudding. The drug/food mixture should be swallowed immediately (avoid chewing) and not stored for future use. Each capsule is oversized to allow ease of opening.
Depakote Sprinkle Capsules are for oral administration. Depakote Sprinkle Capsules contain specially coated particles of divalproex sodium equivalent to 125 mg of valproic acid in a hard gelatin capsule.
Depakote Sprinkle Capsules should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)].
Depakote Sprinkle Capsules is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.10)].
Depakote Sprinkle Capsules is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.4)].
Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Caution should be observed when administering Depakote products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed Warning and Contraindications (4)].
Use of Depakote during pregnancy can cause congenital malformations including neural tube defects. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Depakote should be considered for women of childbearing potential only after the risks have been thoroughly discussed with the patient and weighed against the potential benefits of treatment.
Data suggest that there is an increased incidence of congenital malformations associated with the use of valproate by women with seizure disorders during pregnancy when compared to the incidence in women with seizure disorders who do not use antiepileptic drugs during pregnancy, the incidence in women with seizure disorders who use other antiepileptic drugs, and the background incidence for the general population.
There are multiple reports in the clinical literature that indicate the use of antiepileptic drugs during pregnancy results in an increased incidence of congenital malformations in offspring. Antiepileptic drugs, including valproate, should be administered to women of childbearing potential only if they are clearly shown to be essential in the management of their medical condition.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus [see Boxed Warning and Use in Specific Populations (8.1)].
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning].
Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.7)].
Antiepileptic drugs (AEDs), including Depakote 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 1 shows absolute and relative risk by indication for all evaluated AEDs.
| Indication | Placebo Patients with Events Per 1000 Patients | Drug Patients with Events Per 1000 Patients | Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients | Risk Difference: Additional Drug Patients with Events Per 1000 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 Depakote 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.
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. In a clinical trial of Depakote as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.4)].
Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.9)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.4, 5.8)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.
Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.9)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.4, 5.7)].
Hypothermia, defined as an unintentional drop in body core temperature to < 35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. 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 associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.
Carbapenem antibiotics (ertapenem, imipenem, meropenem) may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)].
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.4)].
Since Depakote may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7)].
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown [see Adverse Events (6.2)].
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Hepatic failure (5.1)
Teratogenicity (5.2)
Pancreatitis (5.3)
Hyperammonemic encephalopathy (5.4, 5.7)
Somnolence in the elderly (5.12)
Thrombocytopenia (5.6)
Multi-organ hypersensitivity reactions (5.10)
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Based on a placebo-controlled trial of adjunctive therapy for treatment of partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote -treated patients (6%), compared to 1% of placebo-treated patients.
In a long term (12-month) safety study in pediatric patients (N=169) between the ages of 3 and 10 years old, no clinically meaningful differences in the adverse event profile were observed when compared to adults.
Table 2 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote -treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
| Body System/Event | Depakote (%) (n = 77) | Placebo (%) (n = 70) |
| Body as a Whole | ||
| Headache | 31 | 21 |
| Asthenia | 27 | 7 |
| Fever | 6 | 4 |
| Gastrointestinal System | ||
| Nausea | 48 | 14 |
| Vomiting | 27 | 7 |
| Abdominal Pain | 23 | 6 |
| Diarrhea | 13 | 6 |
| Anorexia | 12 | 0 |
| Dyspepsia | 8 | 4 |
| Constipation | 5 | 1 |
| Nervous System | ||
| Somnolence | 27 | 11 |
| Tremor | 25 | 6 |
| Dizziness | 25 | 13 |
| Diplopia | 16 | 9 |
| Amblyopia/Blurred Vision | 12 | 9 |
| Ataxia | 8 | 1 |
| Nystagmus | 8 | 1 |
| Emotional Lability | 6 | 4 |
| Thinking Abnormal | 6 | 0 |
| Amnesia | 5 | 1 |
| Respiratory System | ||
| Flu Syndrome | 12 | 9 |
| Infection | 12 | 6 |
| Bronchitis | 5 | 1 |
| Rhinitis | 5 | 4 |
| Other | ||
| Alopecia | 6 | 1 |
| Weight Loss | 6 | 0 |
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose Depakote group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
| Body System/Event | High Dose (%) (n = 131) | Low Dose (%) (n = 134) |
a. Headache was the only adverse event that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. | ||
| Body as a Whole | ||
| Asthenia | 21 | 10 |
| Digestive System | ||
| Nausea | 34 | 26 |
| Diarrhea | 23 | 19 |
| Vomiting | 23 | 15 |
| Abdominal Pain | 12 | 9 |
| Anorexia | 11 | 4 |
| Dyspepsia | 11 | 10 |
| Hemic/Lymphatic System | ||
| Thrombocytopenia | 24 | 1 |
| Ecchymosis | 5 | 4 |
| Metabolic/Nutritional | ||
| Weight Gain | 9 | 4 |
| Peripheral Edema | 8 | 3 |
| Nervous System | ||
| Tremor | 57 | 19 |
| Somnolence | 30 | 18 |
| Dizziness | 18 | 13 |
| Insomnia | 15 | 9 |
| Nervousness | 11 | 7 |
| Amnesia | 7 | 4 |
| Nystagmus | 7 | 1 |
| Depression | 5 | 4 |
| Respiratory System | ||
| Infection | 20 | 13 |
| Pharyngitis | 8 | 2 |
| Dyspnea | 5 | 1 |
| Skin and Appendages | ||
| Alopecia | 24 | 13 |
| Special Senses | ||
| Amblyopia/Blurred Vision | 8 | 4 |
| Tinnitus | 7 | 1 |
The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal
The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients.
CNS Effects
Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and Precautions (5.4)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy.
Dermatologic
Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7.2)].
Psychiatric
Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration.
Musculoskeletal
Weakness.
Hematologic
Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions (5.6)]. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic
Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine
Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.14)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.
Pancreatic: Acute pancreatitis including fatalities [see Warnings and Precautions (5.3)].
Metabolic: Hyperammonemia [see Warnings and Precautions (5.7 and 5.8)], hyponatremia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia [see Warnings and Precautions (5.9)].
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can d
