Nimodipine

Class: Dihydropyridines
VA Class: CV200
Chemical Name: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl ester
Molecular Formula: C₂₁H₂₆N₂O₇
CAS Number: 66085-59-4
Brands: Nimotop

• 
  

  Do not administer contents of nimodipine oral capsules by IV or other parenteral routes.^{1 245 246 248 249 250}

  
  


• 
  

  Death and serious, life-threatening adverse effects reported following parenteral injection of the contents of nimodipine capsules.^{1 245 246 248 249 250} (See Parenteral Administration under Cautions and see Hypotension and Other Cardiovascular Effects under Cautions and see Oral Administration under Dosage and Administration.)

  
  

Introduction

A dihydropyridine-derivative calcium-channel blocking agent that affects the CNS preferentially.^{1 4 5 13 22 96 d}

Uses for Nimodipine

Subarachnoid Hemorrhage

Used to improve neurologic outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage resulting from ruptured intracranial berry aneurysms regardless of the patient’s postictal neurologic condition (e.g., Hunt and Hess grades I–V).^{1 2 4 5 8 20 21 22 23 69 95 109 230 231}

Decreases severity and incidence of delayed ischemic neurologic deficits associated with subarachnoid hemorrhage.^{1 2 5 20 21 22 23 40 82 95 231}

Efficacy in reducing mortality from subarachnoid hemorrhage after oral administration not fully established.^{1 20 69 95}

Acute Ischemic Stroke

Limited evidence suggests that nimodipine may improve neurologic recovery and reduce mortality compared with plasma volume expansion therapy or placebo in some patients with acute ischemic stroke†.^{4 10 76 77 220 240 241 247}

Migraine

Has been used with equivocal results for reduction of frequency and possibly severity and duration of vascular headaches (e.g., migraine attacks) in patients with classic or common migraine†.^{4 8 11 12 78 79 80 90 101 114 206 233 244}

Also has been used in a few patients with cluster headache†.^{90 100 114}

Additional studies are needed to determine the role of nimodipine relative to that of other therapies used in the management of migraine headaches^{78 79 80 206 230 231} and to determine whether tolerance to the prophylactic effects of the drug develops during chronic therapy.²⁰⁶

Nimodipine Dosage and Administration

Administration

Oral Administration

Nimodipine capsules are for oral administration only.^{1 245 246 248 249 250} (See Boxed Warning.)

Administer orally every 4 hours, preferably at least 1 hour before or 2 hours after meals.¹

Nasogastric Tube

If the oral capsule cannot be swallowed (e.g., when administered at the time of surgery or to an unconscious patient), puncture the capsule at both ends with an 18-gauge needle and empty the contents into a syringe,^{1 249 250} preferably using a syringe designed for nasogastric or percutaneous endoscopic gastrostomy administration (e.g., Toomey syringe).^{246 250} To help minimize administration errors, label the syringe for oral use only; not for IV use.^{1 245 248 249 250} The contents of the capsule should then be emptied into the patient’s nasogastric tube.^{1 249 250} Following administration, flush with 30 mL of 0.9% sodium chloride solution.^{1 245 246 249}

Reinforce awareness among health-care professionals of potential medical errors that may result in inadvertent injection of syringe contents into an IV line or via other parenteral routes.^{246 248 249 250} (See Parenteral Administration under Cautions, see Hypotension and Other Cardiovascular Effects under Cautions, and see Boxed Warning.)

If inadvertent IV administration of contents of nimodipine capsules occurs, administer vasopressor agents for cardiovascular support if required for clinically important hypotension and promptly administer specific treatment for overdosage associated with calcium-channel blocking agents.^{1 246}

The contents of the capsule should not be admixed with any solution prior to oral administration because of the possibility of drug decomposition.²³⁰

IV Administration

The contents of nimodipine capsules must not be administered by IV injection or any other parenteral route; serious adverse effects such as hypotension, cardiovascular collapse, and cardiac arrest have occurred with such administration.^{1 248 249 250} Report adverse events or medication errors involving nimodipine capsules to the FDA MedWatch program.^{248 250}

Has been administered by IV infusion† (IV dosage form currently is not commercially available in the US)^d in patients with subarachnoid hemorrhage, often in conjunction with intracisternal† application during surgery^{67 117 119 120 214} and usually followed by oral therapy.^{5 67 93 116 117 118 119 120 214}

Dosage

Adults

Subarachnoid Hemorrhage

Oral

60 mg every 4 hours for 21 consecutive days.^{1 5} Initiate therapy as soon as possible after the occurrence of subarachnoid hemorrhage, preferably within 96 hours.^{1 4 5 20 230 231}

It has been suggested that the drug may be discontinued after 14 consecutive days (but not earlier) in some uncomplicated cases in which early aneurysm surgery is performed.²³¹

In patients in whom surgical repair of the aneurysm is performed relatively late (e.g., day 20), some clinicians suggest continuation of therapy for ≥5 days after surgery to minimize the possibility of postoperative vasospasm.^{4 231}

It has been suggested that patients with unstable BP receive a lower dosage (e.g., 30 mg every 4 hours);^{4 231} however, the manufacturer states that the usual adult dosage should be used in such patients.²³⁰ (See Hypotension and Other Cardiovascular Effects under Cautions.)

Acute Ischemic Stroke†

Oral

120 mg daily given in divided doses for 21 or 28 days has been used.^{76 77 242 247}

Migraine†

Prophylaxis of Classic or Common Migraine†

Oral

120 mg daily given in divided doses has been used.^{4 8 11 12 78 79 80 101 114 206}

Special Populations

Hepatic Impairment

Subarachnoid Hemorrhage

Oral

Initially, 30 mg every 4 hours.^{1 5 89}

Monitor BP and heart rate closely.^{1 5 89} May use pharmacologic support of BP (e.g., vasopressors such as norepinephrine or dopamine), if necessary.^{230 231}

Renal Impairment

No specific dosage recommendations.¹

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Nimodipine

Contraindications

• 
  

  No known contraindications in patients with subarachnoid hemorrhage.¹

  
  

Warnings/Precautions

Warnings

Parenteral Administration

Do not administer contents of nimodipine oral capsules by IV or other parenteral routes.^{1 245 246 248 249 250} Death and serious life-threatening adverse effects (e.g., cardiac arrest, cardiovascular collapse, hypotension, bradycardia) reported following parenteral injection of nimodipine capsule contents.^{1 245 246 248 249 250} (See Hypotension and Other Cardiovascular Effects under Cautions and see Boxed Warning.)

IV use of nimodipine, with serious and sometimes fatal outcomes, continues to be reported despite revisions to the drug’s labeling (including addition of a boxed warning) that warn against such use.^{248 249 250}

Factors identified by FDA as contributing to this error include use of IV syringes to administer the drug by NG tube (IV syringes sometimes are used to remove the liquid contents from the capsules) and the fact that most patients receiving the drug are in critical care settings and are receiving other IV therapy.^{249 250}

Report adverse events or medication errors involving nimodipine capsules to the FDA MedWatch program.^{248 250}

General Precautions

Hypotension and Other Cardiovascular Effects

IV administration of the contents of nimodipine capsules† has resulted in serious cardiovascular effects.^{1 248 249 250} (See Parenteral Administration under Cautions and see Boxed Warning.)

Possible decreased systemic BP;¹ decreases generally are not marked with usual oral dosages.^{1 2 6 7 20 21 22 23 54 69 132}

Monitor BP closely during therapy.¹ In patients with unstable BP, frequently monitor BP and heart rate; a lower dosage has been suggested.²³¹ (See Subarachnoid Hemorrhage under Dosage and Administration.)

Shares the toxic potentials of other calcium-channel blocking agents; consider possible occurrence of other adverse effects associated with these drugs (e.g., AV-conduction disturbances).^{1 7 128 230 231}

GI Effects

Intestinal pseudo-obstruction and ileus responsive to conservative management has been reported rarely.^{1 127}

Specific Populations

Pregnancy

Category C.¹

Lactation

Distributed into milk in rats;^{1 91} not known whether distributed into human milk.¹ Discontinue nursing because of potential risk to nursing infants.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 230}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.¹

Hepatic Impairment

Possible decreased metabolism, substantially reduced clearance, and increased peak plasma concentrations.^{1 89} (See Absorption: Special Populations and see also Elimination: Special Populations, under Pharmacokinetics.)

Possible hypotension.^{1 4 90 230 231} Use with caution; monitor BP and pulse rate closely; dosage adjustment recommended.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Clearance may be decreased.⁸⁸ (See Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Decreased BP, headache.^{1 4 5 23 112 122 154 230 231}

Interactions for Nimodipine

Specific Drugs

Drug	Interaction	Comments
Anesthetic agents	Does not appear to potentiate hemodynamic effects of anesthetic agents during surgery54 230 231
Antineoplastic agents	Risk of enhanced cytotoxic effects of certain antineoplastic agents140 141 190 191 192 193 195 215 216 217 218 219	Clinical importance not known230 231
Antihypertensive agents	Possible additive antihypertensive effects1 93	Monitor BP carefully if used concomitantly; when possible use short-acting antihypertensive agents231 Reduced dosage or cautious discontinuance of the antihypertensive agent and/or initiation of pharmacologic support of BP may be required230 231
Calcium-channel blockers (e.g., diltiazem)	Possible potentiation of cardiovascular effects of nimodipine (e.g., negative inotropic effect)155	Clinical importance not known;1 230 231 avoid combined therapy if possible231
Cimetidine	Decreased clearance and increased plasma nimodipine concentrations1 243	Clinical importance not known243
Digoxin	Low doses (i.e., 30 mg twice daily) of nimodipine do not alter the pharmacokinetics or hemodynamic effects of digoxin137
Fentanyl	Possible potentiation of analgesia in patients undergoing heart surgery154
Phenytoin	Possible decreased phenytoin metabolism1 179	Monitor plasma phenytoin concentrations when nimodipine is initiated or discontinued179 No drug interactions reported in patients with subarachnoid hemorrhage receiving concomitant therapy 230

Nimodipine Pharmacokinetics

Absorption

Bioavailability

Rapidly^{1 46 85 89 213} and almost completely^{4 5 213} absorbed following oral administration, with peak concentrations attained within 1 hour.^{1 46 89 213}

Bioavailability is about 13% and variable due to extensive first-pass metabolism in the liver.^{1 46 85 213 230}

Food

Food substantially decreases the extent of absorption; peak plasma concentrations reduced by 68% and bioavailability by 38%.¹

Special Populations

In patients with hepatic cirrhosis, systemic availability, peak serum drug concentrations, and AUCs may be increased substantially.^{1 89 230}

Distribution

Extent

Widely distributed into body tissues after oral or IV administration in animals.⁸⁷

Distributes to a limited extent into CSF.^{4 22 86 231}

May distribute more extensively into CSF in patients with subarachnoid hemorrhage.^{1 230}

In animals, nimodipine crosses the placenta^{4 87} and is distributed into milk.^{1 91}

Plasma Protein Binding

>95%.^{1 4 213}

Elimination

Metabolism

Extensively metabolized in the liver^{1 5 4 88 89 213} to either inactive or substantially less active metabolites^{1 124 125 213} principally via demethylation followed by dehydrogenation.^{4 85 86}

Elimination Route

Following oral administration, approximately 50% excreted in urine as metabolites and to a lesser extent in feces (possibly secondary to biliary excretion).⁴

In animals, nimodipine and/or its metabolites appear to undergo extensive enterohepatic circulation;¹²³ possible enterohepatic circulation in humans.⁸⁹

Half-life

Following oral administration: 1.7–9 hours.^{1 4 5 46 85 86 88 89 213}

Following IV (IV dosage form currently is not commercially available in the US)^d administration: 0.9–1.5 hours.^{4 46 85 86 213}

Special Populations

Substantially decreased clearance in patients with hepatic dysfunction.^{4 89 231} Mean clearance rates in patients with hepatic cirrhosis were decreased by >50% in one study.⁸⁹

Increased half-life and reduced plasma clearance reported in patients with renal impairment; findings may have been related in part to age-related reductions in liver function.⁸⁸

Hemodialysis or peritoneal dialysis not likely to affect elimination.^{1 230 231}

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C) in the original container.¹ Do not freeze; protect from light.^{1 129}

ActionsActions

• 
  

  Inhibits transmembrane influx of extracellular calcium ions across the membranes of myocardial, vascular smooth muscle, and neuronal cells.^{1 4 7 10 14 41 48 49 53 126 128 132 133 236}

  
  


• 
  

  Appears to affect the CNS preferentially.^{1 4 7 8 13 17 35 42 45 55 82 155 185 206 229 230}

  
  


• 
  

  Mechanism of selectivity for cerebral tissue is complex and has not been fully elucidated; tissue selectivity of 1,4-dihydropyridine calcium-channel blockers may be related to differences in chemical structure, binding site characteristics, and/or calcium-channel gating behavior.^{47 48 210}

  
  


• 
  

  Mechanism(s) of clinical benefit in patients with subarachnoid hemorrhage has not been fully elucidated;^{1 4 20 69 102} current evidence suggests that dilation of small cerebral resistance vessels,^{2 23 36 102 131} with a resultant increase in collateral circulation,^{4 5 23 52 67 83 98 131} and/or a direct effect involving prevention of calcium overload in neurons^{2 4 5 13 23 68 69 82 83 96 102 104 132 206} may be responsible.

  
  

Advice to Patients

• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Nimodipine

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules, liquid-filled	30 mg	Nimotop	Bayer

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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35. Müller-Schweinitzer E, Neumann P. In vitro effects of calcium antagonists PN 200-110, nifedipine, and nimodipine on human and canine cerebral arteries. J Cereb Blood Flow Metab. 1983; 3:354-61. [PubMed 6223932]

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38. Gotoh O, Mohamed AA, McCulloch J et al. Nimodipine and the haemodynamic and histopathological consequences of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab. 1986; 6:321-31. [PubMed 3711159]

39. Bellemann P, Schade A, Towart R. Dihydropyridine receptor in rat brain labeled with [3H]nimodipine. Proc Natl Acad Sci USA. 1983; 80:2356-60. [PubMed 6300912]

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42. Singh BN. The mechanism of action of calcium antagonists relative to their clinical applications. Br J Clin Pharmacol. 1986; 21:109-21S.

43. Auer LM, Ito Z, Suzuki A et al. Prevention of symptomatic vasospasm by topically applied nimodipine. Acta Neurochir. 1982; 63:297-302.

44. Kistler JP, Ropper AH, Martin JB. Cerebrovascular diseases. In: Braunwald E et al, eds. Harrison’s principles of internal medicine. 11th ed. New York: McGraw-Hill; 1987:1930-60.

45. Dompert WU, Traber J. Binding sites for dihydropyridine calcium antagonists. Perspect Cardiovasc Res. 1984; 9:175-9.

46. Ramsch KD, Lücker PW, Wetzelsberger N. Pharmacokinetics of intravenously and orally administered nimodipine. Clin Pharmacol Ther. 1987; 41:216.

47. Hess P, Lansman JB, Tsien RW. Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists. Nature. 1984; 311:538-44. [PubMed 6207437]

48. Triggle DJ, Janis RA. The 1,4-dihydropyridine receptor: a regulatory component of the Ca²⁺ channel. J Cardiovasc Pharmacol. 1984; 6(Suppl 7):S949-55.

49. Triggle DJ, Swamy VC. Calcium antagonists: some chemical-pharmacologic aspects. Circ Res. 1983; 52(Suppl I):I-17-28. [IDIS 169740] [PubMed 6299605]

50. Schmidli J, Santillan GG, Saeed M et al. The effect of nimodipine, a calcium antagonist, on intracortical arterioles in the cat brain. Curr Ther Res. 1985; 38:94-103.

51. Auer LM, Mokry M. Effect of topical nimodipine versus its ethanol-containing vehicle on cat pial arteries. Stroke. 1985; 17:225-8.

52. Brandt L, Ljunggren B, Saveland H et al. Cerebral vasospasm and calcium channel blockade. Nimodipine treatment in patients with aneurysmal subarachnoid hemorrhage. Acta Pharmacol Toxicol (Copenh). 1986; 58(Suppl 2):151-5. [PubMed 3521193]

53. Kanda K, Flaim SF. Effects of nimodipine on cerebral blood flow in conscious rat. J Pharmacol Exp Ther. 1986; 236:41-7. [PubMed 3941399]

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55. Peroutka SJ, Banghart SB, Allen GS. Relative potency and selectivity of calcium antagonists used in the treatment of migraine. Headache. 1984; 24:55-8. [PubMed 6715160]

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60. Grabowski M, Johansson BB. Nifedipine and nimodipine: effect on blood pressure and regional cerebral blood flow in conscious normotensive and hypertensive rats. J Cardiovasc Pharmacol. 1985; 7:1127-33. [PubMed 2418299]

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63. McCalden TA, Nath RG, Thiele K. The effects of a calcium antagonist (nimodipine) on basal cerebral blood flow and reactivity to various agonists. Stroke. 1984; 15:527-30. [PubMed 6427982]

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72. Ulrich G, Stieglitz RD. Effect of nimodipine upon electroencephalographic vigilance in elderly persons with minor

Care Antiseptic First Aid Cream

1. Name Of The Medicinal Product

Cetrimide Cream BP

Care Antiseptic First Aid Cream

Sainsburys Antiseptic First Aid Cream

2. Qualitative And Quantitative Composition

Contains Cetrimide BP 0.5% w/w as active ingredient.

3. Pharmaceutical Form

Cream.

4. Clinical Particulars

4.1 Therapeutic Indications

For use in minor burns, napkin rash and abrasions.

4.2 Posology And Method Of Administration

Topical: Apply directly to the affected part.

This product is suitable for adults, children, and the elderly.

4.3 Contraindications

Contra-indicated in patients with known hypersensitivity to cetrimide.

4.4 Special Warnings And Precautions For Use

Prolonged and repeated applications of cetrimide to the skin may lead to hypersensitivity.

Labels to state: FOR EXTERNAL USE ONLY.

Keep out of reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

No information is available on the safety or use of the product in the above conditions.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

None known.

4.9 Overdose

Overdose by the recommended route of administration is considered unlikely. Ingestion may cause nausea and vomiting. Toxic symptoms include dyspnoea and cyanosis, possibly leading to asphyxia. Depression of the central nervous system, hypotension and coma may also occur.

Treatment of poisoning is symptomatic. Emesis and lavage should be avoided.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Cetrimide is a quaternary ammonium cationic disinfectant with bactericidal activity against gram-positive and some gram-negative organisms. Cetrimide is relatively ineffective against viruses.

5.2 Pharmacokinetic Properties

No information available.

5.3 Preclinical Safety Data

None.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Cetostearyl Alcohol BP, Liquid Paraffin BP, Chlorocresol BP, Purified Water BP.

6.2 Incompatibilities

Cetrimide is incompatible with soaps and other anionic surfactants, Bentonite, Iodine, Phenylmercuric Nitrate and Alkali Hydroxides.

6.3 Shelf Life

30g:	30 months (unopened).
50g:	30 months (unopened).
500g:	30 months (unopened).

6.4 Special Precautions For Storage

Store below 25°C. Do not allow to freeze.

6.5 Nature And Contents Of Container

30g:	30g lacquered aluminium tube and cap.
50g:	50g lacquered aluminium tube and cap.
500g:	Polypropylene jar and lid.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Thornton & Ross Ltd.

Linthwaite Laboratories

Huddersfield

HD7 5QH.

8. Marketing Authorisation Number(S)

PL: 00240/6277R.

9. Date Of First Authorisation/Renewal Of The Authorisation

10.02.87 / 10.02.92, 25.06.98.

10. Date Of Revision Of The Text

31.08.2008

11 DOSIMETRY (IF APPLICABLE)

Not Applicable

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Not Applicable

Zarontin Capsules

Dosage Form: capsule
Zarontin®

(Ethosuximide Capsules, USP)

Zarontin Capsules Description

Zarontin (ethosuximide) is an anticonvulsant succinimide, chemically designated as alpha-ethyl-alpha-methyl-succinimide, with the following structural formula:

Each Zarontin capsule contains 250 mg ethosuximide, USP. Also contains: polyethylene glycol 400, NF. The capsule contains D&C yellow No. 10; FD&C red No. 3; gelatin, NF; glycerin, USP; and sorbitol.

Zarontin Capsules - Clinical Pharmacology

Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.

Indications and Usage for Zarontin Capsules

Zarontin is indicated for the control of absence (petit mal) epilepsy.

CONTRAINDICATION

Ethosuximide should not be used in patients with a history of hypersensitivity to succinimides.

Warnings

Blood dyscrasias

Blood dyscrasias, including some with fatal outcome, have been reported to be associated with the use of ethosuximide; therefore, periodic blood counts should be performed. Should signs and/or symptoms of infection (e.g., sore throat, fever) develop, blood counts should be considered at that point.

Effects on Liver and Kidneys

Ethosuximide is capable of producing morphological and functional changes in the animal liver. In humans, abnormal liver and renal function studies have been reported. Ethosuximide should be administered with extreme caution to patients with known liver or renal disease. Periodic urinalysis and liver function studies are advised for all patients receiving the drug.

Systemic Lupus Erythematosus

Cases of systemic lupus erythematosus have been reported with the use of ethosuximide. The physician should be alert to this possibility.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Zarontin, 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.

Table 1 Risk by indication for antiepileptic drugs in the pooled analysis

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 Zarontin or any other AED must balance the risk of suicidal thoughts and 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.

Usage in Pregnancy

Ethosuximide crosses the placenta.

Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to phenytoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.

Cases of birth defects have been reported with ethosuximide. The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodological problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, eg, genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be 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 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.

The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of childbearing potential.

Ethosuximide is excreted in human breast milk. Because the effects of ethosuximide on the nursing infant are unknown, caution should be exercised when ethosuximide is administered to a nursing mother. Ethosuximide should be used in nursing mothers only if the benefits clearly outweigh the risks.

Precautions

General

Ethosuximide, when used alone in mixed types of epilepsy, may increase the frequency of grand mal seizures in some patients.

As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt withdrawal of anticonvulsant medication may precipitate absence (petit mal) status.

Information for Patients

Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Zarontin. Instruct patients to take Zarontin only as prescribed.

Ethosuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a motor vehicle or other such activity requiring alertness; therefore, the patient should be cautioned accordingly.

Patients taking ethosuximide should be advised of the importance of adhering strictly to the prescribed dosage regimen.

Patients should be instructed to promptly contact their physician if they develop signs and/or symptoms (e.g., sore throat, fever), suggesting an infection.

Patients, their caregivers, and families should be counseled that AEDs, including Zarontin, 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.

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 section).

Drug Interactions

Since Zarontin (ethosuximide) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (e.g., ethosuximide may elevate phenytoin serum levels and valproic acid has been reported to both increase and decrease ethosuximide levels).

Pregnancy

To provide information regarding the effects of in utero exposure to Zarontin, physicians are advised to recommend that pregnant patients taking Zarontin enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website: http://www.aedpregnancyregistry.org/

See WARNINGS.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 3 years have not been established. (See DOSAGE AND ADMINISTRATION section.)

Adverse Reactions

Body As A Whole: Allergic reaction.

Gastrointestinal System: Gastrointestinal symptoms occur frequently and include anorexia, vague gastric upset, nausea and vomiting, cramps, epigastric and abdominal pain, weight loss, and diarrhea. There have been reports of gum hypertrophy and swelling of the tongue.

Hemopoietic System: Hemopoietic complications associated with the administration of ethosuximide have included leukopenia, agranulocytosis, pancytopenia, with or without bone marrow suppression, and eosinophilia.

Nervous System: Neurologic and sensory reactions reported during therapy with ethosuximide have included drowsiness, headache, dizziness, euphoria, hiccups, irritability, hyperactivity, lethargy, fatigue, and ataxia. Psychiatric or psychological aberrations associated with ethosuximide administration have included disturbances of sleep, night terrors, inability to concentrate, and aggressiveness. These effects may be noted particularly in patients who have previously exhibited psychological abnormalities. There have been rare reports of paranoid psychosis, increased libido, and increased state of depression with overt suicidal intentions.

Integumentary System: Dermatologic manifestations which have occurred with the administration of ethosuximide have included urticaria, Stevens-Johnson syndrome, systemic lupus erythematosus, pruritic erythematous rashes, and hirsutism. DRESS syndrome (drug rash, eosinophilia and systemic symptoms) has been reported in the post-marketing database.

Special Senses: Myopia.

Genitourinary System: Vaginal bleeding, microscopic hematuria.

Overdosage

Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. A relationship between ethosuximide toxicity and its plasma levels has not been established. The therapeutic range of serum levels is 40 mcg/mL to 100 mcg/mL, although levels as high as 150 mcg/mL have been reported without signs of toxicity.

Treatment

Treatment should include emesis (unless the patient is or could rapidly become obtunded, comatose, or convulsing) or gastric lavage, activated charcoal, cathartics, and general supportive measures. Hemodialysis may be useful to treat ethosuximide overdose. Forced diuresis and exchange transfusions are ineffective.

Zarontin Capsules Dosage and Administration

Zarontin is administered by the oral route. The initial dose for patients 3 to 6 years of age is one capsule (250 mg) per day; for patients 6 years of age and older, 2 capsules (500 mg) per day. The dose thereafter must be individualized according to the patient's response. Dosage should be increased by small increments. One useful method is to increase the daily dose by 250 mg every four to seven days until control is achieved with minimal side effects. Dosages exceeding 1.5 g daily, in divided doses, should be administered only under the strictest supervision of the physician. The optimal dose for most pediatric patients is 20 mg/kg/day. This dose has given average plasma levels within the accepted therapeutic range of 40 to 100 mcg/mL. Subsequent dose schedules can be based on effectiveness and plasma level determinations.

Zarontin may be administered in combination with other anticonvulsants when other forms of epilepsy coexist with absence (petit mal). The optimal dose for most pediatric patients is 20 mg/kg/day.

How is Zarontin Capsules Supplied

Zarontin is supplied as:

NDC 0071-0237-24:Bottles of 100. Each capsule contains 250 mg ethosuximide.

Store at 25° C (77° F); excursions permitted to 15–30° C (59–86° F) [see USP Controlled Room Temperature].

LAB-0094-7.0

April 2011

MEDICATION GUIDE


ZARONTIN, (Ză rŏn' tĭn)

(ethosuximide)


Capsules, Oral Solution

Read this Medication Guide before you start taking ZARONTIN and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about ZARONTIN, ask your healthcare provider or pharmacist.

What is the most important information I should know about ZARONTIN?

Do not stop taking ZARONTIN without first talking to your healthcare provider.

Stopping ZARONTIN suddenly can cause serious problems.

ZARONTIN can cause serious side effects, including:

1. Rare but serious blood problems that may be life-threatening. Call your healthcare provider right away if you have:
   
   • fever, swollen glands, or sore throat that come and go or do not go away
   
   
   • frequent infections or an infection that does not go away
   
   
   • easy bruising
   
   
   • red or purple spots on your body
   
   
   • bleeding gums or nose bleeds
   
   
   • severe fatigue or weakness
   
   


2. Systematic Lupus Erythematosus. Call your healthcare provider right away if you have any of these symptoms:
   
   • joint pain and swelling
   
   
   • muscle pain
   
   
   • fatigue
   
   
   • low-grade fever
   
   
   • pain in the chest that is worse with breathing
   
   
   • unexplained skin rash
   
   


3. Like other antiepileptic drugs, ZARONTIN may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
   
   Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
   
   • thoughts about suicide or dying
   
   
   • attempts to commit suicide
   
   
   • new or worse depression
   
   
   • new or worse anxiety
   
   
   • feeling agitated or restless
   
   
   • panic attacks
   
   
   • trouble sleeping (insomnia)
   
   
   • new or worse irritability
   
   
   • acting aggressive, being angry, or violent
   
   
   • acting on dangerous impulses
   
   
   • an extreme increase activity and talking (mania)
   
   
   • other unusual changes in behavior or mood
   
   

   How can I watch for early symptoms of suicidal thoughts and actions?

   
   
   • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
   
   
   • Keep all follow-up visits with your healthcare provider as scheduled.
   
   

   Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

   
   

   Do not stop ZARONTIN without first talking to a healthcare provider.

   
   
   • Stopping ZARONTIN suddenly can cause serious problems.
   
   
   • Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).
   
   

   Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

   
   

What is ZARONTIN?

ZARONTIN is a prescription medicine used to treat absence (petit mal) seizures.

Who should not take ZARONTIN?

Do not take ZARONTIN if you are allergic to succinimides (methsuximide or ethosuximide), or any of the ingredients in ZARONTIN. See the end of this Medication Guide for a complete list of ingredients in ZARONTIN.

What should I tell my healthcare provider before taking ZARONTIN?

Before you take ZARONTIN, tell your healthcare provider if you:

• have or had liver problems


• have or have had depression, mood problems or suicidal thoughts or behavior


• have any other medical conditions


• are pregnant or plan to become pregnant. It is not known if ZARONTIN can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking ZARONTIN. You and your healthcare provider should decide if you should take ZARONTIN while you are pregnant.
  
  • If you become pregnant while taking ZARONTIN, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. You can enroll in this registry by calling 1-888-233-2334.
  
  


• are breast-feeding or plan to breast-feed. It is not known if ZARONTIN can pass into breast milk. You and your healthcare provider should decide how you will feed your baby while you take ZARONTIN.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking ZARONTIN with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine.

How should I take ZARONTIN?

• Take ZARONTIN exactly as prescribed. Your healthcare provider will tell you how much ZARONTIN to take.


• Your healthcare provider may change your dose. Do not change your dose of ZARONTIN without talking to your healthcare provider.


• If you take too much ZARONTIN, call your healthcare provider or your local Poison Control Center right away.

What should I avoid while taking ZARONTIN?

• Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking ZARONTIN without first talking to your healthcare provider. ZARONTIN taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
  
  • Do not drive, operate heavy machinery, or do other dangerous activities until you know how ZARONTIN affects you. ZARONTIN can slow your thinking and motor skills.
  
  

What are the possible side effects of ZARONTIN?

• See "What is the most important information I should know about ZARONTIN?"

ZARONTIN may cause other serious side effects, including:

• Serious allergic reactions. Call your healthcare provider right away if you have any of these symptoms:
  
  • skin rash
  
  
  • hives
  
  
  • sores in your mouth
  
  
  • blistering or peeling skin
  
  
  • Changes in thinking, mood, or behavior. Some patients may get abnormally suspicious thoughts, hallucinations (seeing or hearing things that are not there), or delusions (false thoughts or beliefs).
  
  
  • Grand mal seizures can happen more often or become worse
  
  

Call your healthcare provider right away, if you have any of the symptoms listed above.

The most common side effects of ZARONTIN include

nausea or vomiting indigestion, stomach pain diarrhea weight loss loss of appetite hiccups

fatigue dizziness or lightheadedness unsteadiness when walking headache loss of concentration

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects with ZARONTIN. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ZARONTIN?

• Store Zarontin Capsules at room temperature, between 59°F to 86°F (15°C to 30°C).


• Store ZARONTIN syrup (oral solution) at 20°–25°C (68°–77°F). Preserve in tight containers. Protect from freezing and light.

Keep ZARONTIN and all medicines out of the reach of children.

General information about ZARONTIN

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ZARONTIN for a condition for which it was not prescribed. Do not give ZARONTIN to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about ZARONTIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ZARONTIN that is written for healthcare professionals.

For more information, go to www.pfizer.com or call 1-800-438-1985.

What are the ingredients in ZARONTIN?

Active ingredient: ethosuximide

Capsules

Inactive ingredients: Polyethylene glycol 400, NF; D&C yellow No. 10; FD&C red No. 3; gelatin, NF; glycerin, USP; and sorbitol.

Oral Solution

Inactive ingredients: Each 5 ml (teaspoonful) of oral solution contains 250 mg ethosuximide in a raspberry flavored base. Also contains citric acid, anhydrous, USP; FD&C red No. 40; FD&C yellow No. 6; flavor; glycerin, USP; purified water, USP; saccharin sodium, USP; sodium benzoate, NF; Sodium Citrate, USP; sucrose, NF.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

LAB-0403-1.0

September 2010

PRINCIPAL DISPLAY PANEL - 100 Capsule Bottle Label

NDC 0071-0237-24

100 Capsules

Rx only

Zarontin®

(Ethosuximide

Capsules, USP)

250 mg

Pfizer

Distributed by

Parke-Davis

Division of Pfizer Inc, NY, NY 10017

ZARONTIN  ethosuximide  capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0071-0237 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Ethosuximide (Ethosuximide) Ethosuximide 250 mg

Inactive Ingredients Ingredient Name Strength polyethylene glycol 400   D&C yellow No. 10   FD&C red No. 3   gelatin   glycerin   sorbitol

Product Characteristics Color ORANGE Score no score Shape CAPSULE Size 8mm Flavor Imprint Code P;D;237 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0071-0237-24 100 CAPSULE In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA012380	09/22/2000

Labeler - Parke-Davis Div of Pfizer Inc (829076962)

Establishment
Name	Address	ID/FEI	Operations
Katwijk Chemie B.V.		416984441	Manufacture

Establishment
Name	Address	ID/FEI	Operations
Catalent Pharma Solutions		051762268	Manufacture

Revised: 04/2011Parke-Davis Div of Pfizer Inc

More Zarontin Capsules resources

• Zarontin Capsules Side Effects (in more detail)
• Zarontin Capsules Use in Pregnancy & Breastfeeding
• Drug Images
• Zarontin Capsules Drug Interactions
• Zarontin Capsules Support Group
• 5 Reviews for Zarontin - Add your own review/rating

Compare Zarontin Capsules with other medications

• Seizures

Boots Decongestant Tablets

1. Name Of The Medicinal Product

Decongestant Tablets

2. Qualitative And Quantitative Composition

Active ingredient
Pseudoephedrine hydrochloride	60mg/tablet

3. Pharmaceutical Form

Tablets

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of nasal and sinus congestion without causing drowsiness.

For oral administration.

4.2 Posology And Method Of Administration

Adults and children over 12 years: One tablet if necessary, up to four times daily at intervals of not less than 4 hours.

Children under 12 years: Not recommended.

Elderly: There is no need for dosage reduction in the elderly.

4.3 Contraindications

Hypersensitivity to any of the ingredients. Avoid in patients with cardiovascular disease, hypertension, severe renal impairment, diabetes mellitus, closed angle glaucoma, hyperthyroidism, prostatic enlargement and phaeochromocytoma.

4.4 Special Warnings And Precautions For Use

If symptoms are not controlled by Boots Decongestant Tablets, medical advice should be sought.

Keep all medicines out of the reach of children.

Warning: Do not exceed the stated dose.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Should not be given to patients being treated with monoamine oxidase inhibitors or within 14 days of stopping such treatment. May enhance the effects of anticholinergic drugs such as tricyclic antidepressants. May increase the possibility of arrhythmias in digitalised patients. May increase the vasoconstrictor effects of ergot alkaloids.

4.6 Pregnancy And Lactation

The safety of decongestant tablets during pregnancy and lactation has not been established but in view of a possible association of foetal abnormalities with first trimester exposure to pseudoephedrine, the use of the product during pregnancy should be avoided. The amounts of pseudoephedrine secreted into breast milk are considered to be too small to be harmful.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

Adverse effects may include dry mouth, anxiety, restlessness, tremor, insomnia, tachycardia, cardiac arrhythmias, palpitations, hypertension, nausea, vomiting, headache and occasionally urinary retention in males and skin rashes. Hallucinations have been reported rarely, particularly in children.

4.9 Overdose

Symptoms of overdosage include irritability, restlessness, palpitations, hypertension, difficulty in micturition, nausea, vomiting, thirst and convulsions. In severe overdosage gastric lavage and aspiration should be performed. Symptomatic and supportive measures should be undertaken, particularly with regard to cardiovascular and respiratory systems. Convulsions should be controlled with intravenous diazepam. Chlorpromazine may be used to control marked excitement and hallucinations. Severe hypertension may need to be treated with an alpha-adrenoreceptor blocking drug, such as phentolamine. A beta blocker may be required to control cardiac arrhythmias.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pseudoephedrine is a sympathomimetic agent with direct and indirect effects on adrenergic receptors. It has alpha and beta adrenergic activity and some stimulant effect on the central nervous system. The sympathomimetic effect of pseudoephedrine produces vasoconstriction which in turn relieves nasal congestion.

5.2 Pharmacokinetic Properties

Pseudoephedrine is readily and completely absorbed from the gastrointestinal tract. It is resistant to metabolism by monoamine oxidase and is largely excreted in the urine unchanged. It has an elimination half-life of 5 to 8 hours but its urinary elimination and hence half-life is pH dependent. Pseudoephedrine is rapidly distributed throughout the body, its volume of distribution being 2 to 3L/KG bodyweight.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Starch Glycolate

Maize Starch prd

Microcrystalline Cellulose

Pregelled Maize Starch

Purified Water

Stearic Acid

6.2 Incompatibilities

None are known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Blister pack of white or clear 250 microns PVC coated with 40gsm PVdC and 20 micron aluminium foil.

Pack sizes: 6, 7, 10, 12 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham

NG2 3AA

8. Marketing Authorisation Number(S)

PL 00014/0375

9. Date Of First Authorisation/Renewal Of The Authorisation

28 January 1988 / 17 December 1997 / 17 December 2002

10. Date Of Revision Of The Text

September 2007