Sodium Phenylacetate and Sodium Benzoate

Class: Ammonia Detoxicants
Chemical Name: Benzeneacetic acid, sodium salt
Molecular Formula: C₈H₇NaO₂C₇H₅NaO₂
CAS Number: 114-70-5
Brands: Ammonul

Introduction

Fixed combination of 2 ammonia detoxicants.¹

Uses for Sodium Phenylacetate and Sodium Benzoate

Acute Hyperammonemia

Adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in patients with urea cycle disorders (e.g., deficiency in carbamyl phosphate synthetase [CPS], ornithine transcarbamylase [OTC], argininosuccinate synthetase [ASS], or argininosuccinate lyase [ASL]);^{1 2 3 4 5 7} designated an orphan drug by FDA for this use.⁵

Treat any episode of acute symptomatic hyperammonemia as a life-threatening emergency; prompt use of all necessary therapies (e.g., dialysis [preferably hemodialysis], caloric supplementation, protein restriction) to reduce ammonia concentrations is essential.^{1 3 4 7}

Hemodialysis is the preferred therapy for acute neonatal hyperammonemic coma, moderate to severe episodes of hyperammonemic encephalopathy, and episodes of hyperammonemia that fail to respond to an initial course of sodium phenylacetate and sodium benzoate therapy.^{1 3 4} In such patients, administration of sodium phenylacetate and sodium benzoate helps prevent reaccumulation of ammonia by increasing waste nitrogen excretion.^{1 3 4}

Concomitant therapy with IV arginine hydrochloride is required in patients with CPS, OTC, ASS, or ASL deficiency; however, IV arginine hydrochloride is contraindicated in patients with arginase deficiency.^{1 2 3 4 6 7} Pending specific diagnosis, also give IV arginine hydrochloride to hyperammonemic infants with suspected urea cycle disorders.^{1 3 7}

If a urea cycle disorder is suspected based on family history, document hyperammonemia before administering sodium phenylacetate and sodium benzoate.¹

Sodium Phenylacetate and Sodium Benzoate Dosage and Administration

General

• 
  

  Initiate therapy immediately following the diagnosis of hyperammonemia.^{1 7}

  
  


• 
  

  Prior to infusion, discontinue analogous oral agents (e.g., sodium phenylbutyrate).¹

  
  


• 
  

  May administer an antiemetic during the infusion for management of possible nausea and vomiting.^{1 6}

  
  


• 
  

  Start or resume oral therapy (e.g., sodium phenylbutyrate), dietary management, and protein restriction when ammonia concentrations reduced to the normal range.^{1 7}

  
  


• 
  

  Dialysis is recommended for those patients who do not have a significant reduction in plasma ammonia levels within 4–8 hours after receiving sodium phenylacetate and sodium benzoate.¹

  
  


• 
  

  Concomitant therapy with arginine hydrochloride may be required.^{1 3 4 7} Consult the prescribing information for arginine hydrochloride for complete dosing and other information.

  
  

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion through a central venous line only; administration through a peripheral line may cause burns.¹

Vials are for single use only.¹

Dilution

Must be diluted in 10% dextrose injection prior to administration.^{1 3 4 7}

Always use the Millex Durapore GV 33-mm sterile syringe filter (0.22 mcm) provided by the manufacturer when diluting sodium phenylacetate and sodium benzoate injection regardless of whether particulate matter is visible in the vial.⁹ Particulate matter has been reported but may not be readily observed on visual inspection; removal of these particulates by this filter has been confirmed.⁹ (See Detection of Particulate Matter in Commercial Preparations under Cautions.)

Prepare IV infusion in glass or PVC container. ¹

Determine the volume of diluent based on the patient’s weight (neonates, infants, and children weighing ≤20 kg) or BSA (children weighing >20 kg, adolescents, and adults).¹ Dilute each loading or maintenance dose of injection concentrate in ≥25 mL/kg of body weight of 10% dextrose injection.^{1 3}

Rate of Administration

Administer loading dose over 90–120 minutes.^{1 3 7}

Administer maintenance dose over 24 hours.^{1 3 7}

Dosage

Available as sodium phenylacetate and sodium benzoate; dosage expressed in terms of the salts.¹

Base dosages in neonates, infants, and children weighing ≤20 kg on body weight; base dosages in pediatric patients weighing >20 kg and in adults on body surface area.^{1 3 7}

Pediatric Patients

Acute Hyperammonemia

IV

Pediatric patients weighing ≤20 kg: Loading dose of 250 mg/kg sodium phenylacetate in fixed combination with 250 mg/kg sodium benzoate infused over 90–120 minutes.^{1 3 7} Maintenance dose of 250 mg/kg of sodium phenylacetate and 250 mg/kg sodium benzoate infused over 24 hours.^{1 3 7}

Pediatric patients weighing >20 kg: Loading dose of 5.5 g/m² sodium phenylacetate and 5.5 g/m² sodium benzoate infused over 90–120 minutes.^{1 3} Maintenance dose of 5.5 g/m² sodium phenylacetate and 5.5 g/m² of sodium benzoate infused over 24 hours.^{1 3}

Continue maintenance infusions until elevated plasma ammonia concentrations decrease to normal levels or until patient can tolerate oral nutrition and drug therapy.^{1 3 7}

Repeat Loading Doses

IV

Manufacturer states do not repeat loading doses;¹ however, some experts state that a repeat loading dose within 24 hours should be considered only in neonates with severe disorders and/or those receiving dialysis; space loading doses ≥6 hours apart.^{3 4} (See Laboratory Monitoring and also see Repeat Loading Doses under Cautions.)

Adults

Acute Hyperammonemia

IV

Loading dose: 5.5 g/m² sodium phenylacetate and 5.5 g/m² sodium benzoate infused over 90–120 minutes.^{1 3} Manufacturer states do not repeat loading doses.¹

Maintenance dose: 5.5 g/m² sodium phenylacetate and 5.5 g/m² sodium benzoate infused over 24 hours.^{1 3}

Continue maintenance infusions until elevated plasma ammonia concentrations decrease to normal levels or until patient can tolerate oral nutrition and drug therapy.^{1 3 7}

Special Populations

No special population dosage recommendations at this time.¹ (See Hepatic Impairment and see Renal Impairment under Cautions and also see Special Populations under Pharmacokinetics.)

Cautions for Sodium Phenylacetate and Sodium Benzoate

Contraindications

• 
  

  Known hypersensitivity to sodium phenylacetate or sodium benzoate or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Emergency Treatment of Hyperammonemia

Risk of rapid brain damage or death if acute symptomatic hyperammonemia is left uncontrolled; treat as a life-threatening emergency.^{1 7} Prompt use of all therapies to reduce serum ammonia concentrations (e.g., dialysis [preferably hemodialysis]) is essential.^{1 3 4 6 7} (See Acute Hyperammonemia under Uses.)

Manage hyperammonemia due to inborn errors of metabolism in coordination with medical personnel familiar with such conditions; usually requires health-care facilities able to provide multidisciplinary treatment (e.g., hemodialysis, nutritional management, medical support).^{1 3}

Laboratory Monitoring

Closely monitor plasma ammonia concentrations, neurologic status, laboratory tests, and clinical response during treatment.¹

Monitor serum electrolyte concentrations; maintain within the normal range.¹

Urinary loss of potassium is enhanced by excretion of nonabsorbable anions phenylacetylglutamine and hippurate; carefully monitor plasma potassium concentrations and provide replacement therapy, when necessary.^{1 6}

Perform blood chemistry profiles and frequent blood pH and blood gases (e.g., pCO₂) evaluations to check for salicylate-like toxicity.¹ (See Salicylate-like Toxicity under Cautions.)

The Urea Cycle Disorders Conference Group and some experts recommend monitoring plasma concentrations of ammonia scavenging drugs (e.g., sodium phenylacetate and sodium benzoate) to avoid toxicity.⁶ Weigh the risk of overdosage against potential benefits of repeating a loading dose in the absence of facilities for drug concentration monitoring.⁴ (See Repeat Loading Doses under Dosage and Administration and also see Repeat Loading Doses under Cautions.)

Possible Prescribing Errors

Experts recommend double-checking the accuracy of prescription orders to avoid possible overdosage.⁴

Detection of Particulate Matter in Commercial Preparations

Particulate matter has been detected in sodium phenylacetate and sodium benzoate injections.⁹ Particulates may not be readily observed on visual inspection.⁹ Because these particulates could potentially affect injection safety, always use the Millex Durapore GV 33-mm sterile syringe filter (0.22 mcm) provided by the manufacturer when diluting the injection (see Dilution under Dosage and Administration).⁹ Removal of these particulates by this filter has been confirmed.⁹

Report any quality problems or suspected adverse effects to the manufacturer (800-900-6389) or the FDA MedWatch program.⁹

For addditional information, see or .⁹

Extravasation

Do not administer injection concentrate undiluted; only administer via a central line.¹ Peripheral venous administration may cause burns.¹

Extravasation into perivenous tissue may lead to skin necrosis.¹ Carefully monitor the infusion site during infusion.¹ If extravasation is suspected, discontinue the infusion and resume at a different site, if necessary.¹ Treatment for extravasation may include aspiration of residual drug from the catheter, limb elevation, and intermittent cooling with cold packs.¹

Sodium Content

Each g of sodium phenylacetate provides 6.3 mEq (145 mg) of sodium, and each g of sodium benzoate provides 7 mEq (160 mg) of sodium; each mL of injection concentrate labeled as containing 100 mg each of sodium phenylacetate and sodium benzoate provides 1.33 mEq (30.5 mg) of sodium.^{1 7}

Consider sodium content and use with caution, if at all, in patients with CHF, severe renal impairment, or sodium retention with edema.¹ If adverse effects associated with increased sodium concentrations occur, discontinue the drug, promptly evaluate the patient, and take appropriate measures.¹

Salicylate-like Toxicity

Structurally similar to salicylate; possibility of adverse effects (e.g., hyperventilation, metabolic acidosis) typically associated with acute salicylate toxicity.^{1 2} (See Laboratory Monitoring under Cautions.)

Major Toxicities

Neurotoxicity

Adverse neurotoxic effects (e.g., somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, exacerbation of existing neuropathy) reported in cancer patients receiving IV phenylacetate.¹ Acute onset (mainly mild) occurred upon initiation of therapy; reversible upon discontinuance of the drug.¹

General Precautions

Repeat Loading Doses

The manufacturer states that, because plasma concentrations of phenylacetate are prolonged, do not repeat loading doses.¹ However, some experts state that a repeat loading dose within 24 hours should be considered only in neonates with severe disorders and/or those receiving dialysis; space loading doses at least 6 hours apart.^{3 4} (See Repeat Loading Doses under Dosage and Administration and see Laboratory Monitoring under Cautions.)

Hyperbilirubinemia

Risk of indirect hyperbilirubinemia.⁷ Use with caution in neonates with hyperbilirubinemia.⁷ In infants at risk, reduce serum bilirubin concentrations to normal range before initiating therapy with sodium phenylacetate and sodium benzoate.⁷

Dialysis

Manufacturer states drug is complementary with dialysis (e.g., standard hemodialysis, peritoneal dialysis, arteriovenous hemofiltration).¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether sodium phenylacetate or sodium benzoate or their conjugated metabolites are distributed into milk.¹ Use with caution in nursing women.¹

Pediatric Use

Efficacy is established for treatment of hyperammonemia in pediatric patients 0–16 years of age, including neonates (0–30 days of age) and infants (31 days–2 years of age).¹

Use with caution in neonates with hyperbilirubinemia.⁷ (See Hyperbilirubinemia under Cautions.)

Hepatic Impairment

Use with caution in patients with hepatic impairment.¹ (See Metabolism under Pharmacokinetics.)

Renal Impairment

Use with caution and carefully monitor patients with renal impairment.¹ (See Elimination under Pharmacokinetics.)

Common Adverse Effects

Vomiting, hyperglycemia, hypokalemia, seizures, mental impairment.¹

Interactions for Sodium Phenylacetate and Sodium Benzoate

No formal drug interaction studies to date.¹

Specific Drugs

Drug	Interaction
Anti-infective agents (e.g., penicillin)	Some anti-infective agents may compete with phenylacetylglutamine and hippurate for active renal tubular secretion, affecting drug disposition1
Corticosteroids	Corticosteroids may increase plasma ammonia concentrations by causing protein catabolism1
Probenecid	Probenecid inhibits renal transport of organic compounds (including aminohippuric acid)1 Probenecid may affect renal excretion of phenylacetylglutamine and hippurate1
Valproic acid	Valproic acid may induce hyperammonemia via inhibition of N-acetylglutamate, a co-factor for carbamyl phosphate synthetase1 Concomitant use may exacerbate urea cycle disorders and antagonize plasma ammonia-lowering effects of the ammonia detoxicant1

Sodium Phenylacetate and Sodium Benzoate Pharmacokinetics

Absorption

Onset

Mean ammonia concentrations decrease significantly within 4 hours in patients responding to therapy.¹

Distribution

Extent

Not known whether sodium phenylacetate or sodium benzoate or their conjugated metabolites are distributed into milk.¹

Elimination

Metabolism

Sodium phenylacetate is metabolized in the liver and kidneys to phenylacetylglutamine.¹

Sodium benzoate is metabolized in the liver and kidneys to hippuric acid.¹

Elimination Route

Phenylacetylglutamine and hippuric acid are principally excreted in urine via glomerular filtration and tubular secretion.¹

Special Populations

Sodium phenylacetate and sodium benzoate are metabolized in the liver; limited information available in impaired hepatic function.¹

Sodium phenylacetate and sodium benzoate are metabolized and excreted by the kidneys; renal clearance of drug metabolites and ammonia is required.¹

Stability

Storage

Parenteral

Injection Concentrate

25°C (may be exposed to 15–30°C).¹ Diluted solutions are stable for up to 24 hours at room temperature and room lighting conditions.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible
Dextrose 10% in water1

Do not admix with other infusion solutions.¹

Drug Compatibility

Admixture Compatibility

Compatible
Arginine HCl 10%

Do not admix with other drugs.¹

ActionsActions

• 
  

  Sodium phenylacetate and sodium benzoate decrease ammonia concentrations by serving as alternatives to urea for nitrogen waste excretion.^{1 3 7}

  
  


• 
  

  Nitrogen content of phenylacetylglutamine is identical to urea (i.e., 2 moles of nitrogen).¹

  
  


• 
  

  Two moles of nitrogen are removed per mole of phenylacetate conjugated with glutamine; one mole of nitrogen is removed per mole of benzoate conjugated with glycine.^{1 7}

  
  


• 
  

  Glutamine and glycine used in these reactions are replaced by synthesis, reducing the nitrogen pool and attenuating the risk of ammonia and glutamine-induced neurotoxicity.^{1 3 7}

  
  

Advice to Patients

• 
  

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

  
  


• 
  

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

  
  


• 
  

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

  
  

Preparations

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

Manufacturer has notified health-care professionals that particular matter was detected in sodium phenylacetate and sodium benzoate injections.⁹ Use the syringe filter provided by the manufacturer when diluting the injection.⁹ Report any quality problems or suspected adverse effects to the manufacturer (800-900-6389) or the FDA MedWatch program.⁹ (See Detection of Particulate Matter in Commercial Preparations uunder Cautions.)

Sodium Phenylacetate and Sodium Benzoate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection concentrate, for IV use only	100 mg/mL (of sodium phenylacetate) and 100 mg/mL (of sodium benzoate)	Ammonul 10%/10%	Ucyclyd

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 April 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Medicis Pharma. Ammonul (sodium phenylacetate and sodium benzoate injection 10%/10%) prescribing information. Scottsdale, AZ; 2005 Oct.

2. Summar M, Tuchman M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr. 2001; 138: S6-10.

3. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr. 2001; 138: S30-9.

4. The Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. J Pediatr. 2001; 138: S1-5.

5. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA website. Accessed 2005 Mar 21.

6. Batshaw ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr. 2001; 138: S46-55.

7. Rezvani I. Urea cycle and hyperammonemia (arginine, citrulline, ornithine). In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. Philadelphia: Saunders; 2004:424-9.

8. Ucyclyd Pharma, Scottsdale, AZ: Personal communication.

9. Dear health care provider letter regarding important safety information concerning particular matter detected in Ammonul (sodium phenylacetate and sodium benzoate) injections 10%/10%. Scottsdale, AZ: Ucyclyd; 2008 Sep 15.

a. AHFS drug information 2008. McEvoy GK, ed. Sodium phenylacetate and sodium benzoate. Bethesda, MD: American Society of Health-System Pharmacists; 2008:2719–20.

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• Hyperammonemia

Trandolapril and Verapamil

Dosage Form: tablet, film coated, extended release
Trandolapril and Verapamil Hydrochloride Extended-Release Tablets

USE IN PREGNANCY

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, Trandolapril and Verapamil hydrochloride extended-release tablets should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

Trandolapril and Verapamil Description

Trandolapril and Verapamil hydrochloride extended-release tablets combine a slow release formulation of a calcium channel blocker, verapamil hydrochloride, and an immediate release formulation of an angiotensin converting enzyme inhibitor, trandolapril. The verapamil hydrochloride component of the formulation is designed for sustained release in the gastrointestinal tract.

Verapamil Component - Verapamil hydrochloride USP is chemically described as benzeneacetonitrile, α [3- [[2-(3,4- dimethoxyphenyl) ethyl] methylamino] propyl] -3,4-dimethoxy-α-( 1 -methylethyl) hydrochloride. Its empirical formula is C27H38N2O4 HCl and its structural formula is:

Verapamil hydrochloride USP is an almost white crystalline powder, with a molecular weight of 491.08. It is soluble in water, chloroform, and methanol. It is practically free of odor, with a bitter taste.

Trandolapril Component - Trandolapril USP is the ethyl ester prodrug of a nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, trandolaprilat. It is chemically described as (2S,3aR,7aS)-1- [(S)-N-[(S)-Carboxy-3-phenylpropyl] alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester. Its empirical formula is C24H34N2O5 and its structural formula is:

Trandolapril USP is a colorless, crystalline substance with a molecular weight of 430.54. It is soluble (>100 mg/mL) in chloroform, dichloromethane, and methanol.

Trandolapril and Verapamil hydrochloride extended-release tablets are formulated for oral administration, containing verapamil hydrochloride USP as a controlled release formulation and trandolapril USP as an immediate release formulation. The tablet strengths are Trandolapril and Verapamil hydrochloride extended-release tablets 1 mg/240 mg , Trandolapril and Verapamil hydrochloride extended-release tablets 2 mg/180 mg, Trandolapril and Verapamil hydrochloride extended-release tablets 2 mg/240 mg, and Trandolapril and Verapamil hydrochloride extended-release tablets 4 mg/240 mg. The tablets also contain the following ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, ferric oxide red, hypromellose, lactose monohydrate, povidone, sodium alginate, sodium stearyl fumarate, magnesium stearate, microcrystalline cellulose and Opadry White 03B580006 (Trandolapril and Verapamil hydrochloride extended-release tablet 1 mg/240 mg) Opadry Pink 03B540030 (Trandolapril and Verapamil hydrochloride extended-release tablet 2 mg/180 mg), Opadry Green 03B510006 (Trandolapril and Verapamil hydrochloride extended-release tablet 2 mg/240 mg) and Opadry Brown 03B565020 (Trandolapril and Verapamil hydrochloride extended-release tablet 4 mg/240 mg).

Trandolapril and Verapamil - Clinical Pharmacology

Verapamil hydrochloride and trandolapril have been used individually and in combination for the treatment of hypertension. For the four dosing strengths, the antihypertensive effect of the combination is approximately additive to the individual components.

Verapamil Component - Verapamil is a calcium channel blocker that exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. Verapamil exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia. During isometric or dynamic exercise, verapamil does not alter systolic cardiac function in patients with normal ventricular function. Verapamil does not alter total serum calcium levels.

Trandolapril Component - Trandolapril is de-esterified to its diacid metabolite, trandolaprilat. Both inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. Trandolaprilat is about 8 times more potent than trandolapril. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In controlled clinical trials, treatment with Trandolapril and Verapamil hydrochloride extended-release tablets resulted in mean increases in potassium of 0.1 mEq/L (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA).

ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effect of Trandolapril and Verapamil hydrochloride extended-release tablets remains to be elucidated.

While the mechanism through which trandolapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, trandolapril has an antihypertensive effect even in patients with low renin hypertension. Trandolapril is an effective antihypertensive in all races studied. Both black patients (usually a predominantly low renin group) and non-black patients respond to 2 to 4 mg of trandolapril.

Pharmacokinetics and Metabolism:

Trandolapril and Verapamil hydrochloride extended-release tablet

Following a single oral dose of Trandolapril and Verapamil hydrochloride extended-release tablets in healthy subjects, peak plasma concentrations are reached within 0.5-2 hours for trandolapril and within 4-15 hours for verapamil. Peak plasma concentrations of the active desmethyl metabolite of verapamil, norverapamil, are reached within 5-15 hours. Cleavage of the ester group converts trandolapril to its active diacid metabolite, trandolaprilat, which reaches peak plasma concentrations within 2-12 hours. The pharmacokinetics of trandolapril and trandolaprilat are not altered when trandolapril is administered in combination with verapamil, compared to monotherapy. The AUC and Cmax for both verapamil and norverapamil are increased when 240 mg of controlled release verapamil is administered concomitantly with 4 mg trandolapril. The increase in Cmax is 54 and 30% and the AUC is increased by 65 and 32% for verapamil and norverapamil, respectively. Administration of Trandolapril and Verapamil hydrochloride extended-release tablets 4 mg/240 mg (4 mg trandolapril and 240 mg verapamil hydrochloride extended-release) with a high-fat meal does not alter the bioavailability of trandolapril whereas verapamil peak concentrations and area under the curve (AUC) decrease 37% and 28%, respectively. Food thus decreases verapamil bioavailability and the time to peak plasma concentration for both verapamil and norverapamil are delayed by approximately 7 hours. Both optical isomers of verapamil are similarly affected.

Trandolaprilat has an effective elimination half-life of approximately 10 hours but like all ACE inhibitors, it has a prolonged terminal elimination half-life. The terminal half-life of verapamil is 6-11 hours. Steady-state plasma concentrations of the two components are achieved after about a week of once-daily dosing of Trandolapril and Verapamil hydrochloride extended-release tablets. At steady-state, plasma concentrations of verapamil and trandolaprilat are up to two-fold higher than those observed after a single oral Trandolapril and Verapamil hydrochloride extended-release tablet dose.

The pharmacokinetics of verapamil and trandolaprilat are significantly different in the elderly (≥ 65 years) than in younger subjects. The bioavailability of verapamil and norverapamil are increased by 87% and 77%, respectively, and that of trandolapril by approximately 35% in the elderly. AUCs are approximately 80% and 35% higher, respectively.

Verapamil Component

With the immediate release formulation, more than 90% of the orally administered dose is absorbed with peak plasma concentrations of verapamil observed 1 to 2 hours after dosing. A delayed rate but similar extent of absorption is observed for the sustained release formulation when compared to the immediate release formulation. Because of the rapid biotransformation of verapamil during its first pass through the portal circulation, absolute bioavailability ranges from 20% to 35%. A nonlinear correlation exists between verapamil dose and plasma concentrations.

In early dose titration with verapamil, a relationship exists between plasma concentrations of verapamil and prolongation of the PR interval. However, during chronic administration, this relationship may disappear. No relationship has been established between the plasma concentration of verapamil and reduction in blood pressure.

In healthy subjects, orally administered verapamil undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. Urinary excretion of unchanged drug is about 3% to 4% of the dose. Verapamil is approximately 90% bound to plasma proteins.

In patients with hepatic insufficiency, verapamil clearance is decreased about 30% and the elimination half-life is prolonged up to 14 to 16 hours (see PRECAUTIONS). In patients with liver dysfunction, a dosage adjustment may be required. In the elderly (≥ 65 years), verapamil clearance is reduced resulting in increases in elimination half-life.

Trandolapril Component

Following oral administration of trandolapril, the absolute bioavailability of trandolapril is approximately 10% as trandolapril and 10% as trandolaprilat. Plasma concentrations of trandolaprilat but not trandolapril increase in proportion with dose. Plasma concentrations of trandolaprilat decline in a triphasic manner. The more prolonged terminal elimination phase probably represents a small fraction of dose saturably bound to ACE.

After an oral radiolabeled dose of trandolapril, excretion of trandolapril and metabolites account for 33% of the dose in the urine and about 66% in the feces. Less than 1% of the dose is excreted in the urine as unchanged drug. Serum protein binding of trandolapril is about 80%, and is independent of concentration. Binding of trandolaprilat is concentration-dependent, varying from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating saturation of binding with increasing concentration.

Compared to normal subjects, the plasma concentrations of trandolapril and trandolaprilat are approximately 2-fold greater and renal clearance is reduced by about 85% in patients with creatinine clearance below 30 mL/min and in patients on hemodialysis. Dosage adjustment is recommended in renally impaired patients. (See DOSAGE AND ADMINISTRATION).

Following oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were, respectively, 9-fold and 2-fold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be considered in patients with hepatic insufficiency. (see DOSAGE AND ADMINISTRATION).

Pharmacodynamics:

Trandolapril and Verapamil hydrochloride extended-release tablet

Verapamil does not interfere with ACE inhibition by trandolapril. Trandolapril does not alter the effect of verapamil on intra-cardiac conduction.

Verapamil Component

Verapamil dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of verapamil in vasospastic (Prinzmetal’s or variant) as well as unstable angina at rest.

Verapamil regularly reduces the total systemic resistance (afterload) by dilating peripheral arterioles. By decreasing the influx of calcium, verapamil prolongs the effective refractory period within the AV node and slows AV conduction in a rate- related manner.

Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, verapamil may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects (see WARNINGS).

Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. Verapamil may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see WARNINGS).

Hemodynamics and Myocardial Metabolism:

Verapamil reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with idiopathic hypertrophic subaortic stenosis (IHSS) and those with coronary heart disease has also been observed with verapamil therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil is countered by a reduction of afterload and cardiac index is usually not reduced. However, in patients with severe left ventricular dysfunction (e.g., pulmonary wedge pressure about 20 mmHg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardio-depressant drugs, deterioration of ventricular function may occur (see DRUG INTERACTIONS).

Pulmonary Function:

Verapamil does not induce bronchoconstriction and hence, does not impair ventilatory function.

Trandolapril Component

After a single 2 mg dose of trandolapril, inhibition of ACE activity reaches a maximum (70-85%) at 4 hours with about 1% decline at 24 hours. Eight days after dosing, ACE inhibition is still 40%.

Four placebo-controlled dose response studies were conducted using once daily oral dosing of trandolapril in doses from 0.25 to 16 mg per day in 827 black and non-black patients with mild to moderate hypertension. The minimal effective once daily dose was 1.0 mg in non-black patients and 2.0 mg in black patients. Further decreases in trough supine diastolic blood pressure were obtained in non-black patients with higher doses, and no further response was seen with doses above 4 mg (up to 16 mg). The antihypertensive effect diminished somewhat at the end of the dosing interval.

During chronic therapy, the maximum reduction in blood pressure with any dose is achieved within one week. Following 6 weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once daily doses of 2 to 4 mg lowered supine or standing systolic/diastolic blood pressure 24 hours after dosing by an average 7-10/4-5 mmHg below placebo responses in non-black patients. Once daily doses of 2 to 4 mg lowered blood pressures 4-6/3-4 mmHg below placebo responses in black patients.

Clinical Studies

In controlled clinical trials, once daily doses of Trandolapril and Verapamil hydrochloride extended-release tablets, Trandolapril and Verapamil hydrochloride extended-release tablets 4 mg/240 mg or Trandolapril and Verapamil hydrochloride extended-release tablets 2 mg/180 mg, decreased placebo-corrected seated pressure (systolic/diastolic) 24 hours after dosing by about 7-12/6-8 mmHg. Each of the components of Trandolapril and Verapamil hydrochloride extended-release tablet added to the antihypertensive effect. Treatment effects were consistent across age groups (<65, ≥ 65 years), and gender (male, female).

Blood pressure reductions were significantly greater for the Trandolapril and Verapamil hydrochloride extended-release tablet 4 mg and 240 mg combination than for either of the components used alone.

The antihypertensive effects of Trandolapril and Verapamil hydrochloride extended-release tablets have continued during therapy for at least 1 year.

Indications and Usage for Trandolapril and Verapamil

Trandolapril and Verapamil hydrochloride extended-release tablets are indicated for the treatment of hypertension.

This fixed combination drug is not indicated for the initial therapy of hypertension (see DOSAGE and ADMINISTRATION).

In using Trandolapril and Verapamil hydrochloride extended-release tablets, consideration should be given to the fact that an angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that trandolapril does not have similar risk (see WARNINGS: Neutropenia/Agranulocytosis).

Contraindications

Trandolapril and Verapamil hydrochloride extended-release tablets are contraindicated in patients who are hypersensitive to any ACE inhibitor or verapamil.

Because of the verapamil component, Trandolapril and Verapamil hydrochloride extended-release tablet is contraindicated in:

1. Severe left ventricular dysfunction (see WARNINGS).


2. Hypotension (systolic pressure less than 90 mmHg) or cardiogenic shock.


3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker).


4. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).


5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see WARNINGS).

Because of the trandolapril component, Trandolapril and Verapamil hydrochloride extended-release tablets are contraindicated in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor.

Warnings

Heart Failure:

Verapamil Component

Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%, pulmonary wedge pressure above 20 mmHg, or severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta adrenergic blocker (see DRUG INTERACTIONS). Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (Note interactions with digoxin under: PRECAUTIONS).

Trandolapril Component

Trandolapril, as an ACE inhibitor, may cause excessive hypotension in patients with congestive heart failure (see WARNINGS, Hypotension).

Hypotension:

Verapamil Component

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension.

Trandolapril Component

Trandolapril can cause symptomatic hypotension. Like other ACE inhibitors, trandolapril has only rarely been associated with symptomatic hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who are salt- or volume-depleted as a result of prolonged treatment with diuretics, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating treatment with trandolapril (see PRECAUTIONS, Drug Interactions, and ADVERSE REACTIONS).

In controlled studies, hypotension was observed in 0.6% of patients receiving any combination of Trandolapril and Verapamil hydrochloride extended-release tablets.

In patients with concomitant congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia, and, rarely, with acute renal failure and death (see DOSAGE AND ADMINISTRATION).

If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, normal saline may be administered intravenously. A transient hypotensive response is not a contraindication to further doses; however, lower doses of verapamil hydrochloride extended-release tablets and/or trandolapril or reduced concomitant diuretic therapy should be considered.

Elevated Liver Enzymes/Hepatic Failure:

Verapamil Component

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT, and alkaline phosphatase.

Trandolapril Component

ACE inhibitors rarely have been associated with a syndrome of cholestatic jaundice, fulminant hepatic necrosis, and death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Liver abnormalities were noted in 3.2% of patients taking any of several combinations of Trandolapril and Verapamil doses. Periodic monitoring of liver function in patients taking Trandolapril and Verapamil hydrochloride extended-release tablets is therefore prudent.

Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine Syndromes):

Verapamil Component

Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS).

Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

Atrioventricular Block:

Verapamil Component

The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phases of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil hydrochloride and institution of appropriate therapy depending upon the clinical situation.

Patients with Hypertrophic Cardiomyopathy (IHSS):

Verapamil Component

In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mmHg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.

Anaphylactoid and Possibly Related Reactions:

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including trandolapril may be subject to a variety of adverse reactions, some of them serious.

Angioedema:

Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors including trandolapril. Symptoms suggestive of angioedema or facial edema occurred in 0.13% of trandolapril-treated patients. Two of the four cases were life-threatening and resolved without treatment or with medication (corticosteroids). Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with Trandolapril and Verapamil hydrochloride extended-release tablets should be discontinued immediately, the patient treated in accordance with accepted medical care and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, emergency therapy, including but not limited to subcutaneous epinephrine solution 1:1,000 (0.3 to 0.5 mL) should be promptly administered. (seePRECAUTIONS: Information for Patientsand ADVERSE REACTIONS).

Anaphylactoid Reactions During Desensitization:

Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered.

Anaphylactoid Reactions During Membrane Exposure:

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

Neutropenia/Agranulocytosis:

Trandolapril Component

Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of trandolapril or Trandolapril and Verapamil hydrochloride extended-release tablets are insufficient to show that trandolapril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen-vascular disease and/or renal disease should be considered.

Fetal/Neonatal Morbidity and Mortality:

Trandolapril Component

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.

These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of Trandolapril and Verapamil hydrochloride extended-release tablets as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, Trandolapril and Verapamil hydrochloride extended-release tablets should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Trandolapril in doses of 0.8 mg/kg/day in rabbits, 100.0 mg/kg/day in rats, and 25 mg/kg/day in cynomolgus monkeys (10, 1250, and 312 times the maximum projected human dose, respectively, assuming a 50 kg woman) did not produce teratogenic effects.

Precautions

Use in Patients with Impaired Hepatic Function:

Trandolapril and Verapamil hydrochloride extended-release tablets have not been evaluated in subjects with impaired hepatic function.

Verapamil Component

Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients.

Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE) should be carried out.

Trandolapril Component

Trandolapril and trandolaprilat concentrations increase in patients with impaired liver function.

Use in Patients with Impaired Renal Function:

Trandolapril and Verapamil hydrochloride extended-release tablets have not been evaluated in patients with impaired renal function.

Verapamil Component

About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by hemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see OVERDOSAGE).

Trandolapril Component

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including trandolapril, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when ACE inhibitors have been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or the ACE inhibitor may be required.

Evaluation of hypertensive patients should always include assessment of renal function (see DOSAGE AND ADMINISTRATION ).

Use in Patients with Attenuated (Decreased) Neuromuscular Transmission:

Verapamil Component

It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission. (See PRECAUTIONS - Surgery/Anesthesia.)

Hyperkalemia and potassium-sparing diuretics:

Trandolapril Component:

In clinical trials, hyperkalemia (serum potassium> 6.00 mEq/L) occurred in approximately 0.4 percent of hypertensive patients receiving trandolapril and in 0.8% of patients receiving a dose of trandolapril (0.5-8 mg) in combination with a dose of verapamil hydrochloride extended-release tablets (120-240 mg). In most cases, elevated serum potassium levels were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with trandolapril (see PRECAUTIONS, Drug Interactions).

Cough:

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. In controlled trials of trandolapril, cough was present in 2% of trandolapril patients and 0% of patients given placebo. There was no evidence of a relationship to dose.

Surgery/anesthesia:

Trandolapril Component

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, trandolapril will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. (See PRECAUTIONS — Use in Patients with Attenuated (Decreased) Neuromuscular Transmission.)

Drug Interactions

Digitalis:

Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. Chronic verapamil treatment can increase serum digoxin levels by 50 to 75% during the first week of therapy, and this can result in digoxin toxicity. In patients with hepatic cirrhosis, the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance digoxin doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over- or under-digitalization. Whenever overdigitalization is suspected, the daily dose of digoxin should be reduced or temporarily discontinued. Upon discontinuation of any verapamil-containing regime including Trandolapril and Verapamil hydrochloride extended-release tablets, the patient should be reassessed to avoid underdigitalization. Neither trandolapril nor its metabolites have been found to interact with digoxin.

Lithium:

Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. Trandolapril and Verapamil hydrochloride extended-release tablets and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Clarithromycin:

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent clarithromycin.

Erythromycin:

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent erythromycin ethylsuccinate.

Cimetidine:

The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. Neither trandolapril nor its metabolites have been found to interact with cimetidine.

Beta Blockers:

Verapamil Component

Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The use of verapamil in combination with a beta-blocker should be used only with caution, and close monitoring.

Asymptomatic bradycardia (36 beats/mm) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.

Antiarrhythmic Agents:

Verapamil Component

Disopyramide

Data on possible interactions between verapamil and disopyramide phosphate are not available. Therefore, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.

Flecainide

A study of healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.

Quinidine

In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided.

The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.

Nitrates

Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.

Other:

Verapamil Component

Carbamazepine

Rifampin

Phenobarbital

Cyclosporin

Theophylline

Inhalation Anesthetics

Neuromuscular Blocking Agents

Concomitant diuretic therapy:

Trandolapril Component

As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Trandolapril and Verapamil hydrochloride extended-release tablets. The possibility of exacerbation of hypotensive effects with Trandolapril and Verapamil hydrochloride extended-release tablets may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with Trandolapril and Verapamil hydrochloride extended-release tablets. If it is not possible to discontinue the diuretic, the starting dose of Trandolapril and Verapamil hydrochloride extended-release tablets should be reduced (see DOSAGE AND ADMINISTRATION).

Fluorouracil 25 mg / ml Injection (Hospira UK Ltd)

1. Name Of The Medicinal Product

Fluorouracil 25mg/ml Injection.

2. Qualitative And Quantitative Composition

Each 1 ml contains 25mg of fluorouracil.

Presentations

250mg / 10ml

500mg / 20ml

2.5g / 100ml

Amount fluorouracil present (as sodium salt) per vial

250mg

500mg

2.5g

For excipients see 6.1

3. Pharmaceutical Form

Solution for injection.

Clear, colourless or slightly yellow solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Fluorouracil may be used alone, or in combination, for the management of common malignancies particularly cancer of the colon and breast.

4.2 Posology And Method Of Administration

Adults:

Selection of an appropriate dose and treatment regime depends upon the condition of the patient, the type of carcinoma being treated and whether fluorouracil is to be administered alone or in combination with other therapy. Initial treatment should be given in hospital and the total daily dose should not exceed 0.8 - 1 gram. It is customary to calculate the dose in accordance with the patient's actual bodyweight unless there is obesity, oedema or some form of abnormal fluid retention such as ascites. Ideal weight is used as the basis for calculation in such cases. The initial dose should be reduced by one-third to one half in patients with any of the following:

1. Cachexia.

2. Major surgery within preceding 30 days.

3. Reduced bone marrow function.

4. Impaired hepatic or renal function.

Initial Treatment:

This may be in the form of an infusion or an injection, the former usually being preferred because of lesser toxicity.

Intravenous infusion:

15mg/kg bodyweight but not more than 1g per infusion, diluted in 300 - 500ml of 5% glucose or 0.9% NaCl injection and given over 4 hours. Alternatively the daily dose may be infused over 30 - 60 minutes or may be given as a continuous infusion over 24 hours. The infusion may be repeated daily until there is evidence of toxicity or a total dose of 12 - 15g has been reached.

Intravenous Injection:

12mg/kg bodyweight may be given daily for 3 days and then, if there is no evidence of toxicity, 6mg/kg on alternate days for 3 further doses.

An alternative regimen is 15mg/kg as a single intravenous injection once a week throughout the course.

Intra-arterial infusion:

5/7.5mg/kg bodyweight daily may be given by 24 hour continuous intra-arterial infusion.

Maintenance therapy:

An initial intensive course may be followed by maintenance therapy providing there are no significant toxic effects.

In all instances, toxic side effects must disappear before maintenance therapy is started.

The initial course of fluorouracil can be repeated after an interval of 4 to 6 weeks from the last dose or, alternatively, treatment can be continued with intravenous injections of 5-15mg/kg bodyweight at weekly intervals.

This sequence constitutes a course of therapy. Some patients have received up to 30g at a maximum rate of 1 g daily.

A more recent alternative method is to give 15mg/kg IV once a week throughout the course of treatment. This obviates the need for an initial period of daily administration.

In combination with irradiation

Irradiation combined with fluorouracil has been found to be useful in the treatment of certain types of metastatic lesions in the lungs and for the relief of pain caused by recurrent, inoperable growth. The standard dose of fluorouracil should be used.

Children:

No recommendations are made regarding the use of fluorouracil in children.

Elderly:

Fluorouracil should be used in the elderly with similar considerations as in younger adults. notwithstanding that incidence of concomitant medical illness is higher in the former group.

4.3 Contraindications

Fluorouracil is contraindicated in seriously debilitated patients or those with bone marrow depression after radiotherapy or treatment with other antineoplastic agents.

Fluorouracil is strictly contraindicated in pregnant or breast feeding women.

Fluorouracil should not be used in the management of non-malignant disease.

4.4 Special Warnings And Precautions For Use

It is recommended that fluorouracil be given only by, or under the strict supervision of , a qualified physician who is conversant with the use of potent antimetabolites.

All patients should be admitted to hospital for initial treatment.

Adequate treatment with fluorouracil is usually followed by leucopenia, the lowest white blood cell (W.B.C.) count commonly being observed between the 7th and 14th day of the first course, but occasionally being delayed for as long as 20 days. The count usually returns to normal by the 30th day. Daily monitoring of platelet and W.B.C. Count is recommended and treatment should be stopped if platelets fall 100,000 per mm³ or the W.B.C. count falls below 3,500 per mm³. If the total count is less than 2000 per mm³, and especially if there is granulocytopenia, it is recommended that the patient be placed in protective isolation in the hospital and treated with appropriate measures to prevent systemic infection.

Treatment should also be stopped at the first sign of oral ulceration or if there is evidence of gastrointestinal side effects such as stomatitis, diarrhoea or bleeding from the gastrointestinal tract or haemorrhage at any site. The ratio between effective and toxic dose is small and therapeutic response is unlikely without some degree of toxicity. Care must be taken therefore, in the selection of patients and adjustment of dosage.

Fluorouracil should be used with caution in patients with reduced renal or liver function or jaundice. Isolated cases of angina, ECG abnormalities and rarely, myocardial infarction have been reported following administration of Fluorouracil. Caution should therefore be exercised in treating patients who experience chest pain during courses of treatment, or patients with a history of heart disease.

There have been reports of increased toxicity in patients who have reduced activity/deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Various agents have been reported to biochemically modulate the antitumour efficacy or toxicity of Fluorouracil, common drugs include Methotrexate, Metronidazole, Leucovorin as well as Allopurinol and Cimetidine which can affect the availability of the active drug.

Marked elevations of prothrombin time and INR have been reported in a few patients stabilised on warfarin therapy following initiation of fluorouracil regimes.

A clinically significant interaction between the antiviral sorivudine and fluorouracil prodrugs, resulting from inhibition of dihydropyrimidine dehydrogenase by sorivudine or chemically related analogues. Caution should be taken when using Fluorouracil in conjunction with medications which may affect dihydropyrimidine dehydrogenase activity.

4.6 Pregnancy And Lactation

Fluorouracil is strictly contraindicated in pregnant or breast feeding women.

4.7 Effects On Ability To Drive And Use Machines

Not applicable

4.8 Undesirable Effects

Diarrhoea, nausea and vomiting are observed quite commonly during therapy and may be treated symptomatically. An anti-emetic may be given for nausea and vomiting.

Alopecia may be seen in a substantial number of cases particularly in females, but is reversible. Other side effects Include dermatitis, pigmentation, changes in the nails , ataxia and fever.

There have been reports of chest pain, tachycardia ,breathlessness and ECG changes after administration of fluorouracil. Special attention is therefore advisable in treating patients with a history of heart disease or those who develop chest pain during treatment.

Systemic fluorouracil treatment has been associated with various types of ocular toxicity. Peripheral neuropathy may occur.

A transient reversible cerebellar syndrome has been reported following fluorouracil treatment. Rarely, a reversible confusional state may occur. Cases of leucoencephalopathy have also been reported.

Additionally several other reports have been noted including:

Incidences of excessive lacrimation, dacryostenosis, visual changes and photophobia.

Palmar-plantar erythrodysesthesia syndrome has been reported as an unusual complication of high dose bolus or protracted continuous therapy for 5-fluorouracil.

4.9 Overdose

The symptoms and signs of overdosage are qualitatively similar to the adverse reactions and should be managed as indicated under "Special Warnings and Precautions and " Undesirable Effects".

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Fluorouracil is an analogue of uracil, a component of ribonucleic acid. The drug is believed to function as an antimetabolite. After intracellular conversion to the active deoxynucleotide, it interferes with the synthesis of DNA by blocking the conversion of deoxyuridylic acid to thymidylic acid by the cellular enzyme thymidylate synthetase. Fluorouracil may also interfere with RNA synthesis.

5.2 Pharmacokinetic Properties

After intravenous administration, fluorouracil is distributed through the body water and disappears from the blood within 3 hours. It is preferentially taken up by actively dividing tissues and tumours after conversion to its nucleotide. Fluorouracil readily enters the C.S.F. and brain tissue.

Following I.V. administration, the plasma elimination half-life averages about 16 minutes and is dose dependent. Following a single I.V. dose of Fluorouracil approximately 15% of the dose is excreted unchanged in the urine within 6 hours; over 90% of this is excreted in the first hour. The remainder is mostly metabolised in the liver by the usual body mechanisms for uracil.

5.3 Preclinical Safety Data

Preclinical information has not been included because the toxicity profile of fluorouracil has been established after many years of clinical use. Please refer to section 4.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium hydroxide

Water for Injections.

6.2 Incompatibilities

5-Fluorouracil is incompatible with Carboplatin, Cisplatin, Cytarabine. Diazepam, Doxorubicin, other Anthracyclines and possibly Methotrexate.

Formulated solutions are alkaline and it is recommended that admixture with acidic drugs or preparations should be avoided.

6.3 Shelf Life

Before use: 24 months

In use: Chemical and physical in-use stability has been demonstrated for 5 days at 20-21°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2-8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Do not store above 25°C. Do not refrigerate or freeze. Keep container in the outer carton.

The pH of fluorouracil injection is 8.9 and the drug has maximal stability over the pH range 8.6 to 9.0.

If a precipitate has formed as a result of exposure to low temperatures, redissolve by heating to 60°C accompanied by vigorous shaking. Allow to cool to body temperature prior to use.

The product should be discarded if it appears brown or dark yellow in solution.

6.5 Nature And Contents Of Container

Type I Conventional Clear Glass Vials with rubber closures.

Type I Clear Onco-Tain^® Vials with rubber closures.

250 mg/10ml: Pack Size 5.

500 mg/20ml: Pack Size 10.

2.5 g/100 ml: Pack Size Singles and 10's.

Not all presentations or pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Cytotoxic Handling Guidelines

Should be administered only by or under the direct supervision of a qualified physician who is experienced in the use of cancer chemotherapeutic agents.

Fluorouracil Injection should only be prepared for administration by professionals who have been trained in the safe use of the preparation. Preparation should only be carried out in an aseptic cabinet or suite dedicated for the assembly of cytotoxics.

In the event of spillage, operators should put on gloves, face mask, eye protection and disposable apron and mop up the spilled material with a absorbent material kept in the area for that purpose. The area should then be cleaned and all contaminated material transferred to a cytotoxic spillage bag or bin and sealed for incineration.

Contamination

Fluorouracil is an irritant, contact with skin and mucous membranes should be avoided.

In the event of contact with the skin or eyes, the affected area should be washed with copious amounts of water or normal saline. A bland cream may be used to treat the transient stinging of the skin. Medical advice should be sought if the eyes are affected or if the preparation is inhaled or ingested.

Please refer to company for COSHH hazard datasheets.

Preparation Guidelines

a) Chemotherapeutic agents should be prepared for administration only by professionals who have been trained in the safe use of the preparation.

b) Operations such as reconstitution of powder and transfer to syringes should be carried out only under aseptic conditions in a suite or cabinet dedicated for the assembly of cytotoxics.

c) The personnel carrying out these procedures should be adequately protected with clothing, gloves and eye shield.

d) Pregnant personnel are advised not to handle chemotherapeutic agents.

Disposal

Syringes, Onco•Vials^® and adaptors containing remaining solution, absorbent materials, and any other contaminated material should be placed in a thick plastic bag or other impervious container and incinerated at 700°C.

Diluents

Fluorouracil Injection may be diluted with Glucose 5% Injection or Sodium Chloride 0.9% Injection or Water for Injections immediately before parenteral use.

7. Marketing Authorisation Holder

Hospira UK Limited

Queensway,

Royal Leamington Spa,

Warwickshire CV31 3RW

United Kingdom.

8. Marketing Authorisation Number(S)

PL 04515/0024

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of First Authorisation: 20 August 1985

Renewal of Authorisation: 19 July 2004

10. Date Of Revision Of The Text

12 August 2011