Verelan PM

verapamil hydrochloride

Dosage Form: capsule, extended release
FULL PRESCRIBING INFORMATION

Indications and Usage for Verelan PM

Verelan® PM (verapamil hydrochloride extended-release capsules) for oral use is indicated for the management of essential hypertension.

Verelan PM Dosage and Administration

THE CONTENTS OF THE Verelan PM CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. Verelan PM CAPSULES ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO APPLESAUCE.

Essential Hypertension

Administer Verelan PM once daily at bedtime. Clinical trials studied doses of 100 mg, 200 mg, 300 mg and 400 mg. The usual daily dose of extended-release Verelan PM in clinical trials has been 200 mg given by mouth once daily at bedtime. In rare instances, initial doses of 100 mg a day may be warranted in patients who have an increased response to verapamil [e.g. patients with impaired renal function, impaired hepatic function, elderly, low-weight patients, etc. (see Use in Specific Populations (8.5, 8.6, 8.7))]. Base upward titration on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of Verelan PM are evident within the first week of therapy.

If an adequate response is not obtained with 200 mg of Verelan PM, the dose may be titrated upward in the following manner:

a) 300 mg each evening b) 400 mg each evening (2 × 200 mg)

When Verelan PM is administered at bedtime, office evaluation of blood pressure during morning and early afternoon hours is essentially a measure of peak effect. The usual evaluation of trough effect, which sometimes might be needed to evaluate the appropriateness of any given dose of Verelan PM, would be just prior to bedtime.

Sprinkling the Capsule Contents on Food

Verelan PM capsules may also be administered by carefully opening the capsule and sprinkling the pellets onto one tablespoonful of applesauce. Swallow the applesauce immediately without chewing and follow with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot, and it should be soft enough to be swallowed without chewing. Use any pellet/applesauce mixture immediately and do not store for future use. Absorption of the pellets sprinkled onto other foods has not been tested. This method of administration may be beneficial for patients who have difficulty swallowing whole capsules. Subdividing the contents of a Verelan PM capsule is not recommended.

Dosage Forms and Strengths

Extended-release capsules controlled onset: 100 mg, 200 mg, 300 mg.

100 mg: white opaque cap imprinted SCHWARZ/4085 and amethyst body imprinted 100 mg.

200 mg: amethyst opaque cap imprinted SCHWARZ/4086 and amethyst body imprinted 200 mg.

300 mg: lavender opaque cap imprinted SCHWARZ/4087 and amethyst body imprinted 300 mg.

Contraindications

Verapamil is contraindicated in:

• Severe left ventricular dysfunction [see Warnings and Precautions (5.1)].


• Hypotension (less than 90 mm Hg systolic pressure) or cardiogenic shock.


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


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


• Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) [see Warnings and Precautions (5.4)].

Warnings and Precautions

Heart Failure

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 previous clinical experience with 4,954 patients primarily with immediate-release verapamil, 87 (1.8%) developed congestive heart failure or pulmonary edema. Avoid verapamil in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30% or moderate to 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 (7.4)]. Control patients with milder ventricular dysfunction, if possible, with optimum doses of digitalis and/or diuretics before verapamil treatment is started [see Drug Interactions (7.5)].

Hypotension

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. In hypertensive patients, decreases in blood pressure below normal are unusual. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials of other verapamil formulations was 2.5% [see Adverse Reactions (6.1)]. In clinical studies of Verelan PM, 1.7% of the patients developed significant hypotension. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.

Elevated Liver Enzymes

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. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

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

Some patients with paroxysmal and/or chronic atrial flutter or atrial fibrillation 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 (4)]. Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

Atrioventricular Block

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 phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed in previous verapamil clinical trials [see Adverse Reactions (6.1)].

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 and institution of appropriate therapy depending upon the clinical situation.

Patients with Hypertrophic Cardiomyopathy

In 120 patients with hypertrophic cardiomyopathy, idiopathic hypertrophic subaortic stenosis (IHSS) (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 history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mm Hg) pulmonary capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine [see Drug Interactions (7.10)] preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2% [see Adverse Reactions (6)]. 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.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. See Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5) for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil.

The following reactions (Table 1) to orally administered Verelan PM occurred at rates of 2.0% or greater or occurred at lower rates but appeared to be drug-related in clinical trials in hypertension.

Table 1. Adverse Events Occurring in ≥ 2% of Verelan PM Patients in Placebo-Controlled Clinical Trials

	All Doses Studied N = 297 %	Placebo N = 116 %		All Doses Studied N = 297 %	Placebo N = 116%
* Infection, primarily upper respiratory infection (URI) and unrelated to study medication. Constipation was typically mild and easily manageable. At the usual once-daily dose of 200 mg, the observed incidence of constipation was 3.9%.
Headache	12.1	11.2	Dyspepsia	2.7	1.7
Infection	12.1*	6.9	Rhinitis	2.7	2.6
Constipation	8.8*	0.9	Diarrhea	2.4	1.7
Flu Syndrome	3.7	2.6	Pain	2.4	1.7
Peripheral edema	3.7	0.9	Edema	1.7	0.0
Dizziness	3.0	0.9	Nausea	1.7	0.0
Pharyngitis	3.0	2.6	Accidental Injury	1.5	0.0
Sinusitis	3.0	2.6

In previous experience with other formulations of verapamil (N=4,954) the following reactions (Table 2) have occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug related in clinical trials in 4,954 patients.

Table 2. Adverse Events Occurring in >1% (or lower rates and clearly drug related) of Patients with Other Verapamil Formulations

Constipation	7.3%	Fatigue	1.7%
Dizziness	3.3%	Bradycardia (HR<50/min)	1.4%
Nausea	2.7%	Rash	1.2%
Hypotension	2.5%	AV block (total 1º, 2º, 3º)	1.2%
Headache	2.2%	AV block (2º and 3º)	0.8%
Edema	1.9%	Flushing	0.6%
CHF/Pulmonary Edema	1.8%

In clinical trials related to the control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rate below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.

Open Trials / Postmarketing Experience

The following reactions, reported with orally administered verapamil in 2.0% or less of patients, occurred under conditions (open verapamil trials, postmarketing experience [reactions added since the initial US approval of Verelan PM in 1998 are marked with an asterisk]) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular: angina pectoris, atrioventricular dissociation, ECG Abnormal*, chest pain, claudication, hypertension*, myocardial infarction, palpitations, purpura (vasculitis), syncope.

Digestive System: diarrhea, dry mouth, elevated liver enzymes* [see Warnings and Precautions (5.3)], gastrointestinal distress, gingival hyperplasia.

Hemic and Lymphatic: ecchymosis or bruising.

Nervous System: cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence.

Respiratory: dyspnea.

Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme.

Special Senses: blurred vision, tinnitus.

Urogenital: gynecomastia, galactorrhea/hyperprolactinemia, impotence, increased urination, spotty menstruation.

Other: allergy aggravated, asthenia*.

Treatment of Acute Cardiovascular Adverse Reactions

The frequency of cardiovascular adverse reactions that require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, apply the appropriate emergency measures immediately; e.g., intravenously administered norepinephrine bitartrate, atropine sulfate, isoproterenol HCl (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy, use alpha-adrenergic agents (phenylephrine HCl, metaraminol bitartrate, or methoxamine HCl) to maintain blood pressure, and isoproterenol and avoid norepinephrine. If further support is necessary, inotropic agents (dopamine HCl or dobutamine HCl) may be administered. Actual treatment and dosage depends on the severity of the clinical situation and the judgment and experience of the treating physician.

Drug Interactions

CYP3A4 Inhibitors and Inducers

In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, and CYP2C. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics. Inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of verapamil.

HMG-CoA Reductase Inhibitors

The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis.

Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs.

Grapefruit Juice

Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice given to nine healthy volunteers increased S- and R- verapamil AUC0-12 by 36% and 28%, respectively. Steady state Cmax and Cmin of S-verapamil increased by 57% and 16.7%, respectively with grapefruit juice compared to control. Similarly, Cmax and Cmin of R-verapamil increased by 40% and 13%, respectively. Grapefruit juice did not affect half-life, nor was there a significant change in AUC0-12 ratio R/S compared to control. Grapefruit juice did not cause a significant difference in the pharmacokinetics of norverapamil. This increase in verapamil plasma concentration is not expected to have any clinical consequences.

Beta Blockers

Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The combination of extended-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excess bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension. For hypertensive patients, the risk of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring. Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.

A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together.

Digitalis

Consider reducing digoxin dose when verapamil and digoxin are to be given together. Monitor digoxin level periodically during therapy. Chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin pharmacokinetics is magnified. Verapamil may reduce total body clearance and extra-renal clearance of digoxin by 27% and 29%, respectively. If digoxin toxicity is suspected, suspend or discontinue digoxin therapy.

In previous clinical trials with other verapamil formulations related to the control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients, and asymptomatic hypotension occurred in 5% of patients.

Alcohol

Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol.

Clonidine

Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine.

Telithromycin

Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics.

Antineoplastic Agents

Verapamil can increase doxorubicin levels. The absorption of verapamil can be reduced by the cyclophosphamide, oncovin, procarbazine, prednisone (COPP) and the vindesine, adriamycin, cisplatin (VAC) cytotoxic drug regimens. Concomitant administration of R verapamil can decrease the clearance of paclitaxel.

Quinidine

In a small number of patients with hypertrophic cardiomyopathy, concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, avoid combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy.

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.

Aspirin

In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone.

Antihypertensive agents

Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood pressure. Monitor patients receiving these combinations appropriately. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.

Disopyramide

Until data on possible interactions between verapamil and disopyramide are obtained, do not administer disopyramide within 48 hours before or 24 hours after verapamil administration.

Flecainide

A study in 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.

Carbamazepine

Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.

Cyclosporine

Verapamil therapy may increase serum levels of cyclosporine.

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. However, the addition of verapamil has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs must be monitored carefully.

Inhalation Anesthetics

Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, titrate slowly to avoid excessive cardiovascular depression.

Neuromuscular Blocking Agents

Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

Phenobarbital

Phenobarbital therapy may increase verapamil clearance.

Rifampin

Therapy with rifampin may markedly reduce oral verapamil bioavailability.

Theophylline

Verapamil may inhibit the clearance and increase the plasma levels of theophylline.

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.

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.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral doses up to 1.9 (15 mg/kg/day) and 7.5 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Verapamil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.

Labor and Delivery

It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Nursing Mothers

Verapamil is excreted into human milk. In case studies where verapamil concentration in human milk was calculated, the nursing infant doses ranged from less than 0.01% to 0.1% of the mother's verapamil dose. Consider possible infant exposure when verapamil is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Verelan PM were not adequate to determine if subjects aged 65 or over respond differently from younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients; however, greater sensitivity to Verelan PM by some older individuals cannot be ruled out.

Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly [see Clinical Pharmacology (12.3)].

Verapamil is highly metabolized by the liver, and about 70% of the administered dose is excreted as metabolites in the urine. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered [see Use in Specific Populations (8.6, 8.7)]. In general, lower initial doses of Verelan PM may be warranted in the elderly [see Dosage and Administration (2.1)].

Impaired Hepatic Function

Since verapamil is highly metabolized by the liver, consider lower dosages and closely monitor responses to the drug in 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. Monitor for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects [see Overdosage (10)] .

Impaired Renal Function

About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data are available, monitor these patients for abnormal prolongation of the PR interval or other signs of overdosage [see Overdosage (10)].

Attenuated (decreased) Neuromuscular Transmission

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 and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

Overdosage

There is no specific antidote for verapamil overdosage; treatment is supportive. Delayed pharmacodynamic consequences may occur with sustained-release formulations, and observe patients for at least 48 hours, preferably under continuous hospital care. Reported effects include hypotension, bradycardia, cardiac conduction defects, arrhythmias, hyperglycemia, and decreased mental status. In addition, there have been literature reports of noncardiogenic pulmonary edema in patients taking large overdoses of verapamil (up to approximately 9 g).

In acute overdosage, consider gastrointestinal decontamination with cathartics and whole bowel irrigation. Calcium, inotropes (i.e., isoproterenol HCl, dopamine HCl, and glucagon), atropine sulfate, vasopressors (i.e., norepinephrine, and epinephrine), and cardiac pacing have been used with variable results to reverse hypotension and myocardial depression. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride.

Calcium chloride is preferred to calcium gluconate since it provides 3 times more calcium per volume. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. Verapamil cannot be removed by hemodialysis.

Verelan PM Description

Verelan PM (verapamil hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Verelan PM is available for oral administration as a 100 mg hard gelatin capsule (white opaque cap/amethyst body), a 200 mg hard gelatin capsule (amethyst opaque cap/amethyst body), and as a 300 mg hard gelatin capsule (lavender opaque cap/amethyst body). Verapamil is administered as a racemic mixture of the R and S enantiomers.

The structural formulae of the verapamil HCl enantiomers are:

C27H38N2O4•HCl M.W.=491.07

Chemical name: Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]- 3,4-dimethoxy-α-(1-methylethyl)-, monohydrochloride,(±)-.

Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform and methanol. Verapamil HCl is not structurally related to other cardioactive drugs.

In addition to verapamil HCl the Verelan PM capsule contains the following inactive ingredients: D&C Red #28, FD & C Blue #1, FD&C red #40, fumaric acid, gelatin, povidone, shellac, silicon dioxide, sodium lauryl sulfate, starch, sugar spheres, talc, and titanium dioxide.

System Components and Performance: Verelan PM uses the proprietary CODAS® (Chronotherapeutic Oral Drug Absorption System) technology, which is designed for bedtime dosing, incorporating a 4 to 5-hour delay in drug delivery. The controlled-onset delivery system results in a maximum plasma concentration (Cmax) of verapamil in the morning hours. These pellet filled capsules provide for extended-release of the drug in the gastrointestinal tract. The Verelan PM formulation has been designed to initiate the release of verapamil 4-5 hours after ingestion. This delay is introduced by the level of non-enteric release-controlling polymer applied to drug loaded beads. The release-controlling polymer is a combination of water soluble and water insoluble polymers. As water from the gastrointestinal tract comes into contact with the polymer coated beads, the water soluble polymer slowly dissolves and the drug diffuses through the resulting pores in the coating. The water insoluble polymer continues to act as a barrier, maintaining the controlled release of the drug. The rate of release is essentially independent of pH, posture and food. Multiparticulate systems such as Verelan PM have been shown to be independent of gastrointestinal motility.

Verelan PM - Clinical Pharmacology

Mechanism of Action

Verapamil is a calcium ion influx inhibitor (L-type calcium channel blocker or calcium channel antagonist). Verapamil exerts its pharmacologic effects by selectively inhibiting the transmembrane influx of ionic calcium into arterial smooth muscle as well as in conductile and contractile myocardial cells without altering serum calcium concentrations. Verapamil binding is voltage-dependent with affinity increasing as the vascular smooth muscle membrane potential is reduced. In addition, verapamil binding is frequency dependent and apparent affinity increases with increased frequency of depolarizing stimulus.

The L-type calcium channel is an oligomeric structure consisting of five putative subunits designated alpha-1, alpha-2, beta, tau, and epsilon. Biochemical evidence points to separate binding sites for 1,4-dihydropyridines, phenylalkylamines, and the benzothiazepines (all located on the alpha-1 subunit). Although they share a similar mechanism of action, calcium channel blockers represent three heterogeneous categories of drugs with differing vascular-cardiac selectivity ratios.

Pharmacodynamics

Essential Hypertension: Verapamil produces its antihypertensive effect by a combination of vascular and cardiac effects. It acts as a vasodilator with selectivity for the arterial portion of the peripheral vasculature. As a result the systemic vascular resistance is reduced and usually without orthostatic hypotension or reflex tachycardia. Bradycardia (rate less than 50 beats/min) is uncommon. 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. However, one report has suggested that calcium levels above the normal range may alter the therapeutic effect of verapamil.

Verapamil regularly reduces the total systemic resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles.

Electrophysiologic Effects: Electrical activity through the AV node depends, to a significant degree, upon the transmembrane influx of extracellular calcium through the L-type (slow) channel. 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 pre-existing conduction defects [see Warnings and Precautions (5.5)].

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 the accessory bypass tract. 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 and Precautions (5.4)].

Verapamil has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man.

Hemodynamics: Verapamil reduces afterload and myocardial contractility. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil is countered by reduction of afterload and cardiac index remains unchanged. During isometric or dynamic exercise, verapamil does not alter systolic cardiac function in patients with normal ventricular function. In patients with severe left ventricular dysfunction (e.g., pulmonary wedge pressure above 20 mm Hg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur [see Drug Interactions (7.4)].

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

Verapamil has been shown to have either a neutral or relaxant effect on bronchial smooth muscle.

Pharmacokinetics

Verapamil is administered as a racemic mixture of the R and S enantiomers. The systemic concentrations of R and S enantiomers, as well as overall bioavailability, are dependent upon the route of administration and the rate and extent of release from the dosage forms. Upon oral administration, there is rapid stereoselective biotransformation during the first pass of verapamil through the portal circulation.

Absorption: In a study in 5 subjects with oral immediate-release verapamil, the systemic bioavailability was from 33% to 65% for the R enantiomer and from 13% to 34% for the S enantiomer. Following oral administration of an immediately releasing formulation every 8 hours in 24 subjects, the relative systemic availability of the S enantiomer compared to the R enantiomer was approximately 13% following a single day's administration and approximately 18% following administration to steady-state. The degree of stereoselectivity of metabolism for Verelan PM was similar to that for the immediately releasing formulation. The R and S enantiomers have differing levels of pharmacologic activity. In studies in animals and humans, the S enantiomer has 8 to 20 times the activity of the R enantiomer in slowing AV conduction. In animal studies, the S enantiomer has 15 to 50 times the activity of the R enantiomer in reducing myocardial contractility in isolated blood-perfused dog papillary muscle, respectively, and twice the effect in reducing peripheral resistance. In isolated septal strip preparations from 5 patients, the S enantiomer was 8 times more potent than the R in reducing myocardial contractility. Dose escalation study data indicate that verapamil concentrations increase disproportionally to dose as measured by relative peak plasma concentrations (Cmax) or areas under the plasma concentration vs time curves (AUC).

Consumption of a high fat meal just prior to dosing in the morning had no effect on the extent of absorption and a modest effect on the rate of absorption from Verelan PM. The rate of absorption was not affected by whether the volunteers were supine two hours after night-time dosing or non-supine for four hours following morning dosing. Administering Verelan PM in the morning increased the extent of absorption of verapamil and/or decreased the metabolism to norverapamil.

When the contents of the Verelan PM capsule were administered by sprinkling onto one tablespoonful of applesauce, the rate and extent of verapamil absorption were found to be bioequivalent to the same dose when administered as an intact capsule. Similar results were observed with norverapamil.

Distribution: Although some evidence of lack of dose linearity was observed for Verelan PM, this non-linearity was enantiomer specific, with the R enantiomer showing the greatest degree of non-linearity.

Table 3. Pharmacokinetic Characteristics of Verapamil Enantiomers After Administration of Escalating Doses of Verelan PM

	ISOMER	200	300	400
Dose Ratio		1	1.5	2
Relative Cmax	R S	1 1	1.89 1.88	2.34 2.5
Relative AUC	R S	1 1	1.67 1.35	2.34 2.20

Racemic verapamil is released from Verelan PM by diffusion following the gradual solubilization of the water soluble polymer. The rate of solubilization of the water soluble polymer produces a lag period in drug release for approximately 4-5 hours. The drug release phase is prolonged with the peak plasma concentration (Cmax) occurring approximately 11 hours after administration. Trough concentrations occur approximately 4 hours after bedtime dosing while the patient is sleeping. Steady-state pharmacokinetics were determined in healthy volunteers. Steady-state concentration is achieved by day 5 of dosing.

In healthy volunteers, following administration of Verelan PM (200 mg per day), steady-state pharmacokinetics of the R and S enantiomers of verapamil is as follows: Mean Cmax of the R isomer was 77.8 ng/ml and 16.8 ng/ml for the S isomer; AUC (0-24h) of the R isomer was 1037 ng∙h/ml and 195 ng∙h/ml for the S isomer.

In general, bioavailability of verapamil is higher and half life longer in older (>65 yrs) subjects. Lean body weight also affects its pharmacokinetics inversely. It was not possible to observe a gender difference in the clinical trials of Verelan PM due to the small sample size. However, there are conflicting data in the literature suggesting that verapamil clearance decreased with age in women to a greater degree than in men.

Metabolism and Excretion: Orally administered verapamil undergoes extensive metabolism in the liver. Verapamil is metabolized by O-demethylation (25%) and N-dealkylation (40%), and is subject to pre-systemic hepatic metabolism with elimination of up to 80% of the dose. The metabolism is mediated by hepatic cytochrome P450, and animal studies have implied that the mono-oxygenase is the specific isoenzyme of the P450 family. Thirteen metabolites have been identified in urine. Norverapamil enantiomers can reach steady-state plasma concentrations approximately equal to those of the enantiomers of the parent drug. For Verelan PM, the norverapamil R enantiomer reached steady-state plasma concentrations similar to the verapamil R enantiomer, but the norverapamil S enantiomer concentrations were approximately twice that of the verapamil S enantiomer concentrations. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug.

R verapamil is 94% bound to plasma albumin, while S verapamil is 88% bound. In addition, R verapamil is 92% and S verapamil 86% bound to alpha-1 acid glycoprotein. In patients with hepatic insufficiency, metabolism of immediate-release verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours because of the extensive hepatic metabolism [see Use in Specific Populations (8.6)]. In addition, in these patient

Vivitrol

Generic Name: naltrexone (Intramuscular route)

nal-TREX-one

Intramuscular route(Powder for Suspension, Extended Release)

Naltrexone can cause hepatocellular injury when given in excessive doses, is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver disease must be carefully considered in light of its hepatotoxic effects. Patients should be warned of the risk of hepatic injury and advised to stop the use of naltrexone and seek medical attention if they experience symptoms of acute hepatitis .

Commonly used brand name(s)

In the U.S.

• Vivitrol

Available Dosage Forms:

• Powder for Suspension, Extended Release

Therapeutic Class: Ethanol Dependency

Pharmacologic Class: Opioid Antagonist

Uses For Vivitrol

Naltrexone injection is used to help narcotic dependents who have stopped taking narcotics to stay drug-free. It is also used to help alcoholics stay alcohol-free. The medicine is not a cure for addiction. It is used as part of an overall program that may include counseling, attending support group meetings, and other treatment recommended by your doctor.

Naltrexone is not a narcotic. It works by blocking the effects of narcotics, especially the "high'' feeling that makes you want to use them. It also may block the "high'' feeling that may make you want to use alcohol. It will not produce any narcotic-like effects or cause mental or physical dependence. It will not prevent you from becoming impaired while drinking alcohol.

Naltrexone will cause withdrawal symptoms in people who are physically dependent on narcotics. Therefore, naltrexone treatment is started after you are no longer dependent on narcotics. The length of time this takes may depend on which narcotic you took, the amount you took, and how long you took it. Before you start using this medicine, be sure to tell your doctor if you think you are still having withdrawal symptoms.

This medicine is available only with your doctor's prescription.

Before Using Vivitrol

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of naltrexone injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of naltrexone injection in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Alfentanil


• Alphaprodine


• Codeine


• Dihydrocodeine


• Ethylmorphine


• Fentanyl


• Hydrocodone


• Hydromorphone


• Levorphanol


• Meperidine


• Methadone


• Morphine


• Morphine Sulfate Liposome


• Oxycodone


• Oxymorphone


• Propoxyphene


• Sufentanil

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Yohimbine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bleeding problems (e.g., hemophilia) or


• Kidney disease, moderate to severe or


• Liver disease, mild to moderate or


• Lung or breathing problems or


• Thrombocytopenia (low platelets in the blood)—Use with caution. May make these conditions worse.

• Drug dependence, especially narcotic abuse or dependence, history of or


• Failed the naloxone challenge test (medical test to check your dependence to opioid medicine) or


• Hepatitis, acute or


• Liver disease, severe or


• Opioid withdrawal, acute or


• Positive urine test for opioids or


• Receiving opioid analgesics (e.g., morphine)—Should not be used in patients with these conditions.

Proper Use of Vivitrol

A nurse or other trained health professional will give you this medicine. This medicine is given as a shot into the buttocks (gluteal) muscle. It is usually given every 4 weeks or once a month.

Naltrexone injection should only be given to alcohol-dependent patients who can abstain from drinking alcohol and does not need an overnight stay in the hospital.

If you miss your scheduled dose, call your doctor to make another appointment as soon as possible.

This medicine usually comes with a Medication Guide. Read the information carefully and make sure you understand it before receiving this medicine. If you have any questions, ask your doctor.

Precautions While Using Vivitrol

It is very important that your doctor check your progress at regular visits. Your doctor may want to do certain blood and urine tests to see if the medicine is causing unwanted effects.

This medicine may cause serious problems with your liver. Call your doctor right away if you start having dark urine, pain in the upper stomach, or yellowing of the eyes or skin while you are using this medicine.

This medicine may increase your risk of having a lung disease called eosinophilic pneumonia. Tell your doctor right away if you have shortness of breath, coughing, or wheezing after receiving this medicine.

This medicine may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash; itching; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth while you are using this medicine.

You will need to stop using opioids (narcotics) for at least 7 to 10 days before you can start receiving naltrexone injection. Your doctor may need to do the naloxone challenge test or a urine test for opioids to make sure you are opioid-free.

This medicine blocks the "high" feeling you get from narcotic (opioid) drugs, including heroin. Since naltrexone injection may make you more sensitive to lower doses of opioids than you have previously used, you should not use heroin or any other narcotic drugs to overcome what the medicine is doing. You could overdose and develop serious problems.

This medicine may increase thoughts of suicide. Tell your doctor right away if you start to feel more depressed. Also tell your doctor right away if you have thoughts about hurting yourself. Report any unusual thoughts or behaviors that trouble you, especially if they are new or get worse quickly. Make sure your caregiver knows if you feel tired all the time, sleep a lot more or a lot less than usual, feel hopeless or helpless, or if you have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell your doctor if you have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. Let your doctor know if you or anyone in your family has bipolar disorder (manic-depressive disorder) or has tried to commit suicide.

Remember that use of naltrexone is only part of your treatment. Be sure that you follow all of your doctor's orders, including seeing your therapist and/or attending support group meetings on a regular basis.

Do not try to overcome the effects of naltrexone injection by taking narcotics. To do so may cause coma or death. You may be more sensitive to the effects of narcotics than you were before beginning naltrexone treatment.

Naltrexone injection also blocks the useful effects of narcotics. Always use a non-narcotic medicine to treat pain, diarrhea, or a cough. If you have any questions about the proper medicine to use, check with your doctor.

Naltrexone injection will not prevent you from becoming impaired when you drink alcohol. Do not take naltrexone in order to drive or perform other activities while under the influence of alcohol.

After naltrexone is injected into your body, it is impossible to remove it.

It is recommended that you carry an identification card stating that you are receiving naltrexone injection. You may also need to carry a letter to let others know you are receiving this medicine in case you have a medical emergency.

You may experience a serious reaction at the site of the naltrexone injection that includes pain, swelling, tenderness, bruising, itching, and redness. Contact your doctor right away if this skin reaction does not improve or becomes worse within two weeks after receiving the injection. Your doctor should also refer you immediately to a surgeon.

You may experience nausea after the first injection of this medicine that should be mild and subside a few days afterwards. You will be less likely to have nausea with your next injections.

This medicine may cause some people to become dizzy, drowsy, or less alert than they are normally. If any of these side effects occur, do not drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert while you are receiving naltrexone injection.

Before you have any medical tests, tell the medical doctor in charge that you are receiving this medicine. The results of some tests may be affected by this medicine.

Vivitrol Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site


• body aches or pain


• chills


• congestion


• cough


• difficulty with breathing


• discouragement


• dryness or soreness of the throat


• ear congestion


• fear


• feeling sad or empty


• fever


• headache


• hoarseness


• irritability


• lack of appetite


• loss of interest or pleasure


• loss of voice


• nasal congestion


• nervousness


• rash


• runny nose


• sneezing


• sore throat


• tender, swollen glands in the neck


• trouble concentrating


• trouble sleeping


• trouble with swallowing


• unusual tiredness or weakness


• voice changes

Incidence not known

• Abdominal or stomach cramps or pain


• arm, back, or jaw pain


• black, tarry stools


• bladder pain


• bloating


• bloody or cloudy urine


• bloody stools


• blurred vision


• chest pain or discomfort


• chest tightness or heaviness


• chills


• confusion


• confusion as to time, place, or person


• constipation


• cough


• cough producing mucus


• decreased urination


• diarrhea


• difficult, burning, or painful urination


• dilated neck veins


• dizziness or lightheadedness


• dry mouth


• extreme fatigue


• fainting


• false or unusual sense of well-being


• fast, irregular, pounding, or racing heartbeat or pulse


• frequent urge to urinate


• general feeling of discomfort or illness


• hallucinations or seeing, hearing, or feeling things that are not there


• headache, severe and throbbing


• holding false beliefs that cannot be changed by fact


• hyperventilation


• increase in heart rate


• increase in white blood cells


• indigestion


• irregular breathing


• irritability


• itching, pain, redness, swelling, tenderness, or warmth on the skin


• joint or muscle pain


• lightheadedness


• lower back or side pain


• nausea


• nervousness


• numbness or tingling of the face, hands, or feet


• pain or discomfort in the arms, jaw, back, or neck


• pain, redness, or swelling in the arm or leg


• pounding in the ears


• rapid breathing


• redness and soreness of the eyes


• restlessness


• seizures


• severe nausea or vomiting


• shaking


• shivering


• shortness of breath


• skin rash


• slow or fast heartbeat


• sores in the mouth


• stomach cramps


• stomach pain


• sudden shortness of breath or troubled breathing


• sunken eyes


• sweating


• swelling of the face, fingers, feet, or lower legs


• swollen, painful, or tender lymph glands in the neck, armpit, or groin


• tenderness


• thirst


• tightness in the chest


• tooth or gum pain


• trouble sleeping


• troubled breathing


• unusual excitement, nervousness, or restlessness


• vomiting


• vomiting of blood or material that looks like coffee grounds


• watery or bloody diarrhea


• weight gain


• wheezing


• wrinkled skin

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Sleepiness or unusual drowsiness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Difficulty with moving


• muscle stiffness


• swelling or redness in the joints

Incidence not known

• Bleeding after defecation


• bloated


• change in taste


• decreased interest in sexual intercourse


• drowsiness


• excess air or gas in the stomach or intestines


• feeling of warmth


• feeling unusually cold


• full feeling


• heartburn


• inability to have or keep an erection


• increased sweating


• loss in sexual ability, desire, drive, or performance


• loss of taste


• night sweats


• passing gas


• redness of the face, neck, arms, and occasionally, upper chest


• relaxed and calm


• sleepiness


• stuffy nose


• sudden sweating


• toothache


• uncomfortable swelling around anus


• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness


• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

See also: Vivitrol side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Vivitrol resources

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

• Vivitrol Consumer Overview


• Vivitrol MedFacts Consumer Leaflet (Wolters Kluwer)


• Vivitrol Prescribing Information (FDA)


• Naltrexone Prescribing Information (FDA)


• Naltrexone Monograph (AHFS DI)


• Revia MedFacts Consumer Leaflet (Wolters Kluwer)


• Revia Prescribing Information (FDA)

Compare Vivitrol with other medications

• Alcohol Dependence
• Opiate Dependence

Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets

Pronunciation: lor-AT-ah-DEEN/soo-doe-eh-FED-rin
Generic Name: Loratadine/Pseudoephedrine
Brand Name: Examples include Alavert Allergy & Sinus and Claritin-D 12 Hour

Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets are used for:

Temporarily relieving symptoms of hay fever or respiratory allergies such as stuffy or runny nose, sneezing, itchy or watery eyes, itchy nose or throat, or sinus congestion or pressure. It may also be used for other conditions as determined by your doctor.

Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets are an antihistamine and decongestant combination. The antihistamine works by blocking the action of histamine, which helps reduce symptoms such as watery eyes and sneezing. The decongestant promotes sinus and nasal drainage, relieving congestion and pressure.

Do NOT use Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets if:

• you are allergic to any ingredient in Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets


• you have narrow-angle glaucoma, severe high blood pressure, severe heart/blood vessel disease (coronary artery disease), or severe difficulty urinating


• you are taking droxidopa or have taken furazolidone or a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) within the last 14 days


• you have experienced serious side effects such as irregular heart rhythms with decongestants (eg, pseudoephedrine, phenylephrine)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets:

Some medical conditions may interact with Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have high blood pressure, heart or blood vessel disease (eg, ischemic heart disease), diabetes, kidney or liver problems, thyroid problems, glaucoma, difficulty urinating due to an enlarged prostate, or trouble sleeping

Some MEDICINES MAY INTERACT with Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Furazolidone or MAOIs (eg, phenelzine) because side effects, such as headache, fever, and high blood pressure, may occur


• Droxidopa because irregular heartbeat or heart attack may occur


• Guanadrel and guanethidine because their effectiveness may be decreased by Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets


• Bromocriptine because the risk of its side effects or toxic effects may be increased by Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets


• Urinary alkalinizers (eg, sodium bicarbonate) because they may increase the risk of Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets's side effects

This may not be a complete list of all interactions that may occur. Ask your health care provider if Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets:

Use Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets by mouth with or without food.


• Swallow Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets whole. Do not break, crush, or chew before swallowing.


• If you miss a dose of Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets and are using it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets.

Important safety information:

• Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets may cause dizziness. These effects may be worse if you take it with alcohol or certain medicines. Use Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do NOT take more than the recommended dose without checking with your doctor.


• If your symptoms do not get better within 7 days or if they get worse, or if you develop a fever, check with your doctor.


• Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets has pseudoephedrine in it. Before you start any new medicine, check the label to see if it has pseudoephedrine in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Before you begin taking any new medicines, either prescription or nonprescription, check with your doctor or pharmacist. This includes any medicines that contain appetite suppressants, antihistamines, or decongestants.


• Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets may interfere with skin allergy tests. If you are scheduled for a skin test, talk to your doctor. You may need to stop taking Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets for a few days before the tests.


• Use Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets with caution in the ELDERLY; they may be more sensitive to its effects.


• Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets should not be used in CHILDREN younger than 12 years old without first checking with the child's doctor; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets while you are pregnant. Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets are found in breast milk. If you are or will be breast-feeding while you use Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Coughing; dizziness; drowsiness; dry mouth; excitability; fatigue; headache; loss of appetite; mild stomach upset; nausea; nervousness; sleeplessness; sore throat; thirst.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; difficulty urinating; fast or irregular heartbeat; mental or mood changes; seizures; severe dizziness; uncontrolled shaking or tremor.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Loratadine/Pseudoephedrine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include hallucinations; high fever; irregular or unusually slow or fast heartbeat; loss of consciousness; mental or mood changes; seizures; severe drowsiness or dizziness; unusual nervousness or excitement.

Proper storage of Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets:

Store Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets at room temperature, between 59 and 77 degrees F (15 and 25 degrees C), in a tightly closed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets out of the reach of children and away from pets.

General information:

• If you have any questions about Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets, please talk with your doctor, pharmacist, or other health care provider.


• Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Loratadine/Pseudoephedrine 12-Hour Sustained-Release Tablets. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Loratadine/Pseudoephedrine resources

• Loratadine/Pseudoephedrine Side Effects (in more detail)
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Viread

Generic Name: Tenofovir Disoproxil Fumarate
Class: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
VA Class: AM800
Chemical Name: Bis(1 - methyl - ethyl)ester - (R) - 5 - [[2 - (6 - Amino - 9H - purin - 9 - yl) - 1 - methylethoxy]methyl] - 2,4,6,8 - tetraoxa - 5 - phosphanonanedioic acid 5-oxide (E)-2-butenedioate
Molecular Formula: C₉H₁₄N₅O₄P•H₂O
CAS Number: 202138-50-9

• 
  

  Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported rarely in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs) alone or in conjunction with other antiretrovirals.^{1 7} (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  
  


• 
  

  Severe acute exacerbations of hepatitis reported following discontinuance of tenofovir in patients with HBV infection.¹ Monitor hepatic function closely with both clinical and laboratory follow-up for at least several months after tenofovir is discontinued.¹ If appropriate, resumption of treatment for HBV infection may be warranted.¹

  
  

Introduction

Antiretroviral with antiviral activity against hepatitis B virus (HBV); nucleotide reverse transcriptase inhibitor.^{1 2 3 5}

Uses for Viread

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.^{1 6}

For purposes of therapeutic decisions, tenofovir is grouped with nucleoside reverse transcriptase inhibitor (NRTI) antiretrovirals.⁶

A preferred NRTI for use in multiple-drug antiretroviral regimens for initial therapy in adults.⁶

Fixed-combination preparation containing tenofovir and emtricitabine (Truvada) used in conjunction with other antiretrovirals.¹³ Can be used to decrease pill burden,⁶ but should not be used as a component of a triple NRTI regimen.¹³

Fixed-combination preparation containing efavirenz, emtricitabine, and tenofovir (Atripla) used alone or in conjunction with other antiretrovirals.²² Used to decrease pill burden and improve compliance.²²

Because of a high rate of virologic failure, triple NRTI regimens of tenofovir, abacavir, and lamivudine or tenofovir, didanosine, and lamivudine not recommended.^{6 9 12} Because of high rates of early virologic failure and rapid selection of resistant mutations, a regimen of tenofovir and didanosine not recommended for initial therapy.⁶

For patients coinfected with HBV, some experts recommend an NRTI combination of tenofovir and (emtricitabine or lamivudine); avoid use of regimens containing only 1 of these antiretrovirals (may increase risk of HBV resistance).⁶

Postexposure Prophylaxis of HIV

Postexposure prophylaxis of HIV infection† in health-care workers and others exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with risk for transmission of the virus.²⁰ Used in conjunction with other antiretrovirals.²⁰

Postexposure prophylaxis of HIV infection† in individuals who have had nonoccupational exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.¹⁷ Used in conjunction with other antiretrovirals.¹⁷

Chronic HBV Infection

Management of chronic HBV infection in adults with compensated liver function.¹

May be effective in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients.^{1 26}

Safety and efficacy not established in patients with decompensated liver disease.¹ Insufficient data in nucleoside-experienced patients and in those with lamivudine-associated mutations at study entry to establish efficacy in these patients.¹

Patients coinfected with both HBV and HIV who require treatment for HBV and who are not receiving antiretroviral therapy should receive an antiviral agent for HBV infection that does not have activity against HIV.^{6 28}

Viread Dosage and Administration

Administration

Oral Administration

Administer single-entity preparation (Viread) or fixed-combination preparation (Truvada) orally without regard to meals.^{1 6 13} Administer fixed-combination preparation (Atripla) orally once daily on an empty stomach, preferably at bedtime.²²

Because dosage of tenofovir and emtricitabine cannot be adjusted individually, the fixed combination containing tenofovir and emtricitabine (Truvada) should not be used in pediatric patients or patients with severe renal impairment (Cl_cr <30 mL/minute).¹³

Because dosage of efavirenz, emtricitabine, and tenofovir cannot be adjusted individually, the fixed-combination containing efavirenz, emtricitabine, and tenofovir (Atripla) should not be used in patients with moderate to severe renal impairment (Cl_cr <50 mL/minute).²²

Dosage

Available as tenofovir disodium fumarate; dosage expressed in terms of tenofovir disodium fumarate.¹

Dosage of Truvada and Atripla expressed as number of tablets.^{13 22}

For treatment of HIV infection, Viread and Truvada must be given in conjunction with other antiretrovirals.^{1 6 13} Atripla may be used alone or in conjunction with other antiretrovirals.²²

If used with atazanavir, adjustment in treatment regimen necessary.¹⁰ If used with didanosine, adjustment of didanosine dosage necessary.^{1 6} (See Specific Drugs under Interactions.)

Pediatric Patients

Treatment of HIV Infection†

Oral

Children 2–8 years of age: 8 mg/kg once daily under investigation.¹⁵

Children >8 years of age: Median dose 210 mg/m² (maximum 300 mg) once daily under investigation.¹⁵

Adults

Treatment of HIV Infection

Oral

300 mg once daily.^{1 6}

Truvada: 1 tablet once daily.^{13 6}

Atripla: 1 tablet once daily.²²

Postexposure Prophylaxis of HIV†

Occupational Exposure†

Oral

300 mg once daily.²⁰

Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.²⁰

Nonoccupational Exposure†

Oral

300 mg once daily.¹⁷

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.¹⁷

Chronic HBV Infection

Oral

300 mg once daily.¹

Optimal duration of treatment unknown.¹

Special Populations

Hepatic Impairment

Treatment of HIV Infection and Chronic HBV Infection

Oral

Dosage adjustment not needed.¹

Renal Impairment

Treatment of HIV Infection and Chronic HBV Infection

Adjust dosage if Cl_cr <50 mL/minute.¹ Dosage adjustment not necessary in patients with Cl_cr of 50–80 mL/minute.¹

Viread Dosage in Adults with Renal Impairment1

Clcr (mL/min)	Dosage
30–49	300 mg once every 48 hours
10–29	300 mg every 72–96 hours
Hemodialysis patients	300 mg once every 7 days or after a total of approximately 12 hours of hemodialysis (assuming 3 hemodialysis sessions/week each lasting approximately 4 hours)

Manufacturer states dosage recommendations not available for patients with Cl_cr <10 mL/minute who are not undergoing hemodialysis.¹

Truvada Dosage in Adults with Renal Impairment13

Clcr (mL/minute)	Dose and Dosing Interval
≥50	One tablet every 24 hours
30–49	One tablet every 48 hours (monitor clinical response and renal function since dosage has not been evaluated clinically)
<30 (including hemodialysis patients)	Not recommended

Atripla: Dosage adjustment not necessary in patients with Cl_cr ≥50 mL/minute.²² Not recommended in patients with Cl_cr< 50 mL/minute.²²

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 Viread

Contraindications

• 
  

  Manufacturer states none known.¹

  
  

Warnings/Precautions

Warnings

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Possible lactic acidosis and severe hepatomegaly with steatosis (potentially fatal).^{1 6 7} Reported mostly in women; obesity and long-term therapy with NRTIs also may be risk factors.^{1 6} Has been reported in patients with no known risk factors.¹

Cautious use recommended in patients with known risk factors for liver disease.¹

Interrupt therapy if there are clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).¹

Exacerbation of Hepatitis

Severe acute exacerbations of hepatitis reported following discontinuance of HBV therapy in patients with HBV infection.¹

Closely monitor hepatic function at repeated intervals with both clinical and laboratory follow-up for several months or longer after tenofovir is discontinued.¹ If appropriate, resumption of anti-HBV therapy may be warranted.¹

Patients Coinfected with HBV and HIV

Test all HIV-infected patients for presence of HBV before initiating tenofovir.¹

Test all HBV-infected patients for HIV before initiating tenofovir.¹

Use tenofovir with other highly active antiretroviral agents in individuals coinfected with HBV and HIV.¹

Renal Toxicity

Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with hypophosphatemia) reported.¹

Avoid use in patients who are or have recently received nephrotoxic drugs.¹

Obtain Cl_cr before starting tenofovir; monitor periodically thereafter.¹ Monitor Cl_cr and serum phosphorus in those at risk for renal dysfunction.¹

General Precautions

Do not use multiple tenofovir-containing preparations concomitantly.¹

Use of Fixed Combinations

When used in fixed combination with emtricitabine (Truvada), consider the cautions, precautions, and contraindications associated with emtricitabine.¹³

When used in fixed combination with emtricitabine and efavirenz (Atripla), consider the cautions, precautions, and contraindications associated with the concomitant agents.²²

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance.¹

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.¹

Bone Effects

Decreases from baseline in bone mineral density (BMD) at lumbar spine and hip, increases in biochemical markers of bone metabolism, and increased serum parathyroid hormone reported in patients receiving tenofovir with lamivudine and efavirenz; clinical importance unclear.¹

Osteomalacia associated with proximal renal tubulopathy reported during postmarketing surveillance.¹

Consider supplementation with calcium or vitamin D; the effect of such supplementation has not been studied.¹

Consider monitoring BMD in those with a history of pathologic bone fracture and in those at substantial risk for osteopenia.¹ If bone abnormalities are suspected, obtain appropriate consultation.¹

Early Virologic Failure in HIV Infection

Triple NRTI regimens associated with early virologic failure and high rates of resistance.¹ Use with caution; consider modifying the regimen.¹

Specific Populations

Pregnancy

Category B.¹ Antiretroviral Pregnancy Registry at 800-258-4263.^{1 18}

Because of lack of data and concerns regarding potential fetal bone effects, experts recommend the drug be used in pregnant women only after careful consideration of other alternatives.¹⁸

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.¹

Pediatric Use

Safety and efficacy of single entity (Viread) or fixed-combination (Truvada, Atripla) not established in children^{1 15} <18 years of age.^{1 7 22}

Clinical studies underway to evaluate investigational tablets and oral solution of tenofovir in HIV-infected children ≥2 years of age†.¹⁵

Geriatric Use

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

Hepatic Impairment

Limited data indicate dosage adjustment not needed in patients with hepatic impairment.¹

Renal Impairment

Tenofovir principally eliminated by kidneys; pharmacokinetics likely to be affected.¹

Monitor Cl_cr and serum phosphorus in patients with mild renal impairment (Cl_cr 50–80 mL/minute).¹

Dosage adjustments necessary in those with Cl_cr <50 mL/minute.^{1 6} Closely monitor clinical response and renal function; safety and efficacy of reduced dosages not evaluated in clinical studies.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

HIV Infection: Nausea, diarrhea, rash, headache, pain, depression, asthenia.¹

HBV Infection: Nausea.¹

Interactions for Viread

Tenofovir and its prodrug are not substrates of CYP enzymes;¹ tenofovir does not inhibit CYP3A4, 2D6, 2C9, or 2E1, but may have a slight inhibitory effect on 1A.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions with drugs that are inhibitors or substrates of hepatic microsomal enzymes unlikely.¹

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

Potential increased plasma concentrations of tenofovir or the concomitant drug when used with drugs that reduce renal function or compete for active tubular secretion (e.g., acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir).¹ Monitor for dose-related toxicities.⁶

Specific Drugs

Drug	Interaction	Comments
Abacavir	Pharmacokinetic interaction unlikely1 In vitro evidence of additive or synergistic antiretroviral effects1
Adefovir		Manufacturer of tenofovir states that tenofovir should not be used with adefovir for treatment of HBV infection1
Atazanavir	Atazanavir: Decreased plasma concentrations and AUC of atazanavir (minimum concentrations decreased 40%); increased plasma concentrations and AUC of tenofovir1 6 10 Ritonavir-boosted atazanavir: Decreased plasma concentrations and AUC of atazanavir (minimum concentrations decreased 23%); increased plasma concentrations and AUC of tenofovir; 1 6 In vitro evidence of additive antiretroviral effects21	Do not use tenofovir in conjunction with atazanavir without low-dose ritonavir1 6 Regimen of atazanavir 300 mg, ritonavir 100 mg, and tenofovir disoproxil fumarate 300 mg once daily with food recommended1 6 10 Monitor for tenofovir toxicity;1 discontinue tenofovir if adverse effects occur1 If used concomitantly with atazanavir and a histamine H2-receptor antagonist in treatment-experienced patients, a regimen of atazanavir 400 mg, tenofovir disoproxil fumarate 300 mg, and ritonavir 100 mg once daily with food is recommended21
Darunavir	Ritonavir-boosted darunavir: Increased plasma concentrations of tenofovir; no change in plasma concentrations of darunavir6 24	Experts state clinical importance unknown6 Manufacturer of darunavir states usual dosage of ritonavir-boosted darunavir and tenofovir can be used;24 monitor for tenofovir toxicity6
Didanosine	Increased plasma concentrations and AUC of didanosine; no effect on tenofovir pharmacokinetics1 6 Early virologic failure and rapid selection of resistant mutations reported6 Increased risk of didanosine-associated adverse effects (e.g., pancreatitis, neuropathy)1 In vitro evidence of additive or synergistic antiretroviral effects1	Concomitant use of didanosine and tenofovir: Not recommended for initial therapy6 Caution advised; reduce didanosine dosage; closely monitor for didanosine-associated adverse effects; discontinue didanosine if necessary1 In patients weighing ≥60 kg with Clcr ≥60 mL/minute, reduce didanosine dosage to 250 mg (delayed-release capsules) once daily; in patients weighing <60 kg with Clcr ≥60 mL/minute, reduce didanosine dosage to 200 mg (delayed-release capsules) once daily; administer without food or with a light meal1 6 14 19
Emtricitabine	No evidence of clinically important pharmacokinetic interactions1 13 In vitro evidence of additive or synergistic antiretroviral effects13
Entecavir	No evidence of clinically important pharmacokinetic interaction1
Estrogens/Progestins	Hormonal contraceptives containing ethinyl estradiol and norgestimate: Pharmacokinetic interaction unlikely1
Histamine H2-receptor antagonists	Alterations in atazanavir concentrations possible with concomitant use of a histamine H2-receptor antagonist, tenofovir, and atazanavir (with or without ritonavir)21	If used concomitantly with atazanavir and a histamine H2-receptor antagonist in treatment-experienced patients, a regimen of atazanavir 400 mg, tenofovir disoproxil fumarate 300 mg, and ritonavir 100 mg once daily with food is recommended;21
Indinavir	Slight alterations in indinavir and tenofovir concentrations;1 6 not clinically important1 In vitro evidence of additive or synergistic antiretroviral effects1	No dosage adjustment needed6
Lamivudine	Pharmacokinetic interaction not clinically important;1 in vitro evidence of additive or synergistic antiretroviral effects1
Lopinavir and ritonavir	Increased peak plasma concentration and AUC of tenofovir; decreased peak plasma concentration and AUC of lopinavir; decreased peak plasma concentration and AUC of ritonavir1 6	Clinical importance unknown6 Monitor for tenofovir toxicity6
Methadone	Pharmacokinetic interaction unlikely1
Nelfinavir	Pharmacokinetic interaction unlikely1 In vitro evidence of additive or synergistic antiretroviral effects1
Nonnucleoside reverse transcriptase inhibitors (NNRTIs)	No evidence of pharmacokinetic interaction with efavirenz1 In vitro evidence of additive or synergistic antiretroviral effects with delavirdine, efavirenz, or nevirapine1
Ribavirin	Pharmacokinetic interaction unlikely1
Ritonavir	In vitro evidence of additive or synergistic antiretroviral effects1
Saquinavir	Ritonavir-boosted saquinavir (saquinavir 1 g twice daily and ritonavir 100 mg twice daily): No clinically important change in saquinavir concentrations with tenofovir 300 mg once daily1 In vitro evidence of additive or synergistic antiretroviral effects1	Ritonavir-boosted saquinavir: Dosage adjustment not needed 1
Stavudine	In vitro evidence of additive or synergistic antiretroviral effects1
Tacrolimus	No evidence of clinically important pharmacokinetic interaction1
Tipranavir	Ritonavir-boosted tipranavir: Decreased tenofovir concentrations; decreased tipranavir concentrations6 16 In vitro evidence of additive antiretroviral effects16	Clinical importance unknown6
Zidovudine	In vitro evidence of additive or synergistic antiretroviral effects1

Viread Pharmacokinetics

Absorption

Bioavailability

Tenofovir disoproxil fumarate is a diester prodrug of tenofovir.¹ Oral bioavailability approximately 25%; peak plasma concentrations attained in about 1 hour in fasting patients.¹

Fixed-combination tablet containing emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg (Truvada) is bioequivalent to a 200-mg emtricitabine capsule and a 300-mg tenofovir disoproxil fumarate tablet given simultaneously.¹³

Fixed-combination tablet containing efavirenz 600 mg, tenofovir disoproxil fumarate 300 mg, and emtricitabine 200 mg (Atripla) is bioequivalent to a 600-mg efavirenz tablet, a 300-mg tenofovir disoproxil fumarate tablet, and a 200-mg emtricitabine capsule given simultaneously.²²

Food

Food delays time to peak plasma concentrations by approximately 1 hour.¹ Administration with a high-fat meal increases oral bioavailability (14% increase in peak plasma concentrations; 40% increase in AUC);¹ pharmacokinetics not appreciably affected by administration with a light meal.¹

Distribution

Extent

Crosses the human placenta.¹⁸ Not known whether tenofovir is distributed into human milk.¹

Plasma Protein Binding

In vitro binding to plasma or serum proteins is <0.7 or 7.2%, respectively, over tenofovir concentrations of 0.01–25 mcg/mL.¹

Elimination

Metabolism

Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate.¹

Tenofovir and its prodrug are not substrates of CYP enzymes.¹

Elimination Route

Eliminated principally by kidneys using glomerular filtration and active tubular secretion; approximately 32% of an oral dose excreted in urine within 24 hours.¹

Half-life

Approximately 17 hours.¹

Special Populations

No substantial changes in tenofovir pharmacokinetics in individuals with moderate to severe hepatic impairment compared with those with normal hepatic function.¹

Moderate or severe renal impairment results in increased plasma concentrations; dosage adjustment necessary if Cl_cr <50 mL/minute.¹ (See Renal Impairment under Dosage and Administration.)

Stability

Storage

Oral

Tablets, Film-coated

Viread: 25°C (may be exposed to 15–30°C).¹

Truvada: 25°C (may be exposed to 15–30°C).¹³

Atripla: 25°C (may be exposed to 15–30°C).²²

Actions and SpectrumActions

• 
  

  Tenofovir disoproxil fumarate is a prodrug and is inactive until the drug is hydrolyzed in vivo to tenofovir which is then phosphorylated to the active metabolite (tenofovir diphosphate).^{1 2 3 5}

  
  


• 
  

  Active in vitro and in vivo against HIV-1^{1 5} and HBV;^{1 6 26} some activity against HIV-2.¹

  
  


• 
  

  Inhibits replication of retroviruses, including HIV-1, by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).^{1 2 3 5}

  
  


• 
  

  Inhibits HBV replication through competitive inhibition of viral DNA polymerase.²⁹

  
  


• 
  

  Weak inhibitor of mammalian DNA α- and β-polymerases and mitochondrial DNA γ-polymerase.^{1 4 5} Low potential to induce mitochondrial toxicity.^{4 5}

  
  


• 
  

  HIV-1 resistant to tenofovir can be selected in vitro and have been reported in clinical isolates.^{1 5}

  
  


• 
  

  Cross-resistance between tenofovir and some NRTIs reported.¹ Cross-resistance with HIV protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs) unlikely.⁷

  
  

Advice to Patients

• 
  

  Critical nature of HIV therapy compliance.¹ Importance of using tenofovir in conjunction with other antiretrovirals—not for monotherapy.¹

  
  


• 
  

  Antiretroviral therapy is not a cure for HIV infection, and opportunistic infections still may occur.¹ HIV transmission via sexual contact or sharing needles is not prevented by antiretrovirals.¹

  
  


• 
  

  Advise patient of the risks and benefits of tenofovir and other alternatives for treatment of HBV infection.¹

  
  


• 
  

  Importance of reading patient package insert from manufacturer.¹

  
  


• 
  

  Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.¹

  
  


• 
  

  Importance of informing clinicians of concomitant medical problems such as renal or hepatic impairment.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.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.

Tenofovir Disoproxil Fumarate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	300 mg	Viread	Gilead

Tenofovir Disoproxil Fumarate Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	300 mg with Emtricitabine 200 mg	Truvada	Gilead
		300 mg with Emtricitabine 200 mg and Efavirenz 600 mg	Atripta	Bristol-Myers Squibb and Gilead

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Atripla 600-200-300MG Tablets (BRISTOL-MYERS SQUIBB/GILEAD): 30/$1795.72 or 90/$5154.14

Truvada 200-300MG Tablets (GILEAD SCIENCES): 30/$1071.69 or 90/$3180.65

Viread 300MG Tablets (GILEAD SCIENCES): 30/$771.97 or 90/$2196.03

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 November 2009. 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

1. Gilead Sciences Inc. Viread (tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2008 Nov.

2. Squires KE. Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2001; 45:2733-9. [IDIS 469675] [PubMed 11557462]

3. Srinivas RV, Kim C et al. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob Agents Chemother. 1998; 42:612-7. [PubMed 9517941]

4. Birkus G, Hitchcock MJM, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2002; 46:716-23 [PubMed 11850253]

5. Gilead Sciences, Inc. FDA advisory committee briefing document on Viread (tenofovir DF) for the treatment of HIV-1 infection in adults in combination with other antiretroviral agents. NDA 21-356. Aug 30, 2001. From the FDA website.

6. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (November 3, 2008). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

7. Gilead, Foster City, CA: Personal communication

8. Squires K, Pierone G, Berger D et al. Tenofovir DF: a 48-week final analysis from a phase III randomized, double blind placebo controlled study in antiretroviral experienced patients. Poster presented at the 9^th Conference on Retroviruses and Opportunistic Infections. Seattle, WA: 2002 Feb 24-28. Poster No. 413-W

9. Manion DJ. Dear healthcare provider letter: early virologic non-response in patients with HIV infection treated with lamivudine, abacavir, and tenofovir. GlaxoSmithKline; 2003 Jul. From FDA website.

10. Hodder S. Dear healthcare provider letter: important new pharmacokinetic data for Reyataz (atazanavir sulfate) in combination with Viread (tenofovir disoproxil fumarate). Princeton, NJ: Bristol-Myers Squibb; 2003 Aug 8.

11. Gilead Sciences, Inc. Emtriva (emtricitabine) capsules prescribing information. Foster City, CA; 2005 Jul.

12. Toole J. Dear healthcare provider letter: high rate of virologic failure in patients with HIV infection treated with once-daily triple NRTI regimen containing didanosine, lamivudine, and tenofovir. Foster City, CA; 2003 Oct 14. From FDA website.

13. Gilead Sciences, Inc. Truvada (emtricitabine and tenofovir disoproxil fumarate) tablet prescribing information. Foster City, CA; 2008 May.

14. Bristol-Myers Squibb. Videx EC (didanosine) delayed-release capsules enteric-coated beadlets prescribing information. Princeton, NJ; 2006 Feb.

15. Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children of the National Resource Center at the François-Xavier Bagnoud Center, Health Resources and Services Administration (HRSA), and National Institutes of Health (NIH). Guidelines for the use of antiretroviral agents in pediatric HIV infection (February 23, 2009). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

16. Boehringer Ingelheim. Aptivus (tipranavir) capsules prescribing information. Ridgefield, CT; 2005 Nov 11.

17. Center for Disease Control and Prevention. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: Recommendations from the U.S. Department of Health and Human Services. MMWR Recomm Rep. 2005; 54(No. RR-2):1-19.

18. Perinatal HIV Guidelines Working Group. US Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIV-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States (April 29, 2009). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

19. Bristol-Myers Squibb. Videx (didanosine) chewable/dispersible buffered tablets and pediatric powder for oral solution prescribing information. Princeton, NJ; 2006 Feb.

20. Center for Disease Control and Prevention. Updated U.S. public health service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep. 2005; 54(No. RR-9):1-17.

21. Bristol-Myers Squibb. Reyataz(atazanavir sulfate) prescribing information. Princeton, NJ; 2008 Mar

22. Bristol-Myers Squibb and Gilead. Atripla (efavirenz 600 mg/emtricitabine 200mg /tenofovir disoproxil fumarate 300mg) tablets prescribing information. Foster City, CA; 2007 May.

23. Gallant JE, DeJesus E, Arribas JR et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006; 354:251-60. [PubMed 16421366]

24. Tibotec. Prezista (darunavir) prescribing information. Raritan, NJ; 2006 Jun.

25. Hammer SM, Saag MS, Schechter M et al. Treatment of adult HIV infection: 2006 recommendations of the International AIDS Society–USA panel. JAMA. 2006; 296:827-43. [PubMed 16905788]

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