Effects of Excipients on Metoprolol Tertrate Delivery from Biodegradable Polymeric In Situ Implants
1.1. Advanced Drug Delivery System
The term “Drug Delivery System” refers to the technology utilized to present the drug to the desired body site for drug release and absorption. The first drug delivery system developed was the syringe, invented in 1855, used to deliver medicine by injection. The modern transdermal patch is an example of advanced drug delivery system.
The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to promptly achieve and then maintain the desired drug concentration. This idealized objective points to the two aspects most important to the drug delivery, namely:
# Spatial placement: relates to targeting of a drug to a specific organ or tissue.
# Temporal delivery of a drug: refers to controlling the rate of drug delivery to controlling the rate of drug delivery to the target tissue.
The drug delivery technology landscape is highly competitive and rapidly evolving. The market involves both numerous startups and major players in the medical device, pharmaceutical and biotechnology industries. This is a market with intensive intellectual property protection. Products that have been brought to market or that are in clinical trials often involve combinations of technologies from multiple players, with complex licensing and strategic partnering relationships.
New classes of pharmaceuticals and biologics (peptides, proteins and DNA-based therapeutics) are fueling the rapid evolution of drug delivery technology. These new drugs typically cannot be effectively delivered by conventional means. Additionally, it has been determined that, for many conventional pharmaceutical therapies, the efficacy may be improved and the side effects reduced if the therapy is administered continuously (although potentially variable rate), rather than through conventional burst release techniques (oral ingestion, injection, etc). The benefits from targeted, localized delivery of certain therapeutic agents are another driving force in this market. Additional drivers include the desire to eliminate or minimize the danger of needle stick injuries (and blood-born pathogens) to healthcare workers, increase patient compliance by simplified or reduced stigma delivery methods, reduced healthcare worker involvement and reduced health care costs. Increasingly, delivery devices and drugs will be more tightly coupled. In some cases, device development is beginning as early as the discovery phase of the pharmaceutical development process. To compete in this arena companies must be able to demonstrate the value that their combination of drugs and delivery devices and/or systems brings to the market. To improve the odds of a successful product introduction, companies must be implementing advanced development and technology portfolio plans that define the technologies and delivery devices that will be funded. Because drug development can be a 10-year undertaking, advanced development and technology portfolio plans need to be concerned with market requirements and value propositions more than a decade into the future. Short-sightedness in focusing only on near-term shareholder needs in the face of The challenge of identifying and managing complex technology and intellectual property (IP) portfolios, such as those found in the drug delivery arena, and successfully leveraging these assets to create new opportunities is a critical element in the success of the modern, technology and IP driven firm. In today’s hyper-competitive environment, it is not enough for firms to focus only on short-term technology development based on existing core competencies and IP; they must be able to place long-term technology bets, based on the convergence of trends in the stakeholder value chain, user base and technology development.
A structured methodology for the integration and infusion of trend mining and convergence analysis (from emerging technology development, market dynamics, and user and stakeholder needs) into the technology portfolio planning process allows organizations to more effectively leverage their investments in innovation while increasing the probability of major opportunity creation – ultimately translating these discrete wins into overall firm success.
1.2. Challenges
Historically, drug delivery has taken the form of injection, infusion, ingestion, and inhalation, with additional variations of each category. For example ingestion may be in tablet, capsule or liquid form; inhalation may be via use of a dry powder inhaler, an MDI, or a nebulizer. The challenge for both drug and drug delivery companies is to deliver both existing and emerging drug technologies in a manner that improves the benefits to the patients, healthcare workers and the healthcare system. Areas that are being targeted for improvements through device development include:
• Improved efficacy
• Reduced side effects
• Continuous dosing (sustained release)
• Reduced pain from administration
• Increased ease of use
• Increased use compliance
• Improved mobility
• Decreased involvement of healthcare workers
• Improved safety for healthcare workers
• Reduced environmental impact (elimination of CFC’s)
To provide these benefits, a number of approaches are being (or in some cases have been) developed. The common thread running through the approaches is the concept of self-administered, targeted, sustained release with increased bioavailability. Determining which of the emerging approaches best meets stakeholder needs is a complex, multifaceted problem.
Although ingestion is probably the most widely accepted form of delivery it presents difficulties for a number of important classes of drugs. Many drug delivery scientists view oral delivery as the ideal drug delivery method. In the case of proteins and peptides, historical oral delivery mechanisms can only delivery bioavailabities of a few percent. In some cases, dose limiting toxicity levels are caused by lack of selectivity. Although oral delivery meets the need for self-administered drugs, targeted, sustained release and increased bioavailability present the areas of difficulty in meeting the emerging value proposition.
To address this difficulty, companies are developing micro-fabricated drug delivery systems. Technologies such as nano-pore membranes and micro-particles enable the drug to survive stomach acids and be released at specific targeted areas of the gastrointestinal tract. These technologies are being developed to provide more efficient drug absorption and enhanced bioavailability.
Pulmonary delivery provides a number of benefits particularly with regard to absorption area and avoidance of first pass metabolism in the liver. However, meeting the sustained-release goal is somewhat problematic. The lungs tend to expel materials that are introduced and it is therefore difficult to keep the drug in the lung long enough for the sustained release to be effective. Additional challenges revolve around elimination of excipient (enabling delivery of a neat drug), elimination of CFC propellants (in the case of MDI), reduction of the stigma associated with inhalers, and ease of use. A number of companies are working in this arena with technologies varying from ultrasonic de-aggregation, to heat vaporization of the drug.
Transdermal patches have been used for a number of years. To improve their effectiveness for a broader range of drugs, devices are being developed that disrupt the skin barrier to allow drug transfer to the interstitial fluid.
Technologies are being developed that range from ultrasonic disruption of the skin, to micro-projections, to using electro-transport to drive molecules though the skin barrier. These technologies are being developed individually and in various combinations.
Although from a patient standpoint the elimination of injections is ideal, indications are that injection will remain a necessary means of drug delivery. To minimize the pain, biohazard, cost and inconvenience associated with injections, companies are working to reduce the negative aspects of this delivery method. Along these lines, advances in needle-free injection, micro needle injection and MEMS syringes are under development. To minimize the number of injections required new implants and time release approaches are in development.
Meeting the need for better bioavailability and reduced side effects is not being left only to the mechanical delivery systems; methods are being developed to better target the drug once it is introduced into the body.
Ultrasound or other energy sources are being used to activate the drug once it reaches the targeted location. Receptors are being used to target specific cells, and in the event that a targeted cell does not have a required receptor, methods for adding receptors for a specific drug are being developed.
1.3. Competitive Landscape
A top-level view of the competitive landscape and some of the companies involved in various areas has been developed as follows:
Sustained Release Technology
• Injectable: MacroMed (Oligosphere); Alkermes (ProLease, Medisorb)
• Oral: (MacroMed (SQ2Gel); Altus Biologics (Crystalized proteins); Alkermes (PLG microspheres); Spherics (sticky spheres); DepoMed (GR System)
• Ocular: InSite Vision (Durasite polymer eye drops)
• Pulmonary: Acusphere (microspheres); Alkermes (AIR microparticles)
Targeted Delivery Technology
• Ultrasound activated: Point Medical (biSpheres); ImaRx (NanoInjection)
• RF activated: Scintipharma (Intelesite capsule)
Enhanced Absorption/Transport Technology
• Enhanced transmucosal absorption: Generex Biotechnology (oral mucosa target); Anesta Corp. (OTS oral mucosa target)
• Enhanced transdermal absorption: Sontra (ultrasonic); Antares (CombiGel — transdermal gel); Altea
(micropore technology); TransPharma Medical; Norwood Abbey (laser)
Implantable Technology
• Constant release: Alza (DUROS Implant); Guilford Pharmaceuticals (polymer wafers)
• Controllable release: MicroCHIPS (programmable MEMS implant)
Pulmonary Systemic Delivery
• Dry Powder: Nektar Therapeutics (formerly Inhale Therapeutic Systems (inhance, PulmoSpheres)); Alkermes
(AIR); Meridica (Xcelovair); GlaxoSmithKline (Diskus, Advair)
• Liquid Aerosol: Aradigm (AERx); Evit Labs (Sonik, LDI); Meridica (Xcelovent); Chrysalis Technologies ; GlaxoSmithKline (non CFC MDI’s) Transdermal/Intramuscular Technology
• Bolus injection: Becton Dickenson etc.
• Gas-based injection: Bioject (Biojector 2000); PowderJect (powder-based injection)
• Mechanical injection: Bioject (Vitajet 3); antares/Medi-Ject (Vision — Insulin injector, ZomaJet, SciToJet);
Norwood Abbey
• Micro needles: Altea/Elan (MEDIPAD); BioValve; Alza (Macroflux); MEMS Syringe (Berkeley); Norwood Abbey
• Electrotransport (Iontophoresis): Alza (E-Trans); Hisamitu Pharma; Iomed Clinical Systems; Vyteris; 3M Drug
Delivery Systems
• Ambulatory “Wearable/Reusable” Infusion: Abbott (AIM); Medtronic (MiniMed); PRO-MED (Smart Dose);
Electronic Infusion Systems (I-Flow, VIVUS 4000); I-Flow (Homepump Eclipse and C Series, Paragon); Animas (IR 1200 insulin pump)
• Ambulatory “Disposable” Infusion: Insulet (Insulin, basal and bolus)
1.4. Meeting the Challenge
Meeting the challenges that are presented by emerging drug technologies and the requirement for improved stakeholder benefits, including the impact of the aging population, will require some combination of drugs, delivery devices and mechanisms currently underdevelopment, as well as the identification and integration of new yet to be defined technologies. Complicating the need for self-administered, targeted, sustained release with increased bioavailability, is the need to improve patient compliance. To achieve improved compliance will require further simplification of the user experience. The next step can easily be envisioned as involving further integration of devices and drugs to provide means to deliver multiple therapies in a simple, pain free, unobtrusive, and targeted sustained release device. The proper combination of technology portfolios, intellectual property, market and stakeholder understanding required achieve this next step is the challenge on the horizon.
Making sense of this complex interaction of competing companies, intellectual property, core competencies, stakeholder needs, and technology trends, in a manner that will meet the corporate goals requires a structured methodology, such as the Innovation Genesis framework, to drive corporate planning and decision-making. Based on the corporate strategies, portfolio investments can be managed to meet the appropriate mix of high and low risk activities for the company. By establishing a deep understanding of convergent trend (and the conditions and drivers underlying the trends), and by maintaining knowledge of emerging technologies outside the core competencies of the firm, IP and technology portfolio strategies can be optimized. Visibility of long range evolution scenarios enables actionable short and mid range activities and decisions that are aligned with the long term goals. In short, this structured methodology enables Strategic Innovation. The approach enables informed technology investments that deliver meaningful business consequences, and the development of new ideas that fundamentally change the basis of competition within the drug delivery industry.
1.5. Biodegradable Implants
The biodegradable implant technology is a platform for parenteral delivery of drugs for periods of weeks to six months or more. The technology is based on the use of biodegradable polyester excipients, which have a proven record of safety and effectiveness in approved drug delivery and medical device products.
1.5.1. Overview of the Technology
The biodegradable implant technology is based on the use of biodegradable polyesters as excipients for implantable drug formulations. This family of materials, which is used extensively in medical devices and drug delivery applications, includes the polymers and copolymers prepared from glycolide, DL-lactide, L-lactide, and e-caprolactone. These thermoplastic materials are stable when dry but degrade by simple hydrolysis of the polymer backbone when exposed to an aqueous environment. The degradation times and physical properties of the biodegradable excipient can be engineered to achieve a wide variety of drug delivery goals by adjusting monomer composition and distribution, polymer molecular weight, and endgroup chemistry.
In addition to polymer engineering, the physical structure of implants is designed to achieve the desired therapeutic outcome. The overall form of the implant is typically a small rod or pellet that can be placed by means of a needle or trochar. The composition of the rod or pellet can be monolithic, where the drug is uniformly dispersed throughout the excipient. Alternatively, reservoir-type designs are also possible in which the rod or pellet is composed of a drug-rich core surrounded by a rate-controlling membrane. Depending on drug chemistry and desired kinetics, the membrane may or may not contain drug. Typically, the drug and excipient are mixed together, and the mixture is formed into a fiber, rod, tablet, or pellet by an extrusion or molding process. The ratecontrolling membrane, if required, may be applied during or subsequent to the core-forming process. The release of the drug from the implant can occur by degradation of the excipient, diffusion of the drug through the excipient or pores in the excipient, or a combination of degradation and diffusion. The relative contributions of these processes and the overall release profile are controlled by a number of variables including drug content, excipient composition, and implant design. As a result, a variety of drug delivery profiles including first-order, zero-order, delayed, and biphasic drug release can all be achieved with the implant technology.
Durin implant can be formulated with drug loading as high as 80 wt %.
Thus very small implants are able to provide prolonged therapy.
1.5.2. Peptides
Peptides are not typically permeable through dense biodegradable polymeric membranes; hence they are difficult to deliver with polymer implants. We have done a great deal of work with LHRH analogs such as leuprolide and goserelin, and have found that excipient properties can be modified so that these larger, water-soluble compounds can be delivered in a near zero-order manner. The release of a peptide from biodegradable implants compared to conventionally design hydrophobic DL-PLG implants. The implant demonstrates near zero-order release with no initial burst. These implants were later used in Phase I human clinical trials.
1.5.3. Safety and Toxicology
The biodegradable polyester excipients used in implants have been approved in over 30 medical devices and drug delivery systems since the first suture based on poly-glycolide was approved by the FDA in the 1970‘s. One notable example of a commercially successful biodegradable implant formulation is Zoladex®, which delivers goserelin acetate for the treatment of prostate cancer. These excipients and the products based on them have a long history of use and acceptance by the FDA and other regulatory agencies.
1.5.4. Manufacturing
Typically, use melt extrusion at modest temperatures to produce biodegradable implants for drug delivery. The active and excipients are combined and fed to a melt extruder to produce a bulk rod, which is then cut to produce the unit dose. For coaxial, membrane-controlled implants, two extruders are operated to simultaneously produce the core and membrane in a continuous process. For particularly heat labile compounds, the technology is also compatible with proprietary manufacturing methods other than extrusion that ensure drug stability. Because implants are produced using continuous manufacturing processes, batch size is determined by the length of the extrusion run.
1.6. Non Biodegradable Implants
Non Biodegradable implants are available as monolithic systems or reservoir systems. The release kinetics of drugs from such system depends on both the solubility and diffusion coefficient of the drug in the polymer. In case of non biodegradable polymeric implant, a mini surgery is needed to remove the polymer from the body.
1.7. Polymer: Poly Lactic Acid
The disposal problem due to non-degradable petroleum based plastics has raised the demand for biodegradable polymers as means of reducing the environmental impact. Several aliphatic polyesters having similar material properties comparable to conventional plastics have been developed such as: poly (lactide) (PLA), polyhydroxyalkanoates (PHAs), poly (caprolactone) (PCL), and poly (butylene succinate) (PBS).
Among these biodegradable polymers, PLA has received the most attention because its raw material, L-lactic acid can be efficiently produced by fermentation from renewable resources such as starchy materials and sugars. Moreover, it has good properties such as high melting point (175 °C), high degree of transparency, and ease of fabrication. PLA can be synthesized either by condensation polymerization of lactic acid or by ring opening polymerization of lactide (the cyclic dimer of lactic acid). This polymer exists in three stereoforms: poly (L-lactide) (L-PLA), poly (D-lactide) (D-PLA), and poly (DL-lactide) (DL-PLA). L-PLA and D-PLA are semicrystalline and exhibit high tensile strength and low elongation. On the other hand, DL-PLA is more amorphous exhibiting a random distribution of both isomeric forms of lactic acid depending on the amount of D or L.
1.7.1. Medical Applications of PLA
Currently, PLA is primarily used for medical applications such as drug delivery devices, absorbable sutures, and as a material for medical implants and other related applications. The mechanical properties of PLA, which are comparable to polystyrene and polyethylene, have also stimulated interest in its application as packaging materials. Hence, it would be of interest to study the biodegradation mechanisms and biological treatment of PLA. The degradation of PLA has been studied several years ago, but understanding on this subject is still inadequate.
This is clearly evidenced by lack of information on the mechanisms involved and the microorganisms associated with the degradation. Majority of reports concluded that PLA degradation occurred strictly through hydrolysis with no enzymatic involvement. Other reports suggest that enzymes have a significant role in the degradation of PLA
1.7.2. Factors influencing the biodegradation behavior of PLA
In general, polymer degradation takes place through the scission of the main chains or side chains of polymers. Different degradation mechanisms whether chemical or biological can be involved in the degradation of biodegradable polyesters. A combination of these mechanisms can also happen at some stage of degradation.
There are several important factors that affect the biodegradability of polymers. These are:
(1) Factors associated with the first-order structure (chemical structure, molecular weight and molecular weight distribution);
(2) Factors associated with the higher order structure [glass transition temperature (Tg), melting temperature (Tm), crystallinity, crystal structure and modulus of elasticity]; and
(3) Factors related to surface conditions (surface area, hydrophilic, and hydrophobic properties) (Nishida and Tokiwa 1992).
1.7.3. Biodegradation of PLA
Poly (lactide) (PLA) has been developed and made commercially available in recent years. One of the major tasks to be taken before the widespread application of PLA is the fundamental understanding of its biodegradation mechanisms.
Most of the PLA-degrading microorganisms phylogenetically belong to the family of Pseudonocardiaceae and related genera such as Amycolatopsis, Lentzea, Kibdelosporangium, Streptoalloteichus, and Saccharothrix.
Several proteinous materials such as silk fibroin, elastin, gelatin, and some peptides and amino acids were found to stimulate the production of enzymes from PLA-degrading microorganisms. In addition to proteinase K from Tritirachium album, subtilisin, a microbial serine protease and some mammalian serine proteases such as ?-chymotrypsin, trypsin, and elastase could also degrade PLA.
1.8. Drug: Metoprolol Tartrate
Metoprolol tartrate USP, is a selective beta1-adrenoreceptor blocking agent, available as 50- and 100-mg tablets for oral administration and in 5-mL ampoules for ministration. Each ampul contains a sterile solution of metoprolol tartrate USP, 5 mg, and sodium chloride USP, 45 mg, and water for injection USP. Metoprolol tartrate USP is (±)-1-v (Isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol L-(+)-tartrate (2:1) salt.
Metoprolol tartrate USP is a white, practically odorless, crystalline powder with a molecular weight of 684.82. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether.
Pic: Chemical structure of Metoprolol Tartrate
1.8.1. Physical Data
Melt Point: 1200 c (2480 F)
1.8.2. Pharmacokinetic Data
Bioavailability: 12%
Metabolism: Hepatic
Half life: 3-7 hours
Excretion: Renal
1.8.3. Inactive Ingredients
Tablets contain cellulose compounds, colloidal silicon dioxide, D&C Red
No. 30 aluminum lake (50-mg tablets), FD&C Blue No. 2 aluminum lake (100-mg tablets), lactose, magnesium stearate, polyethylene glycol, propylene glycol, povidone, sodium starch glycolate, talc, and titanium dioxide.
1.8.4. CLINICAL PHARMACOLOGY
Metoprolol is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, Metoprolol also inhibits beta2 adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by
(1) reduction in heart rate and cardiac output at rest and upon exercise,
(2) reduction of systolic blood pressure upon exercise,
(3) inhibition of isoproterenol-induced tachycardia, and
(4) reduction of reflex orthostatic tachycardia.
Relative beta1 selectivity has been confirmed by the following:
(1) In normal subjects, Metoprolol is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective (beta1 plus beta2) beta blockers, which completely reverse the vasodilating effects of epinephrine.
(2) In asthmatic patients, Metoprolol reduces FEV1 and FVC significantly less than a nonselective beta blocker, propranolol, at equivalent beta1-receptor blocking doses.
Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at doses much greater than required for beta blockade. Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Animal and human experiments indicate that Metoprolol slows the sinus rate and decreases AV nodal conduction.
In controlled clinical studies, Metoprolol has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100- 450 mg daily. In controlled, comparative, clinical studies, Metoprolol has been shown to be as effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, and to be equally effective in supine and standing positions.
The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed:
(1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output;
(2) a central effect leading to reduced sympathetic outflow to the periphery; and
(3) suppression of renin activity.
By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, Metoprolol reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris. However, in patients with heart failure, beta-adrenergic blockade may increase oxygen requirements by increasing left ventricular fiber length and end-diastolic pressure.
Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
In controlled clinical trials, Metoprolol, administered two or four times daily, has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100-400 mg daily. A controlled, comparative, clinical trial showed that Metoprolol was indistinguishable from propranolol in the treatment of angina pectoris.
In a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, Metoprolol was shown to reduce 3-month mortality by 36% in patients with suspected or definite myocardial infarction. Patients were randomized and treated as soon as possible after their arrival in the hospital, once their clinical condition had stabilized and their hemodynamic status had been carefully evaluated.
Subjects were ineligible if they had hypotension, bradycardia, peripheral signs of shock, and/or more than minimal basal rales as signs of congestive heart failure. Initial treatment consisted of intravenous followed by oral administration of Metoprolol or placebo, given in a coronary care or comparable unit. Oral maintenance therapy with Metoprolol or placebo was then continued for
3 months. After this double-blind period, all patients were given Metoprolol and followed up to 1 year.
The median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the Metoprolol- and placebo-treatment groups. Among patients treated with Metoprolol, there were comparable reductions in 3-month mortality for those treated early (?8 hours) and those in whom treatment was started later.
Significant reductions in the incidence of ventricular fibrillation and in chest pain following initial intravenous therapy were also observed with Metoprolol and were independent of the interval between onset of symptoms and initiation of therapy.
The precise mechanism of action of Metoprolol in patients with suspected or definite myocardial infarction is not known.
In this study, patients treated with metoprolol received the drug both very early (intra-venously) and during a subsequent 3-month period, while placebo patients received no beta-blocker treatment for this period. The study thus was able to show a benefit from the overall metoprolol regimen but cannot separate the benefit of very early intravenous treatment from the benefit of later beta-blocker therapy. Nonetheless, because the overall regimen showed a clear beneficial effect on survival without evidence of an early adverse effect on survival, one acceptable dosage regimen is the precise regimen used in the trial. Because the specific benefit of very early treatment remains to be defined however, it is also reasonable to administer the drug orally to patients at a later time as is recommended for certain other beta blockers.
1.8.5. Pharmacokinetics
In man, absorption of Metoprolol is rapid and complete. Plasma levels following oral administration, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S-enantiomers. Less than 5% of an oral dose of Metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no clinical significance. The systemic availability and half-life of Metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure.
Metoprolol is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of Metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers.
Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of Metoprolol than extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the CYP2D6 dependent metabolism of metoprolol seems to have little or no effect on safety or tolerability of the drug. None of the metabolites of metoprolol contribute significantly to its betablocking effect.
Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1 hour after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum registered effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0, and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice daily, a significant reduction in exercise systolic blood pressure was evident at 12 hours.
Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. When the drug was infused over a 10-minute period, in normal volunteers, maximum beta blockade was achieved at approximately 20 minutes. Doses of 5 mg and 15 mg yielded a maximal reduction in exercise-induced heart rate of approximately 10% and 15%, respectively. The effect on exercise heart rate decreased linearly with time at the same rate for both doses, and disappeared at approximately 5 hours and 8 hours for the 5-mg and 15-mg doses, respectively. Equivalent maximal beta-blocking effect is achieved with oral and intravenous doses in the ratio of approximately 2.5:1.
There is a linear relationship between the log of plasma levels and reduction of exercise heart rate. However, antihypertensive activity does not appear to be related to plasma levels. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to dose, selection of proper dosage requires individual titration.
In several studies of patients with acute myocardial infarction, intravenous followed by oral administration of metoprolol caused a reduction in heart rate, systolic blood pressure, and cardiac output. Stroke volume, diastolic blood pressure, and pulmonary artery end diastolic pressure remained unchanged.
In patients with angina pectoris, plasma concentration measured at 1 hour is linearly related to the oral dose within the range of 50-400 mg. Exercise heart rate and systolic blood pressure are reduced in relation to the logarithm of the oral dose of metoprolol. The increase in exercise capacity and the reduction in left ventricular ischemia are also significantly related to the logarithm of the oral dose. In elderly subjects with clinically normal renal and hepatic function, there are no significant differences in metoprolol pharmacokinetics compared to young subjects.
1.8.6. INDICATIONS AND USAGE
Hypertension
Metoprolol tablets are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive agents.
Angina Pectoris
Metoprolol is indicated in the long-term treatment of angina pectoris.
Myocardial Infarction
Metoprolol ampuls and tablets are indicated in the treatment of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality. Treatment with intravenous Metoprolol can be initiated as soon as the patient’s clinical condition allows (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS). Alternatively, treatment can begin within 3 to 10 days of the acute event (see DOSAGE AND ADMINISTRATION).
1.8.7. CONTRAINDICATIONS
Hypertension and Angina
Metoprolol is contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure (see WARNINGS). Hypersensitivity to Metoprolol and related derivatives, or to any of the excipients; hypersensitivity to other beta blockers (cross sensitivity between beta blockers can occur), Sick-sinus syndrome, Severe peripheral arterial circulatory disorders.
Myocardial Infarction
Metoprolol is contraindicated in patients with a heart rate <45 beats/min; second- and third-degree heart block; significant first-degree heart block (P-R interval ?0.24 sec); systolic blood pressure <100 mmHg; or moderate-to-severe cardiac failure (see WARNINGS).
1.8.8. WARNINGS
1.8.8.1. Hypertension and Angina
Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In hypertensive and angina patients who have congestive heart failure controlled by digitalis and diuretics, Metoprolol should be administered cautiously.
In Patients without a History of Cardiac Failure: Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic. The response should be observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, Metoprolol should be withdrawn.
Ischemic Heart Disease: Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered Metoprolol, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, Metoprolol administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue Metoprolol therapy abruptly even in patients treated only for hypertension.
Bronchospastic Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD,
IN GENERAL, NOT RECEIVE BETA BLOCKERS, including Metoprolol. Because of its
relative beta1 selectivity, however, Metoprolol may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta1 selectivity is not absolute, a beta2-stimulating agent should be administered concomitantly, and the lowest possible dose of Metoprolol should be used.
In these circumstances it would be prudent initially to administer Metoprolol in smaller doses three times daily, instead of larger doses two times daily, to avoid the higher plasma levels associated with the longer dosing interval (see DOSAGE AND ADMINISTRATION).
Major Surgery:
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Diabetes and Hypoglycemia: Metoprolol should be used with caution in diabetic patients if a betablocking agent is required. Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
Pheochromocytoma: If Metoprolol is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.
Thyrotoxicosis: Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid storm.
1.8.8.2. Myocardial Infarction
Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function, and beta blockade carries the potential hazard of depressing myocardial contractility and precipitating or exacerbating minimal cardiac failure.
During treatment with Metoprolol, the hemodynamic status of the patient should be carefully monitored. If heart failure occurs or persists despite appropriate treatment, Metoprolol should be discontinued.
Bradycardia: Metoprolol produces a decrease in sinus heart rate in most patients; this decrease is greatest among patients with high initial heart rates and least among patients with low initial heart rates. Acute myocardial infarction (particularly inferior infarction) may in itself produce significant lowering of the sinus rate. If the sinus rate decreases to <40 beats/min, particularly if associated with evidence of lowered cardiac output, atropine (0.25-0.5 mg) should be administered intravenously. If treatment with atropine is not successful, Metoprolol should be discontinued, and cautious administration of isoproterenol or installation of a cardiac pacemaker should be considered.
AV Block: Metoprolol slows AV conduction and may produce significant first- (P-R interval ?0.26 sec), second-, or third-degree heart block. Acute myocardial infarction also produces heart block. If heart block occurs, Metoprolol should be discontinued and atropine (0.25-0.5 mg) should be administered intravenously. If treatment with atropine is not successful, cautious administration of isoproterenol or installation of a cardiac pacemaker should be considered.
Hypotension: If hypotension (systolic blood pressure ?90 mmHg) occurs, Metoprolol should be discontinued, and the hemodynamic status of the patient and the extent of myocardial damage carefully assessed. Invasive monitoring of central venous, pulmonary capillary wedge, and arterial pressures may be required. Appropriate therapy with fluids, positive inotropic agents, balloon counterpulsation, or other treatment modalities should be instituted. If hypotension is associated with sinus bradycardia or AV block, treatment should be directed at reversing these (see above).
Bronchospastic Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD,
IN GENERAL, NOT RECEIVE BETA BLOCKERS, including Metoprolol. Because of its relative beta1 selectivity, Metoprolol may be used with extreme caution in patients with bronchospastic disease. Because it is unknown to what extent beta2-stimulating agents may exacerbate myocardial ischemia and the extent of infarction, these agents should not be used prophylactically. If bronchospasm not related to congestive heart failure occurs, Metoprolol should be discontinued. A theophylline derivative or a beta2 agonist may be administered cautiously, depending on the clinical condition of the patient. Both theophylline derivatives and beta2 agonists may produce serious cardiac arrhythmias.
1.9. PRECAUTIONS
General
Metoprolol should be used with caution in patients with impaired hepatic function.
Information for Patients
Patients should be advised to take Metoprolol regularly and continuously, as directed, with or immediately following meals. If a dose should be missed, the patient should take only the next scheduled dose (without doubling it). Patients should not discontinue Metoprolol without consulting the physician. Patients should be advised
(1) To avoid operating automobiles and machinery or engaging in other
tasks requiring alertness until the patient’s response to therapy with Metoprolol has been determined;
(2) To contact the physician if any difficulty in breathing occurs;
(3) To inform the physician or dentist before any type of surgery that he or she is taking Metoprolol.
Drug Interactions
Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with Metoprolol plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Risk of Anaphylactic Reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
General Anesthetics
Some inhalation anesthetics may enhance the cardiodepressant effect of beta blockers (see WARNINGS, Major Surgery).
CYP2D6 Inhibitors
Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of Metoprolol. Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer (see Pharmacokinetics section). Caution should therefore be exercised when coadministering potent CYP2D6 inhibitors with Metoprolol. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.
Clonidine
If a patient is treated with clonidine and Metoprolol concurrently, and clonidine treatment is to be discontinued, Metoprolol should be stopped several days before clonidine is withdrawn. Rebound hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta-blocker treatment.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2-year study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type.
The onlyhistologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg per day, benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, or in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.
All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) were negative.
No evidence of impaired fertility due to Metoprolol was observed in a study performed in rats at doses up to 55.5 times the maximum daily human dose of 450 mg.
Pregnancy Category C
Metoprolol has been shown to increase postimplantation loss and decrease neonatal survival in rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution studies in mice confirm exposure of the fetus when Metoprolol is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Metoprolol is excreted in breast milk in a very small quantity. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Caution should be exercised when Metoprolol is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical trials of Metoprolol in hypertension did not include sufficient numbers of elderly patients to determine whether patients over 65 years of age differ from younger subjects in their response to Metoprolol. Other reported clinical experience in elderly hypertensive patients has not identified any difference in response from younger patients.
In worldwide clinical trials of Metoprolol in myocardial infarction, where approximately 478 patients were over 65 years of age (0 over 75 years of age), no age-related differences in safety and effectiveness were found. Other reported clinical experience in myocardial infarction has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some elderly individuals taking Metoprolol cannot be categorically ruled out.
Therefore, in general, it is recommended that dosing proceed with caution in this population.
1.10. ADVERSE REACTIONS
Hypertension and Angina
Most adverse effects have been mild and transient.
Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients.
Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss have been reported. Headache, nightmares, and insomnia have also been reported.
Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; congestive heart failure; peripheral edema; and hypotension have been reported in about 1 of 100 patients. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also been reported very rarely. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS.)
Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100 patients (see WARNINGS). Rhinitis has also been reported.
Gastrointestinal: Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn have been reported in about 1 of 100 patients. Vomiting was a common occurrence. Postmarketing experience reveals very rare reports of hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline phosphatase, and lactic dehydrogenase elevations have also been reported.
Hypersensitive Reactions: Pruritus or rashes have occurred in about 5 of 100 patients. Very rarely, photosensitivity and worsening of psoriasis has been reported.
Miscellaneous: Peyronie’s disease has been reported in fewer than 1 of 100,000 patients. Musculoskeletal pain, blurred vision, and tinnitus have also been reported. There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. There have been very rare reports of weight gain, arthritis, and retroperitoneal fibrosis (relationship to Metoprolol has not been definitely established). The oculomucocutaneous syndrome associated with the beta blocker practolol has not been reported with Metoprolol.
Myocardial Infarction
Central Nervous System: Tiredness has been reported in about 1 of 100 patients. Vertigo, sleep disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reduced libido have also been reported, but a drug relationship is not clear.
Cardiovascular: In the randomized comparison of Metoprolol and placebo described in the CLINICAL PHARMACOLOGY section, the following adverse reactions were reported:
a) Metoprolol (Lopressor®) Placebo
Hypotension (systolic BP <90 mmHg) 27.4% 23.2%
Bradycardia (heart rate <40 beats/min) 15.9% 6.7%
Second- or third-degree heart block 4.7% 4.7%
First-degree heart block (P-R ?0.26 sec) 5.3% 1.9%
Heart failure 27.5% 29.6%
b) Respiratory: Dyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients.
c) Gastrointestinal: Nausea and abdominal pain have been reported in fewer than 1 of 100 patients.
d) Dermatologic: Rash and worsened psoriasis have been reported, but a drug relationship is not clear.
e) Miscellaneous: Unstable diabetes and claudication have been reported, but a drug relationship is not clear.
Potential Adverse Reactions
A variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to Metoprolol.
Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics.
Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS).
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm, and respiratory distress.
Postmarketing Experience
The following adverse reactions have been reported during postapproval use of Metoprolol:
confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein (HDL). Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency.
1.11. OVERDOSAGE
Acute Toxicity
Several cases of overdosage have been reported, some leading to death.
Oral LD 50’s (mg/kg): mice, 1158-2460; rats, 3090-4670.
1.12. Signs and Symptoms
Potential signs and symptoms associated with overdosage with Metoprolol are bradycardia, hypotension, bronchospasm, and cardiac failure.
1.13. Treatment
There is no specific antidote. In general, patients with acute or recent myocardial infarction may be more hemodynamically unstable than other patients and should be treated accordingly (see WARNINGS, Myocardial Infarction). On the basis of the pharmacologic actions of Metoprolol, the following general measures should be employed:
Elimination of the Drug: Gastric lavage should be performed.
Bradycardia: Atropine should be administered. If there is no response to vagal blockade, isoproterenol should be administered cautiously.
Hypotension: A vasopressor should be administered, e.g., levarterenol or dopamine.
Bronchospasm: A beta2-stimulating agent and/or a theophylline derivative should be administered.
Cardiac Failure: A digitalis glycoside and diuretic should be administered. In shock resulting from inadequate cardiac contractility, administration of dobutamine,
isoproterenol, or glucagon may be considered.
1.14. DOSAGE AND ADMINISTRATION
Hypertension
The dosage of Metoprolol tablets should be individualized. Metoprolol tablets should be taken with or immediately following meals. The usual initial dosage of Metoprolol tablets is 100 mg daily in single or divided doses, whether used alone or added to a diuretic. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. The effective dosage range of Metoprolol tablets is 100-450 mg per day. Dosages above 450 mg per day have not been studied. While once daily dosing is effective and can maintain a reduction in blood pressure throughout the day, lower doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period, and larger or more frequent daily doses may be required. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control