Medication Safety Issues

Sound-alike/look-alike issues:

Tetracycline may be confused with tetradecyl sulfate

Achromycin may be confused with actinomycin, Adriamycin PFS®

Pronunciation

(tet ra SYE kleen)

Canadian Brand Names

Apo-Tetra®; Nu-Tetra

Pharmacologic Category

Antibiotic, Tetracycline Derivative

Use: Labeled Indications

Treatment of susceptible bacterial infections of both gram-positive and gram-negative organisms;

also infections due to Mycoplasma, Chlamydia, and Rickettsia; indicated for acne, exacerbations
of chronic bronchitis, and treatment of gonorrhea and syphilis in patients who are allergic to
penicillin; as part of a multidrug regimen for H. pylori eradication to reduce the risk of duodenal
ulcer recurrence

Use: Dental

Treatment of periodontitis associated with presence of Actinobacillus actinomycetemcomitans

(AA); as adjunctive therapy in recurrent aphthous ulcers

Dosing: Adults
Usual dosage range: Oral: 250-500 mg every 6 hours

Acne: Oral: 250-500 twice daily

Chronic bronchitis, acute exacerbation: Oral: 500 mg 4 times/day

Erlichiosis: Oral: 500 mg 4 times/day for 7-14 days

Peptic ulcer disease: Eradication of Helicobacter pylori: Oral: 500 mg 2-4 times/day depending
on regimen; requires combination therapy with at least one other antibiotic and an acid-
suppressing agent (proton pump inhibitor or H2 blocker)

Periodontitis: Oral: 250 mg every 6 hours until improvement (usually 10 days)

Vibrio cholerae: Oral: 500 mg 4 times/day for 3 days

Dosing: Elderly

Refer to adult dosing.

Dosing: Pediatric

Usual dosage range: Children >8 years: Oral: 25-50 mg/kg/day in divided doses every 6 hours

Dosing: Renal Impairment

Clcr 50-80 mL/minute: Administer every 8-12 hours.

Clcr 10-50 mL/minute: Administer every 12-24 hours.

Clcr <10 mL/minute: Administer every 24 hours.

Slightly dialyzable (5% to 20%) via hemo- and peritoneal dialysis or via continuous
arteriovenous or venovenous hemofiltration; supplemental dose is not necessary.

Dosing: Hepatic Impairment

Use caution; no dosing adjustment required

 Calculations

 Creatinine Clearance: Adults

 Creatinine Clearance: Pediatrics

Administration: Oral

Oral should be given on an empty stomach (ie, 1 hour prior to, or 2 hours after meals) to increase
total absorption. Administer at least 1-2 hours prior to, or 4 hours after antacid because
aluminum and magnesium cations may chelate with tetracycline and reduce its total absorption.
Administer around-the-clock to promote less variation in peak and trough serum levels.

Storage

Outdated tetracyclines have caused a Fanconi-like syndrome (nausea, vomiting, acidosis,

proteinuria, glycosuria, aminoaciduria, polydipsia, polyuria, hypokalemia). Protect oral dosage
forms from light.

Contraindications

Hypersensitivity to tetracycline or any component of the formulation; do not administer to

children ≤8 years of age; pregnancy

Allergy Considerations

 Tetracycline Allergy

Warnings/Precautions

Concerns related to adverse effects:

• Increased BUN: May be associated with increases in BUN secondary to antianabolic
effects; use caution in patients with renal impairment.

• Nephropathy: Outdated drug can cause nephropathy.

• Photosensitivity: May cause photosensitivity; discontinue if skin erythema occurs. Use
skin protection and avoid prolonged exposure to sunlight; do not use tanning
equipment.
 • Pseudotumor cerebri: Has been (rarely) reported with tetracycline use; usually resolves
with discontinuation.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection,

including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis;
CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Hepatic impairment: Hepatotoxicity has been reported rarely; risk may be increased in
patients with pre-existing hepatic or renal impairment.

• Renal impairment: Use with caution in patients with renal impairment; dosage
adjustment recommended.

Special populations:

• Pediatrics: May cause tissue hyperpigmentation, enamel hypoplasia, or permanent tooth
discoloration; use of tetracyclines should be avoided during tooth development
(children ≤8 years of age) unless other drugs are not likely to be effective or are
contraindicated. However, recommended in treatment of anthrax exposure.

• Pregnancy: Do not use during pregnancy. In addition to affecting tooth development,
tetracycline use has been associated with retardation of skeletal development and
reduced bone growth.

Geriatric Considerations

The role of tetracycline has decreased because of the emergence of resistant organisms.
Doxycycline is the tetracycline of choice when one is indicated because of its better GI
absorption, less interactions with divalent cations, longer half-life, and the fact that the majority
is cleared by nonrenal mechanisms.

Pregnancy Risk Factor

Pregnancy Considerations

Tetracyclines cross the placenta, enter fetal circulation, and may cause permanent discoloration
of teeth if used during the second or third trimester. Maternal hepatic toxicity has been associated
with the use of tetracycline during pregnancy, especially in patients with azotemia or
pyelonephritis. Because use during pregnancy may cause fetal harm, tetracycline is classified as
pregnancy category D.

Lactation

Enters breast milk/not recommended (AAP rates “compatible”)

Breast-Feeding Considerations

Tetracyclines are excreted in breast milk. Tetracycline binds to calcium. The calcium in the
maternal milk will decrease the amount of tetracycline absorbed by the breast-feeding infant.
Because of this “negligible absorption by the neonate,” the AAP considers tetracycline to
be “usually compatible with breast-feeding.” Nondose-related effects could include
modification of bowel flora.

Pregnancy & Lactation, In-Depth

 Tetracycline in Pregnancy & Lactation

Adverse Reactions

Frequency not defined.

Cardiovascular: Pericarditis

Central nervous system: Intracranial pressure increased, bulging fontanels in infants,

pseudotumor cerebri, paresthesia

Dermatologic: Photosensitivity, pruritus, pigmentation of nails, exfoliative dermatitis

Endocrine & metabolic: Diabetes insipidus syndrome

Gastrointestinal: Discoloration of teeth and enamel hypoplasia (young children), nausea,

diarrhea, vomiting, esophagitis, anorexia, abdominal cramps, antibiotic-associated
pseudomembranous colitis, staphylococcal enterocolitis, pancreatitis

Hematologic: Thrombophlebitis

Hepatic: Hepatotoxicity

Renal: Acute renal failure, azotemia, renal damage

Miscellaneous: Superinfection, anaphylaxis, hypersensitivity reactions, candidal superinfection

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Inhibits CYP3A4 (moderate)

Drug Interactions

Antacids: May decrease the absorption of Tetracycline Derivatives. Risk D: Consider therapy
modification

Atovaquone: Tetracycline may decrease the serum concentration of Atovaquone. Risk C:

Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Tetracycline Derivatives. Risk D:
Consider therapy modification

Bismuth: May decrease the absorption of Tetracycline Derivatives. Risk D: Consider therapy
modification

Bismuth Subsalicylate: May decrease the absorption of Tetracycline Derivatives. Risk D:

Consider therapy modification

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C:
Monitor therapy

CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4
Substrates. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor
therapy

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of

Eplerenone. Management: A lower starting dose of eplerenone (25 mg once daily) is
recommended in patients with hypertension who are also taking drugs that are moderate
inhibitors of CYP3A4. Risk D: Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL.
Risk D: Consider therapy modification

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C:
Monitor therapy
Iron Salts: May decrease the absorption of Tetracycline Derivatives. Only a concern with orally
administered products. Exceptions: Ferric Gluconate; Iron Dextran Complex; Iron Sucrose.
Risk D: Consider therapy modification

Magnesium Salts: May decrease the absorption of Tetracycline Derivatives. Only applicable to
oral preparations of each agent. Risk D: Consider therapy modification

Maraviroc: CYP3A4 Inhibitors may increase the serum concentration of Maraviroc. Risk D:
Consider therapy modification

Neuromuscular-Blocking Agents: Tetracycline Derivatives may enhance the neuromuscular-

blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor therapy

Penicillins: Tetracycline Derivatives may diminish the therapeutic effect of Penicillins. Risk D:
Consider therapy modification

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus.

Risk C: Monitor therapy

Quinapril: May decrease the absorption of Tetracycline Derivatives. Risk D: Consider therapy
modification

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of

Ranolazine. Management: Limit the ranolazine dose to a maximum of 500mg twice daily in
patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil,
erythromycin, etc.). Risk D: Consider therapy modification

Retinoic Acid Derivatives: Tetracycline Derivatives may enhance the adverse/toxic effect of
Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular
concern. Exceptions: Adapalene; Alitretinoin; Tretinoin (Topical). Risk X: Avoid
combination

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol.
Risk C: Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the
live attenuated Ty21a strain is affected. Risk D: Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Tetracycline Derivatives may enhance the anticoagulant
effect of Vitamin K Antagonists. Risk C: Monitor therapy

Zinc Salts: May decrease the absorption of Tetracycline Derivatives. Only a concern when both
products are administered orally. Exceptions: Zinc Chloride. Risk D: Consider therapy
modification
 Ethanol/Nutrition/Herb Interactions

Food: Tetracycline serum concentrations may be decreased if taken with dairy products.

Herb/Nutraceutical: Avoid dong quai, St John's wort (may also cause photosensitization)

Test Interactions

False-negative urine glucose with Clinistix®

Monitoring Parameters

Renal, hepatic, and hematologic function test, temperature, WBC, cultures and sensitivity,
appetite, mental status

Nursing: Physical Assessment/Monitoring

Assess results of culture and sensitivity tests and patient’s allergy history prior to beginning
therapy. Assess potential interactions with other pharmacological agents and herbal products
patient may be using (eg, may decrease levels/effects of penicillins and CYP3A4 inducers,
increase levels/effects of warfarin and CYP3A4 substrates). Assess results of laboratory tests,
therapeutic effectiveness (resolution of infection), and adverse reactions (eg, nausea, diarrhea,
pericarditis, photosensitivity, rash, opportunistic infection, hypersensitivity) at beginning of and
periodically throughout therapy. Caution patients with diabetes to monitor glucose levels closely
(may cause false-positive urine glucose with Clinitest®). Assess knowledge/teach patient
appropriate use, interventions to reduce side effects, and adverse symptoms to report.

Monitoring: Lab Tests

Renal, hepatic, and hematologic function; WBC. Perform culture and sensitivity studies prior to
initiating therapy to determine the causative organism and its susceptibility to tetracycline.

Patient Education

Do not use more or more often than recommended. Preferable to take on an empty stomach, 1
hour before or 2 hours after meals. Take at regularly scheduled times, around-the-clock. Avoid
antacids, iron, or dairy products within 2 hours of taking tetracycline. You may experience
photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight);
dizziness or lightheadedness (use caution when driving or engaging in tasks requiring alertness
until response to drug is known); or nausea/vomiting (small, frequent meals, frequent mouth
care, chewing gum, or sucking lozenges may help). Report rash or intense itching, yellowing of
skin or eyes, fever or chills, blackened stool, vaginal itching or discharge, foul-smelling stools,
excessive thirst or urination, acute headache, unresolved or persistent diarrhea, respiratory
difficulty, condition does not improve, or worsening of condition. Pregnancy/breast-feeding
precautions: Do not get pregnant while taking this medication. Use appropriate barrier
contraceptive measures. Breast-feeding is not recommended.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult
specific product labeling.

Capsule, as hydrochloride: 250 mg, 500 mg

Generic Available

Yes: Capsule

Pricing: U.S. (www.drugstore.com)

Capsules (Tetracycline HCl)

250 mg (100): $14.99

500 mg (100): $19.99

Mechanism of Action

Inhibits bacterial protein synthesis by binding with the 30S and possibly the 50S ribosomal
subunit(s) of susceptible bacteria; may also cause alterations in the cytoplasmic membrane

Pharmacodynamics/Kinetics

Absorption: Oral: 75%

Distribution: Small amount appears in bile

Relative diffusion from blood into CSF: Good only with inflammation (exceeds usual
MICs)

CSF:blood level ratio: Inflamed meninges: 25%

Protein binding: ~65%

Half-life elimination: Normal renal function: 8-11 hours; End-stage renal disease: 57-108 hours

Time to peak, serum: Oral: 2-4 hours

Excretion: Urine (60% as unchanged drug); feces (as active form)

Related Information

 Antacid Drug Interactions

 Antimicrobial Drugs of Choice
 Malaria Treatment

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Esophagitis, superinfections, and candidal
superinfection. Opportunistic “superinfection” with Candida albicans; tetracyclines are not
recommended for use during pregnancy or in children ≤8 years of age since they have been
reported to cause enamel hypoplasia and permanent teeth discoloration. The use of tetracyclines
should only be used in these patients if other agents are contraindicated or alternative
antimicrobials will not eradicate the organism. Long-term use associated with oral candidiasis.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

None reported

Mental Health: Effects on Psychiatric Treatment

Tetracycline may decrease lithium clearance resulting in an increase in serum lithium levels and
potential lithium toxicity although the clinical significance is likely minimal; monitor serum
lithium levels

Index Terms

Achromycin; TCN; Tetracycline Hydrochloride

References

Medication Safety Issues

Sound-alike/look-alike issues:

Cimetidine may be confused with simethicone

Pronunciation

(sye MET i deen)

U.S. Brand Names

Tagamet® HB 200 [OTC]

Canadian Brand Names

Apo-Cimetidine®; Gen-Cimetidine; Novo-Cimetidine; Nu-Cimet; PMS-Cimetidine;
Tagamet® HB

Pharmacologic Category

Histamine H2 Antagonist

Use: Labeled Indications

Short-term treatment of active duodenal ulcers and benign gastric ulcers; long-term prophylaxis
of duodenal ulcer; gastric hypersecretory states; gastroesophageal reflux; prevention of upper GI
bleeding in critically-ill patients; labeled for OTC use for prevention or relief of heartburn, acid
indigestion, or sour stomach

Use: Unlabeled/Investigational

Part of a multidrug regimen for H. pylori eradication to reduce the risk of duodenal ulcer
recurrence

Dosing: Adults

Short-term treatment of active ulcers:

Oral: 300 mg 4 times/day or 800 mg at bedtime or 400 mg twice daily for up to 8 weeks

Note: Higher doses of 1600 mg at bedtime for 4 weeks may be beneficial for a
subpopulation of patients with larger duodenal ulcers (>1 cm defined
endoscopically) who are also heavy smokers (≥1 pack/day).

I.M., I.V.: 300 mg every 6 hours or 37.5 mg/hour by continuous infusion; I.V. dosage should
be adjusted to maintain an intragastric pH ≥5

Prevention of upper GI bleed in critically-ill patients: 50 mg/hour by continuous infusion; I.V.

dosage should be adjusted to maintain an intragastric pH ≥5

Note: Reduce dose by 50% if Clcr <30 mL/minute; treatment >7 days has not been
evaluated.

Duodenal ulcer prophylaxis: Oral: 400 mg at bedtime

Gastric hypersecretory conditions: Oral, I.M., I.V.: 300-600 mg every 6 hours; dosage not to
exceed 2.4 g/day
Gastroesophageal reflux disease: Oral: 400 mg 4 times/day or 800 mg twice daily for 12 weeks

Peptic ulcer disease eradication ofHelicobacter pylori(unlabeled use): Oral: 400 mg twice
daily; requires combination therapy with antibiotics

Heartburn, acid indigestion, sour stomach (OTC labeling): Oral: 200 mg up to twice daily;
may take 30 minutes prior to eating foods or beverages expected to cause heartburn or
indigestion

Dosing: Elderly

Refer to adult dosing.

Dosing: Pediatric

Oral, I.M., I.V.: 20-40 mg/kg/day in divided doses every 6 hours

Heartburn, acid indigestion, sour stomach (OTC labeling): Children ≥12 years: Oral:
Refer to adult dosing.

Dosing: Renal Impairment

Clcr 10-50 mL/minute: Administer 50% of normal dose

Clcr <10 mL/minute: Administer 25% of normal dose

Slightly dialyzable (5% to 20%); administer after dialysis

Dosing: Hepatic Impairment

Usual dose is safe in mild liver disease but use with caution and in reduced dosage in severe liver
disease. Increased risk of CNS toxicity in cirrhosis suggested by enhanced penetration of CNS.

Calculations
 Creatinine Clearance: Adults
 Creatinine Clearance: Pediatrics

Administration: I.V.

May be administered as a slow I.V. push or preferably as an I.V. intermittent or I.V. continuous
infusion. Administer each 300 mg (or fraction thereof) over a minimum of 5 minutes when
giving I.V. push. Rapid intravenous administration has been associated with rare cases of
arrhythmia and/or hypotension. Give intermittent infusion over 15-30 minutes for each 300 mg
dose. Intermittent infusions are administered over 15-30 minutes at a final concentration not to
exceed 6 mg/mL; for patients with an active bleed, preferred method of administration is
continuous infusion.

Administration: I.V. Detail

Rapid infusion may cause cardiac arrhythmias and hypotension.

pH: 3.8-6.0 (injection); 5-7 (premixed infusion)

Administration: Oral

Give with meals so that the drug's peak effect occurs at the proper time (peak inhibition of
gastric acid secretion occurs at 1 and 3 hours after dosing in fasting subjects and approximately 2
hours in nonfasting subjects. This correlates well with the time food is no longer in the stomach
offering a buffering effect). Stagger doses of antacids with cimetidine.

Storage

Tablet: Store between 15°C and 30°C (59°F to 86°F); protect from light.

Solution for injection/infusion: Intact vials should be stored at room temperature, between
15°C and 30°C (59°F to 86°F); protect from light. May precipitate from solution
upon exposure to cold, but can be redissolved by warming without degradation.

Stability at room temperature:

Prepared bags: 7 days

Premixed bags: Manufacturer expiration dating and out of overwrap stability: 15 days

Stable in parenteral nutrition solutions for up to 7 days when protected from light.

Compatibility

Stable in D5LR, D51/4NS, D51/2NS, D5NS, D5W, D10W, D10NS, LR, sodium bicarbonate 5%, NS;
variable stability (consult detailed reference) in TPN.

Y-site administration: Compatible: Acyclovir, amifostine, aminophylline, atracurium,

aztreonam, cisatracurium, cisplatin, cladribine, clarithromycin, cyclophosphamide,
 cytarabine, diltiazem, docetaxel, doxorubicin, doxorubicin liposome, enalaprilat, esmolol,
etoposide, filgrastim, fluconazole, fludarabine, foscarnet, gatifloxacin, gemcitabine,
granisetron, haloperidol, heparin, hetastarch, idarubicin, inamrinone, labetalol, levofloxacin,
linezolid, melphalan, meropenem, methotrexate, midazolam, milrinone, ondansetron,
paclitaxel, pancuronium, piperacillin/tazobactam, propofol, remifentanil, sargramostim,
tacrolimus, teniposide, theophylline, thiotepa, tolazoline, topotecan, vecuronium,
vinorelbine, zidovudine. Incompatible: Allopurinol, amphotericin B cholesteryl sulfate
complex, amsacrine, cefepime, indomethacin, warfarin. Variable (consult detailed
reference): TPN.

Compatibility in syringe: Compatible: Atropine, butorphanol, diatrizoate meglumine and

diatrizoate sodium, diatrizoate sodium, diazepam, diphenhydramine, doxapram, droperidol,
fentanyl, glycopyrrolate, heparin, hydromorphone, hydroxyzine, iohexol, iopamidol,
iothalamate meglumine, lorazepam, meperidine, midazolam, morphine, nafcillin,
nalbuphine, penicillin G sodium, pentazocine, perphenazine, prochlorperazine edisylate,
promazine, promethazine, scopolamine, sodium acetate, sodium chloride, sodium lactate.
Incompatible: Atropine with pentobarbital, cefamandole, cefazolin, chlorpromazine,
ioxaglate meglumine and ioxaglate sodium, pentobarbital, secobarbital.

Compatibility when admixed: Compatible: Acetazolamide, amikacin, aminophylline,

ampicillin, atracurium, cefoperazone, cefoxitin, ceftazidime, chlorothiazide, clindamycin,
colistimethate, cryptenamine, dexamethasone sodium phosphate, digoxin, epinephrine,
erythromycin lactobionate, ethacrynate sodium, floxacillin, flumazenil, furosemide,
gentamicin, insulin (regular), isoproterenol, lidocaine, lincomycin, meropenem,
metaraminol, methylprednisolone sodium succinate, metoclopramide, norepinephrine,
penicillin G potassium, phytonadione, polymyxin B sulfate, potassium chloride, protamine,
quinidine gluconate, sodium nitroprusside, tacrolimus, vancomycin, verapamil, vitamin B
complex, vitamin B complex with C. Incompatible: Amphotericin B, barbiturates.
Variable (consult detailed reference): Cefamandole, cefazolin.

Contraindications

Hypersensitivity to cimetidine, any component of the formulation, or other H2 antagonists

Allergy Considerations
 Histamine H2 Antagonist Allergy

Warnings/Precautions

Concerns related to adverse effects:

• Confusion: Reversible confusional states, usually clearing within 3-4 days after
discontinuation, have been linked to use. Increased age (>50 years) and renal or
hepatic impairment are thought to be associated.
Disease-related concerns:

• Gastric malignancy: Relief of symptoms does not preclude the presence of a gastric
malignancy.

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage
adjustment recommended.

• Renal impairment: Use with caution in patients with renal impairment; dosage
adjustment recommended.

Concurrent drug therapy issues:

• Drugs metabolized through P450 system: Dosage should be adjusted in patients
receiving drugs metabolized through the P450 system.

Other warnings/precautions:

• I.V. administration: Rapid intravenous administration has been associated with rare
cases of arrhythmia and/or hypotension.

• OTC labeling: Should not be taken by individuals experiencing painful swallowing,
vomiting with blood, or bloody or black stools; medical attention should be sought. A
healthcare provider should be consulted prior to use when pain in the stomach,
shoulder, arms or neck is present; if heartburn has occurred for >3 months; or if
unexplained weight loss, or nausea and vomiting occur. Frequent wheezing, shortness
of breath, lightheadedness, or sweating, especially with chest pain or heartburn, should
also be reported. Consultation of a healthcare provider should occur by patients if also
taking theophylline, phenytoin, or warfarin; if heartburn or stomach pain continues or
worsens; or if use is required for >14 days. OTC cimetidine is not approved for use in
patients <12 years of age.

Geriatric Considerations

Patients diagnosed with PUD should be evaluated for Helicobacter pylori. H2 blockers are the
preferred drugs for treating PUD in elderly due to cost and ease of administration. These agents
are no less or more effective than any other therapy. The preferred agents, due to favorable
pharmacokinetic, side effect and drug interaction profiles are ranitidine, famotidine, and
nizatidine. Due to the potential for confusion and drug interactions, cimetidine has been
identified by a panel of experts as a drug to avoid in the elderly. Consider evaluating creatinine
clearance before initiating H2-blocker therapy.

Pregnancy Risk Factor

B

Pregnancy Considerations

Teratogenic events were not observed in animal studies.

Lactation

Enters breast milk/not recommended

Adverse Reactions

1% to 10%:

Central nervous system: Headache (2% to 4%), dizziness (1%), somnolence (1%), agitation

Endocrine & metabolic: Gynecomastia (<1% to 4%)

Gastrointestinal: Diarrhea (1%)

Frequency not defined:

Cardiovascular: AV block, bradycardia, hypotension, tachycardia, vasculitis

Central nervous system: Confusion, fever

Dermatologic: Alopecia, erythema multiforme, exfoliative dermatitis, Stevens-Johnson

syndrome, toxic epidermal necrolysis, rash

Endocrine & metabolic: Edema of the breasts, sexual ability decreased

Gastrointestinal: Nausea, pancreatitis, vomiting

Hematologic: Agranulocytosis, aplastic anemia, hemolytic anemia (immune-based),

neutropenia, pancytopenia, thrombocytopenia

Hepatic: ALT increased, AST increased, hepatic fibrosis (case report)

Neuromuscular & skeletal: Arthralgia, myalgia, polymyositis

Renal: Creatinine increased, interstitial nephritis

Miscellaneous: Anaphylaxis, pneumonia (causal relationship not established)

 Metabolism/Transport Effects

Inhibits CYP1A2 (moderate), 2C9 (weak), 2C19 (moderate), 2D6 (moderate), 2E1 (weak), 3A4
(moderate)

Drug Interactions

Alfentanil: Cimetidine may decrease the metabolism of Alfentanil. Risk C: Monitor therapy

Amiodarone: Cimetidine may decrease the metabolism of Amiodarone. Consider using an

alternative H2 antagonist. Risk D: Consider therapy modification

Anticonvulsants (Hydantoin): Cimetidine may decrease the metabolism of Anticonvulsants

(Hydantoin). Exceptions: Ethotoin. Risk D: Consider therapy modification

Antifungal Agents (Azole Derivatives, Systemic): H2-Antagonists may decrease the absorption
of Antifungal Agents (Azole Derivatives, Systemic). Exceptions: Miconazole;
Voriconazole. Risk D: Consider therapy modification

Atazanavir: H2-Antagonists may decrease the absorption of Atazanavir. Risk D: Consider

therapy modification

Benzodiazepines (metabolized by oxidation): Cimetidine may decrease the metabolism of

Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Calcium Channel Blockers: Cimetidine may decrease the metabolism of Calcium Channel
Blockers. Exceptions: AmLODIPine; Clevidipine; NiCARdipine. Risk D: Consider
therapy modification

CarBAMazepine: Cimetidine may increase the serum concentration of CarBAMazepine. The

serum carbamazepine concentration might return to normal within one week of starting
cimetidine. Risk C: Monitor therapy

Carmustine: Cimetidine may decrease the metabolism of Carmustine. Risk C: Monitor therapy

Carvedilol: Cimetidine may decrease the metabolism of Carvedilol. Risk C: Monitor therapy

Cefpodoxime: H2-Antagonists may decrease the absorption of Cefpodoxime. Separate oral doses
by at least 2 hours. Risk C: Monitor therapy

Cefuroxime: H2-Antagonists may decrease the absorption of Cefuroxime. Separate oral doses by
at least 2 hours. Risk C: Monitor therapy
Cisapride: Cimetidine may decrease the metabolism of Cisapride. Risk D: Consider therapy
modification

Clozapine: Cimetidine may decrease the metabolism of Clozapine. Risk D: Consider therapy
modification

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These
CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active
metabolite morphine. Risk C: Monitor therapy

CYP1A2 Substrates: CYP1A2 Inhibitors (Moderate) may decrease the metabolism of CYP1A2
Substrates. Risk C: Monitor therapy

CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of

CYP2C19 Substrates. Risk C: Monitor therapy

CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6
Substrates. Exceptions: Tamoxifen. Risk C: Monitor therapy

CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4
Substrates. Risk C: Monitor therapy

Dasatinib: H2-Antagonists may decrease the absorption of Dasatinib. Risk D: Consider therapy
modification

Dofetilide: Cimetidine may decrease the excretion of Dofetilide. Cimetidine may decrease the
metabolism of Dofetilide. Risk D: Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of

Eplerenone. Management: A lower starting dose of eplerenone (25 mg once daily) is
recommended in patients with hypertension who are also taking drugs that are moderate
inhibitors of CYP3A4. Risk D: Consider therapy modification

Erlotinib: H2-Antagonists may decrease the serum concentration of Erlotinib. Risk X: Avoid
combination

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL.
Risk D: Consider therapy modification

Fosamprenavir: H2-Antagonists may decrease the serum concentration of Fosamprenavir.

Cimetidine may also inhibit the metabolism of the active metabolite amprenavir, making its
effects on fosamprenavir/amprenavir concentrations difficult to predict. Risk C: Monitor
therapy

Iron Salts: H2-Antagonists may decrease the absorption of Iron Salts. Exceptions: Ferric
Gluconate; Iron Dextran Complex; Iron Sucrose. Risk C: Monitor therapy
Maraviroc: CYP3A4 Inhibitors may increase the serum concentration of Maraviroc. Risk D:
Consider therapy modification

MetFORMIN: Cimetidine may decrease the excretion of MetFORMIN. Risk C: Monitor therapy

Moclobemide: Cimetidine may decrease the metabolism of Moclobemide. Risk D: Consider

therapy modification

Moricizine: Cimetidine may decrease the metabolism of Moricizine. Risk D: Consider therapy
modification

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol.
Risk C: Monitor therapy

Nicotine: Cimetidine may decrease the metabolism of Nicotine. Risk C: Monitor therapy

P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates.

P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates
to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain,
T-lymphocytes, testes, etc.). Risk C: Monitor therapy

P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates.

P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to
specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-
lymphocytes, testes, etc.). Risk C: Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus.

Risk C: Monitor therapy

Praziquantel: Cimetidine may decrease the metabolism of Praziquantel. Risk C: Monitor therapy

Procainamide: Cimetidine may decrease the excretion of Procainamide. Risk D: Consider

therapy modification

Propafenone: Cimetidine may increase the serum concentration of Propafenone. Risk D:

Consider therapy modification

QuiNIDine: Cimetidine may decrease the metabolism of QuiNIDine. Risk D: Consider therapy
modification

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of

Ranolazine. Management: Limit the ranolazine dose to a maximum of 500mg twice daily in
patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil,
erythromycin, etc.). Risk D: Consider therapy modification
Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol.
Risk C: Monitor therapy

Saquinavir: H2-Antagonists may increase the serum concentration of Saquinavir. Risk C:

Monitor therapy

Selective Serotonin Reuptake Inhibitors: Cimetidine may decrease the metabolism of Selective
Serotonin Reuptake Inhibitors. Risk D: Consider therapy modification

Sulfonylureas: Cimetidine may decrease the metabolism of Sulfonylureas. Risk C: Monitor

therapy

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of Tamoxifen.

Specifically, CYP2D6 inhibitors may decrease the formation of highly potent active
metabolites. Risk D: Consider therapy modification

Theophylline Derivatives: Cimetidine may decrease the metabolism of Theophylline Derivatives.

Exceptions: Dyphylline. Risk D: Consider therapy modification

Thioridazine: CYP2D6 Inhibitors may decrease the metabolism of Thioridazine. Risk X: Avoid
combination

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol.
These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active
metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy

Tricyclic Antidepressants: Cimetidine may decrease the metabolism of Tricyclic Antidepressants.

Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Cimetidine may enhance the anticoagulant effect of
Vitamin K Antagonists. Risk D: Consider therapy modification

Zaleplon: Cimetidine may decrease the metabolism of Zaleplon. Risk D: Consider therapy
modification

Zolmitriptan: Cimetidine may increase the serum concentration of Zolmitriptan. Risk C: Monitor
therapy

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may enhance gastric mucosal irritation).

Food: Cimetidine may increase serum caffeine levels if taken with caffeine. Cimetidine peak
serum levels may be decreased if taken with food.
Herb/Nutraceutical: St John's wort may decrease cimetidine levels.

Monitoring Parameters

CBC, gastric pH, occult blood with GI bleeding; monitor renal function to correct dose.

Nursing: Physical Assessment/Monitoring

Use caution in presence of renal or hepatic impairment. Assess other pharmacological or herbal
products patient may be taking for potential interactions. I.V.: Note administration specifics.
Assess results of laboratory tests, therapeutic effectiveness (according to purpose for use), and
adverse effects (eg, changes in CNS, agitation; gastric bleeding) regularly during therapy. Teach
patient proper use, possible side effects/appropriate interventions, and adverse symptoms to
report.

Monitoring: Lab Tests

CBC, gastric pH, occult blood with GI bleeding; monitor renal function to correct dose.

Patient Education

Do not take any new medication during therapy unless approved by prescriber. Take with meals.
Do not increase dose or frequency without consulting prescriber. To be effective, continue to take
for the prescribed time (possibly several weeks) even though symptoms may have improved.
Smoking decreases the effectiveness of cimetidine (stop smoking if possible). Avoid excess
alcohol and caffeine. May cause headache, dizziness, agitation (use caution when driving or
engaging in any potentially hazardous tasks until response to drug is known); nausea or vomiting
(small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or
diarrhea (buttermilk, boiled milk, or yogurt may help). Report chest pain or palpitations; CNS
changes (confusion, agitation); persistent diarrhea, nausea, vomiting, or heartburn; black tarry
stools or coffee ground-like emesis; rash; unusual bleeding or bruising; sore throat; or fever;
unexplained weight lose or other adverse effects.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult
specific product labeling.

Note: Strength is expressed as base

Infusion [premixed in NS]: 300 mg (50 mL)

Injection, solution: 150 mg/mL (2 mL, 8 mL)

Solution, oral: 300 mg/5 mL (240 mL, 480 mL)

Tablet: 200 mg [OTC], 300 mg, 400 mg, 800 mg

Tagamet® HB 200: 200 mg

Generic Available

Yes

Pricing: U.S. (www.drugstore.com)

Solution (Cimetidine HCl)

300 mg/5 mL (237): $35.55

Tablets (Cimetidine)

200 mg (30): $19.99

300 mg (180): $29.00

400 mg (90): $25.49

800 mg (30): $17.99

Tablets (Tagamet)

300 mg (60): $71.80

400 mg (60): $114.89

Mechanism of Action

Competitive inhibition of histamine at H2 receptors of the gastric parietal cells resulting in

reduced gastric acid secretion, gastric volume and hydrogen ion concentration reduced

Pharmacodynamics/Kinetics

Onset of action: 1 hour

Duration: 4-8 hours

Absorption: Rapid

Distribution: Crosses placenta; enters breast milk

Protein binding: 20%

Metabolism: Partially hepatic, forms metabolites

Bioavailability: 60% to 70%

Half-life elimination: Neonates: 3.6 hours; Children: 1.4 hours; Adults: Normal renal function: 2
hours

Time to peak, serum: Oral: 1-2 hours

Excretion: Primarily urine (48% as unchanged drug); feces (some)

Related Information
 Antacid Drug Interactions
 Depression

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause agitation or drowsiness; rare reports of confusion

Mental Health: Effects on Psychiatric Treatment

Rare reports of agranulocytosis; use caution with clozapine and carbamazepine; may inhibit the
metabolism of TCAs and benzodiazepines; monitor for adverse effects

Cardiovascular Considerations
Cimetidine has extensive drug interactions, particularly with antiarrhythmics (lidocaine,
phenytoin, procainamide, quinidine) and may also increase the likelihood of theophylline and
cyclosporine toxicity. Because of inhibition of warfarin metabolism, cimetidine may increase
INR in patients on anticoagulation therapy.

Anesthesia and Critical Care Concerns/Other Considerations

The 2008 Surviving Sepsis Campaign guidelines recommend that stress ulcer prophylaxis using
an H2 blocker (Grade 1A) or proton pump inhibitor (Grade 1B) be given to patients with severe
sepsis to prevent upper GI bleed. Benefit of prevention of upper GI bleed must be weighed
against potential effect of increased stomach pH on development of ventilator-associated
pneumonia.

References

Ezetimibe (Zetia®), Ezetimibe/Simvastatin (Vytorin®), and Simvastatin (Zocor®):

Completed Review of the ENHANCE Trial - January 2009

On January 25, 2008, the U.S. Food and Drug Administration (FDA) communicated that they
would be reviewing the data from the Ezetimibe and Simvastatin in Hypercholesterolemia
Enhances Atherosclerosis Regression (ENHANCE) trial (Kastelein, 2008).

The FDA has completed its review of the ENHANCE trial which evaluated the effects of
simvastatin (Zocor®) and ezetimibe/simvastatin (Vytorin®) on carotid-artery intima-media
thickness (CIMT) in patients with familial hypercholesterolemia. CIMT is a surrogate endpoint
believed to translate in a reduction of future cardiovascular events. It is important to note that
this was an imaging trial and was not powered for clinical outcomes (eg, MI, stroke). Following
two years of treatment, CIMT was increased by 0.011 mm in the ezetimibe and simvastatin
combination group and by 0.006 mm in the simvastatin alone group. This difference was not
statistically significant even though the combination group demonstrated statistically significant
greater reductions in LDL.

Possible explanations for this observation include: 1) Issues with enrolled patient population (eg,
prior exposure to lipid-lowering therapy; baseline CIMT), 2) duration of trial, and 3) other
unknown properties of ezetimibe that may negate the beneficial effects of statin therapy on LDL
reduction.

Based on this information, the FDA has not changed its position that an elevated LDL level is a
risk factor for cardiovascular disease and that lowering LDL reduces this risk. Three large
clinical outcome trials evaluating the use of ezetimibe/simvastatin will be presented over the next
2-3 years.

Patients should not stop taking their ezetimibe/simvastatin (Vytorin®), ezetimibe (Zetia®), or
simvastatin (Zocor®). Instead, patients should talk with their healthcare provider if they have
questions about the ENHANCE trial.

For more information, U.S. healthcare professionals may refer to the following:

FDA: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Ezetimibe

American College of Cardiology (ACC) Statement on ENHANCE Trial:

http://www.acc.org/enhance.htm

HMG-CoA Reductase Inhibitors: Evidence Does Not Suggest Increased Incidence of

Amyotrophic Lateral Sclerosis (ALS) - Results of FDA Analysis - September 30, 2008

The U.S. Food and Drug Administration’s (FDA) review of 41 long-term controlled clinical
trials of HMG-CoA reductase inhibitors finds no evidence of an increased incidence of ALS (also
known as Lou Gehrig’s disease) related to these medications. This analysis occurred after the
FDA had received notice of numerous adverse events of which 109 of these reports mentioned
ALS, Lou Gehrig’s disease, or motor neurone disease. The clinical trials included in the
analysis had a median duration of treatment of 3.3 years (range of duration: 6 months to 5 years)
and involved 120,964 patients. The analysis identified a total of 19 cases of ALS – 9 cases per
64,602 patients (0.014%) with statin therapy and 10 cases per 56,362 patients (0.017%) with
placebo. The incidence rates, based on approximately 400,000 person-years, were 4.2 per
100,000 person-years in the statin-treated group and 5 per 100,000 person-years in the placebo-
treated group.

The FDA recommends that health care providers continue to prescribe, and patients continue to
use these products as described within their labeling.

For more information, healthcare professionals may refer to the following:

http://www.fda.gov/medwatch/safety/2008/safety08.htm#Statin

Colman E, Szarfman A, Wyeth J, et al, “An Evaluation of a Data Mining Signal for
Amyotrophic Lateral Sclerosis and Statins Detected in FDA’s Spontaneous
Adverse Event Reporting System,” Pharmacoepidemiol Drug Saf, 2008 (epub ahead
of print)
Ezetimibe (Zetia®), Simvastatin (Zocor®), and Ezetimibe/Simvastatin (Vytorin®):
Preliminary Results From the SEAS Trial - Updated September 2008

The U.S. Food and Drug Administration (FDA) has communicated important information
regarding an ongoing safety review of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS)
trial. The SEAS trial (Rossebo, 2008), recently available online, evaluated the effects of the
combination ezetimibe/simvastatin (Vytorin®) on clinical outcomes in patients with mild-to-
moderate asymptomatic aortic stenosis. The 5-year trial demonstrated that ezetimibe/simvastatin
was no better than placebo in reducing the primary composite outcomes – major
cardiovascular events (eg, death from cardiovascular causes, aortic-valve replacement, heart
failure) or the composite outcome of aortic-valve-related clinical events and ischemia.
Additionally, a higher incidence of newly diagnosed cancer of any type (105 patients taking
ezetimibe/simvastatin vs 70 patients taking placebo, p=0.01) and cancer-related death (39
patients taking ezetimibe/simvastatin vs 23 patients taking placebo, p=0.05) was observed in the
patients receiving ezetimibe/simvastatin compared to those receiving placebo. Of note, 8 patients
diagnosed with cancer prior to randomization experienced recurrence (3 in the
ezetimibe/simvastatin group vs 5 in the placebo group).

Subsequently, an interim analysis of the ongoing Study of Heart and Renal Protection (SHARP)
trial and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-
IT) with a total of 20,617 randomized patients demonstrated no overall excess of cancer (313
active-treatment vs 326 control, p=0.61) (Peto, 2008). The SHARP trial randomized patients with
chronic kidney disease to either ezetimibe/simvastatin or placebo. The IMPROVE-IT trial
randomized patients with acute coronary syndrome to either ezetimibe/simvastatin or simvastatin
alone. When the SEAS trial data is included in this analysis, there still is no significant excess of
cancer (414 active-treatment vs 391 control, p=0.46). However, cancer-associated deaths were
significantly higher when compared to controls (134 vs 92, respectively; p=0.007). Previous
trials and meta-analyses involving the use of ezetimibe, simvastatin, or ezetimibe/simvastatin
also have not shown an increased risk of cancer.

The FDA estimates that it will take approximately 6 months to fully evaluate the clinical trial
data after receipt of the final SEAS trial report. At this time, the FDA recommends that patients
continue taking their cholesterol-lowering medications.

For more information, U.S. healthcare professionals may refer to the following:

FDA: http://www.fda.gov/medwatch/safety/2008/safety08.htm#ezetimibe2

Peto R, Emberson J, Landray M, et al, “Analysis of Cancer Data From Three Ezetimibe
Trials,” N Engl J Med, 2008,
http://content.nejm.org/cgi/content/full/NEJMsa0806603
 Rossebo AB, Pederson TR, Boman K, et al, “Intensive Lipid Lowering With Simvastatin
and Ezetimibe in Aortic Stenosis,” N Engl J Med, 2008,
http://content.nejm.org/cgi/content/full/NEJMoa0804602

Simvastatin and Amiodarone Concurrent Therapy: Dose-Related Increased Risk of

Rhabdomyolysis - August 2008

The U.S. Food and Drug Administration (FDA) has issued an alert to remind practitioners of a
dose-related increased risk of rhabdomyolysis when amiodarone is used concurrently with
simvastatin at doses >20 mg. If patients require simvastatin >20 mg, an alternative HMG-CoA
reductase inhibitor (statin) should be used. This information has previously been incorporated
into the Lexi-Comp monograph.

Additional information may be found at

http://www.fda.gov/cder/drug/InfoSheets/HCP/simvastatin_amiodaroneHCP.htm

Ezetimibe/Simvastatin (Vytorin®), Ezetimibe (Zetia®), and Simvastatin (Zocor®):

ENHANCE Results - January, 2008

The U.S. Food and Drug Administration (FDA) is communicating important information
regarding the preliminary results of the Effect of Combination Ezetimibe and High-Dose
Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous
Familial Hypercholesterolemia (ENHANCE) trial, originally released on January 14, 2008, by
Merck/Schering Plough. This multinational, randomized, double-blind trial was conducted in 720
patients with heterozygous familial hypercholesterolemia (HeFH) over a two-year period.
Patients were randomized to either ezetimibe 10 mg/simvastatin 80 mg (Vytorin®) or
simvastatin 80 mg alone (Zocor®). The primary endpoint of the trial was mean change in
carotid intima-media thickness (CIMT) which is a surrogate endpoint believed to translate in a
reduction of future cardiovascular events. It is important to note that this was an imaging trial
and was not powered for clinical outcomes (eg, MI, stroke). Although ezetimibe/simvastatin
lowered LDL cholesterol more effectively as compared to simvastatin alone, there was no
difference seen in mean change in CIMT. Adverse events were similar between both groups.

Upon completion of full data analysis, the manufacturer will submit a final report to the FDA.
Once the report is received, the FDA estimates it will take about 6 months to fully evaluate the
data and decide whether or not further regulatory action is necessary. Three large clinical
outcome trials evaluating the use of ezetimibe/simvastatin will be presented over the next 2-3
years.
At this point in time, patients should not stop taking their ezetimibe/simvastatin (Vytorin®),
ezetimibe (Zetia®), or simvastatin (Zocor®). Instead patients should talk with their
healthcare provider if they have questions about the ENHANCE trial.

For more information, U.S. healthcare professionals may refer to the following:

FDA: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Ezetimibe

American College of Cardiology (ACC) Statement on ENHANCE Trial:

http://www.acc.org/enhance.htm

Medication Safety Issues

Sound-alike/look-alike issues:

Zocor® may be confused with Cozaar®, Yocon®, Zoloft®

International issues:

Cardin® [Poland] may be confused with Cardene® which is a brand name for
nicardipine in the U.S.

Cardin® [Poland] may be confused with Cardem® which is a brand name for celiprolol
in Spain

Pronunciation

(sim va STAT in)

U.S. Brand Names

Zocor®

Canadian Brand Names

Apo-Simvastatin®; CO Simvastatin; Dom-Simvastatin; Gen-Simvastatin; Novo-Simvastatin;

Nu-Simvastatin; PHL-Simvastatin; PMS-Simvastatin; ratio-Simvastatin; Riva-Simvastatin;
Sandoz-Simvastatin; Taro-Simvastatin; Zocor®
 Pharmacologic Category

Antilipemic Agent, HMG-CoA Reductase Inhibitor

Use: Labeled Indications

Used with dietary therapy for the following:

Secondary prevention of cardiovascular events in hypercholesterolemic patients with established

coronary heart disease (CHD) or at high risk for CHD: To reduce cardiovascular morbidity
(myocardial infarction, coronary revascularization procedures) and mortality; to reduce the
risk of stroke and transient ischemic attacks

Hyperlipidemias: To reduce elevations in total cholesterol, LDL-C, apolipoprotein B, and

triglycerides, and increase HDL-C in patients with primary hypercholesterolemia
(elevations of 1 or more components are present in Fredrickson type IIa, IIb, III, and IV
hyperlipidemias); treatment of homozygous familial hypercholesterolemia

Heterozygous familial hypercholesterolemia (HeFH): In adolescent patients (10-17 years of

age, females >1 year postmenarche) with HeFH having LDL-C ≥190 mg/dL or
LDL ≥160 mg/dL with positive family history of premature cardiovascular disease
(CVD), or 2 or more CVD risk factors in the adolescent patient

Dosing: Adults

Note: Doses should be individualized according to the baseline LDL-cholesterol levels, the
recommended goal of therapy, and the patient's response; adjustments should be made at
intervals of 4 weeks or more; doses may need adjusted based on concomitant medications

Homozygous familial hypercholesterolemia: Oral: 40 mg once daily in the evening or 80

mg/day (given as 20 mg, 20 mg, and 40 mg evening dose)

Prevention of cardiovascular events, hyperlipidemias: Oral: 20-40 mg once daily in the

evening; range: 5-80 mg/day

Patients requiring only moderate reduction of LDL-cholesterol: May be started at 10 mg

once daily

Patients requiring reduction of >45% in low-density lipoprotein (LDL) cholesterol: May be

started at 40 mg once daily in the evening

Patients with CHD or at high risk for CHD: Dosing should be started at 40 mg once daily in
the evening; simvastatin should be started simultaneously with diet therapy.
Dosage adjustment for simvastatin with concomitant medications:

Cyclosporine or danazol: Initial: 5 mg, should not exceed 10 mg/day

Gemfibrozil: Dose should not exceed 10 mg/day

Amiodarone or verapamil: Dose should not exceed 20 mg/day

Dosing: Elderly

Oral: Initial: Maximum reductions in LDL-cholesterol may be achieved with daily dose ≤20
mg.

Dosing: Pediatric

HeFH: Oral: Children 10-17 years (females >1 year postmenarche): 10 mg once daily in the
evening; range: 10-40 mg/day (maximum: 40 mg/day)

Dosage adjustment with concomitant medications: With concomitant amiodarone,

cyclosporine, danazol, gemfibrozil, or verapamil: Refer to adult dosing.

Note: Doses should be individualized according to the baseline LDL-cholesterol levels, the
recommended goal of therapy, and the patient's response; adjustments should be made at
intervals of 4 weeks or more; doses may need adjusted based on concomitant medications

Dosing: Renal Impairment

Because simvastatin does not undergo significant renal excretion, modification of dose should
not be necessary in patients with mild to moderate renal insufficiency.

Severe renal impairment: Clcr <10 mL/minute: Initial: 5 mg/day with close monitoring.

Calculations
 Creatinine Clearance: Adults
 Creatinine Clearance: Pediatrics

Administration: Oral

May be taken without regard to meals. Administer in the evening for maximal efficacy.
 Dietary Considerations
Red yeast rice contains an estimated 2.4 mg lovastatin per 600 mg rice.

Storage

Tablets should be stored in tightly-closed containers at temperatures between 5°C to 30°C

(41°F to 86°F).

Contraindications

Hypersensitivity to simvastatin or any component of the formulation; active liver disease;

unexplained persistent elevations of serum transaminases; pregnancy; breast-feeding

Allergy Considerations
 HMG-CoA Reductase Inhibitor Allergy

Warnings/Precautions

Concerns related to adverse effects:

• Myopathy/rhabdomyolysis: Patients receiving HMG-CoA reductase inhibitors have

developed rhabdomyolysis with acute renal failure and/or myopathy; patients should
be monitored closely. This risk is dose-related and is increased with concurrent use of
other lipid lowering medications. Temporarily discontinue for elective major surgery,
acute medical or surgical conditions, or in any patient experiencing an acute or serious
condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled
seizures). Based upon current evidence, HMG-CoA reductase inhibitor therapy should
be continued in the perioperative period unless risk outweighs cardioprotective benefit.
Use caution in patients with renal impairment, inadequately treated hypothyroidism,
and those taking other drugs associated with myopathy (eg, colchicine); these patients
are predisposed to myopathy. Patients should be instructed to report unexplained
muscle pain, tenderness, weakness, or brown urine.

Disease-related concerns:

• Hepatic impairment and/or ethanol use: Use with caution in patients who consume large
amounts of ethanol or have a history of liver disease. Use is contraindicated with active
liver disease and with unexplained transaminase elevations.

Concurrent drug therapy issues:

 • High potential for interactions: Use with caution in patients taking strong CYP3A4
inhibitors (see drug interactions); consider alternative agents that avoid or lessen
potential for CYP-mediated interactions.

Special Populations:

• Elderly: Use with caution in patients with advanced age, these patients are predisposed
to myopathy.

• Pediatrics: Safety and efficacy have not been established in patients <10 years of age or
premenarcheal girls.

Other warnings/precautions:

• Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to

therapy.

• Liver function tests: Must be monitored by periodic laboratory assessment.

Geriatric Considerations

Effective and well tolerated in the elderly. The definition of and, therefore, when to treat
hyperlipidemia in the elderly is a controversial issue. The National Cholesterol Education
Program recommends that all adults maintain a plasma cholesterol <160 mg/dL. In elderly with
one additional risk factor, goal LDL would be <130 mg/dL. It is the authors' belief that
pharmacologic treatment be reserved for those who are unable to obtain a desirable plasma
cholesterol concentration by diet alone and for whom the benefits of treatment are believed to
outweigh the potential adverse effects, drug interactions, and cost of treatment.

Pregnancy Risk Factor

Pregnancy Considerations

Cholesterol biosynthesis may be important in fetal development. Contraindicated in pregnancy.

Administer to women of childbearing potential only when conception is highly unlikely and
patients have been informed of potential hazards. If pregnancy occurs during treatment,
discontinue simvastatin immediately.

Lactation

Excretion in breast milk unknown/contraindicated

 Breast-Feeding Considerations

Excretion in breast milk is unknown, but would be expected; other medications in this class are
excreted in human milk. Breast-feeding is contraindicated.

Adverse Reactions

1% to 10%:

Gastrointestinal: Constipation (2%), flatulence (1% to 2%), dyspepsia (1%)

Hepatic: Transaminases increased (>3x ULN; 1%)

Neuromuscular & skeletal: CPK elevation (>3x normal on one or more occasions; 5%)

Respiratory: Upper respiratory infection (2%)

<1%: Abdominal pain, diarrhea, dizziness, fatigue, headache, insomnia, nausea, pruritus,
thrombocytopenia, vertigo, weakness

Postmarketing and/or case reports: Depression, dermatomyositis, hypotension, lichen planus,

muscle pain, muscle tenderness, muscle weakness, myopathy, photosensitivity

Additional class-related events or case reports (not necessarily reported with simvastatin
therapy): Alopecia, alkaline phosphatase increased, alteration in taste, alopecia, anaphylaxis,
angioedema, anorexia, anxiety, arthralgia, arthritis, bilirubin increased, cataracts, chills,
cholestatic jaundice, cirrhosis, decreased libido, depression, dermatomyositis, dryness of
skin/mucous membranes, dyspnea, eosinophilia, erectile dysfunction/impotence, erythema
multiforme, facial paresis, fatty liver, fever, flushing, fulminant hepatic necrosis, gynecomastia,
hemolytic anemia, hepatic failure, hepatitis, hepatoma, hyperbilirubinemia, hypersensitivity
reaction, impaired extraocular muscle movement, increased alkaline phosphatase, increased CPK
(>10x normal), increased ESR, increased GGT, leukopenia, malaise, memory loss, myopathy,
nail changes, nodules, ophthalmoplegia, pancreatitis, paresthesia, peripheral nerve palsy,
peripheral neuropathy, photosensitivity, polymyalgia rheumatica, positive ANA, pruritus, psychic
disturbance, purpura, rash, renal failure (secondary to rhabdomyolysis), rhabdomyolysis, skin
discoloration, Stevens-Johnson syndrome, systemic lupus erythematosus-like syndrome,
thrombocytopenia, thyroid dysfunction, toxic epidermal necrolysis, transaminases increased,
tremor, urticaria, vasculitis, vertigo, vomiting

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Inhibits CYP2C8 (weak), 2C9 (weak), 2D6 (weak)
 Drug Interactions

Amiodarone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Management:

Dose of HMG-CoA reductase inhibitor may need to be reduced (e.g., simvastatin
prescribing information recommends not exceeding 20 mg/day during concurrent therapy).
Risk D: Consider therapy modification

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of HMG-CoA
Reductase Inhibitors. Risk D: Consider therapy modification

Bosentan: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor
therapy

Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of HMG-CoA

Reductase Inhibitors. Risk D: Consider therapy modification

Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase

Inhibitors. Colchicine may increase the serum concentration of HMG-CoA Reductase
Inhibitors. Risk D: Consider therapy modification

CycloSPORINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk
D: Consider therapy modification

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C:
Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C:
Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D:
Consider therapy modification

Danazol: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor
therapy

DAPTOmycin: HMG-CoA Reductase Inhibitors may enhance the adverse/toxic effect of

DAPTOmycin. Specifically, the risk of skeletal muscle toxicity may be increased.
Management: Consider temporarily stopping HMG-CoA reductase inhibitor therapy prior to
daptomycin. If used together, regular (i.e., at least weekly) monitoring of CPK
concentrations is recommended. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor
therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor
therapy

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates.

Management: According to eltrombopag prescribing information, consideration of a
preventative dose reduction may be warranted. Risk D: Consider therapy modification

Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. This
applies to atorvastatin, lovastatin and simvastatin. Conversely, levels of fluvastatin may be
increased. Management: Dose adjustment of the HMG-CoA reductase inhibitor may be
warranted. No interaction is expected with rosuvastatin or pravastatin. Risk C: Monitor
therapy

Fenofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C:
Monitor therapy

Fenofibric Acid: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk
C: Monitor therapy

Fluconazole: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D:

Consider therapy modification

Gemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase

Inhibitors. Gemfibrozil may increase the serum concentration of HMG-CoA Reductase
Inhibitors. Risk D: Consider therapy modification

Grapefruit Juice: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D:
Consider therapy modification

Imatinib: May decrease the metabolism of Simvastatin. Risk C: Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of HMG-CoA Reductase Inhibitors.

Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider
therapy modification

Nefazodone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D:

Consider therapy modification

Niacin: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C:
Monitor therapy

Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C:
Monitor therapy

Phenytoin: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider
therapy modification
Protease Inhibitors: May increase the serum concentration of HMG-CoA Reductase Inhibitors.
Limited data suggest pravastatin may slightly decrease protease inhibitor concentrations.
Management: Lovastatin and simvastatin are contraindicated with many protease inhibitors;
use lowest possible HMG-CoA reductase inhibitor dose and monitor for signs and
symptoms of rhabdomyolysis if these agents are used concomitantly. Risk D: Consider
therapy modification

Ranolazine: May increase the serum concentration of Simvastatin. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk
D: Consider therapy modification

Sildenafil: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider
therapy modification

St Johns Wort: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C:
Monitor therapy

Vitamin K Antagonists (eg, warfarin): HMG-CoA Reductase Inhibitors may enhance the
anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid excessive ethanol consumption (due to potential hepatic effects).

Food: Simvastatin serum concentration may be increased when taken with grapefruit juice; avoid
concurrent intake of large quantities (>1 quart/day). Red yeast rice contains an estimated 2.4
mg lovastatin per 600 mg rice.

Herb/Nutraceutical: St John's wort may decrease simvastatin levels.

Monitoring Parameters

Creatine phosphokinase levels due to possibility of myopathy; serum cholesterol (total and
fractionated)

Obtain liver function tests prior to initiation, dose, and thereafter when clinically indicated.
Patients titrated to the 80 mg dose should be tested prior to initiation and 3 months after initiating
the 80 mg dose. Thereafter, periodic monitoring (ie, semiannually) is recommended for the first
year of treatment. Patients with elevated transaminase levels should have a second
(confirmatory) test and frequent monitoring until values normalize. Discontinue if increase in
ALT/AST is persistently >3 times ULN.
 Nursing: Physical Assessment/Monitoring

Use with caution and monitor closely in presence of impaired liver function. Assess potential for
interactions with other pharmacological agents or herbal products patient may be taking (eg,
other lipid-lowering drugs may increase risk of myopathy or rhabdomyolysis). Assess results of
laboratory tests (LFTs, cholesterol profile) prior to treatment and periodically thereafter. Evaluate
therapeutic response (reduction in lipid levels) and adverse reactions on a regular basis
throughout therapy. Teach patient proper use (as adjunct to diet and exercise program), possible
side effects/appropriate interventions, and adverse symptoms to report. Pregnancy risk factor
X: Determine that patient is not pregnant before starting therapy. Do not give to women of
childbearing age unless they are capable of complying with effective contraceptive use. Instruct
patient in appropriate contraceptive measures.

Monitoring: Lab Tests

Creatine phosphokinase levels due to possibility of myopathy; serum cholesterol (total and
fractionated)

Obtain liver function tests prior to initiation, dose, and thereafter when clinically indicated.
Patients titrated to the 80 mg dose should be tested prior to initiation and 3 months after initiating
the 80 mg dose. Thereafter, periodic monitoring (ie, semiannually) is recommended for the first
year of treatment. Patients with elevated transaminase levels should have a second
(confirmatory) test and frequent monitoring until values normalize. Discontinue if increase in
ALT/AST is persistently >3 times ULN.

Patient Education

Do not take any new prescription or OTC medications or herbal products during therapy without
consulting prescriber. Take at same time each day, in the evening with or without food. Follow
cholesterol-lowering diet and exercise regimen as prescribed. Avoid excessive grapefruit juice
(>1 quart/day) and excessive alcohol while taking this medication. You will have periodic blood
tests to assess effectiveness. You may experience mild GI upset (should diminish with use);
constipation (increased exercise, fluids, fiber, and fruit may help); or headache, dizziness,
insomnia (use caution when driving or engaged in potentially hazardous tasks until response to
drug in known). Contact prescriber immediately with persistent muscle or skeletal pain, joint
pain, or numbness. Report other persistent adverse effects. Pregnancy/breast-feeding
precautions: Inform prescriber if you are pregnant. Do not get pregnant during and for 1 month
following therapy. Consult prescriber for appropriate contraceptive measures. This drug may
cause severe fetal defects. Do not breast-feed.

Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult
specific product labeling.

Tablet: 5 mg, 10 mg, 20 mg, 40 mg, 80 mg

Zocor®: 5 mg, 10 mg, 20 mg, 40 mg, 80 mg

Generic Available

Yes

Manufacturer

Merck & Co

Pricing: U.S. (www.drugstore.com)

Tablets (Simvastatin)

5 mg (30): $17.99

10 mg (30): $19.99

20 mg (30): $27.99

40 mg (30): $27.99

80 mg (30): $32.99

Tablets (Zocor)

5 mg (30): $66.99

10 mg (90): $240.98

20 mg (30): $139.99

40 mg (90): $405.99

80 mg (30): $146.99

Mechanism of Action
Simvastatin is a methylated derivative of lovastatin that acts by competitively inhibiting 3-
hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the
rate-limiting step in cholesterol biosynthesis

Pharmacodynamics/Kinetics

Onset of action: >3 days

Peak effect: 2 weeks

Absorption: 85%

Protein binding:~95%

Metabolism: Hepatic via CYP3A4; extensive first-pass effect

Bioavailability: <5%

Half-life elimination: Unknown

Time to peak: 1.3-2.4 hours

Excretion: Feces (60%); urine (13%)

Related Information
 Hyperlipidemia Management
 Lipid-Lowering Agents

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause drowsiness

Mental Health: Effects on Psychiatric Treatment

Rhabdomyolysis with acute renal failure has occurred; risk is increased with concurrent use of
fluvoxamine nefazodone and verapamil

Cardiovascular Considerations

Primary Prevention: HMG-CoA reductase inhibitors are effective in primary and secondary
prevention of cardiovascular events in patients with hyperlipidemia. For primary prevention, a
patient's major risk factors (cigarette smoking, hypertension or currently taking
antihypertensives, low HDL-C, family history, age, gender) should be evaluated. Patients with
multiple risk factors (≥2) require more intensive therapy guided by the calculation of a 10-
year absolute CHD risk (eg, the percent probability of having a CHD event in next 10 years). An
individual's 10-year absolute CHD risk can be calculated at www.med-
decisions.com/cvtool/phys/phys.html. LDL cholesterol goals, therapeutic lifestyle changes, and
drug therapy are determined based upon a patient's risk factor profile.

Primary prevention trials show that cholesterol-lowering drugs reduce the risk of major coronary
events, coronary death, and cerebrovascular events even in the first 6-12 months of use. The
WOSCOP trial suggested a trend towards enhanced survival using pravastatin in their patients
(mean LDL-cholesterol of 192 mg/dL and no history of MI). In a recent trial (Sever, 2003),
patients with HTN and at least three other risk factors were randomized to 10 mg daily of
atorvastatin or placebo. These patients had a total nonfasting cholesterol <250 mg/dL before
treatment. LDL-C levels were 132 mg/dL before treatment and fell to an average of 90 mg/dL in
the atorvastatin-treated group. There was a significant reduction in stroke, cardiovascular events,
and coronary events in the atorvastatin-treated group as compared to the placebo group. There
was no difference in mortality between the groups.

HMG-CoA reductase inhibitors decrease C-reactive protein (CRP), an inflammatory marker and
an acute phase reactant. Elevated levels of high sensitive CRP (hsCRP), which detects CRP
levels as low as 0.175 mg/L, have been shown to be associated with an increased risk of
cardiovascular events. Recently, the JUPITER trial demonstrated that the use of rosuvastatin in
healthy patients (men ≥50 years and women ≥60 years) without a history of
cardiovascular disease with LDL <130 mg/dL and a hsCRP level ≥2 mg/L reduced the risk of
major cardiovascular events (eg, nonfatal MI, stroke, death from cardiovascular causes), The
number needed to treat over 5 years to prevent 1 cardiovascular event is 25. Current guidelines
do not recommend drug treatment for patients with an LDL <130 mg/dL. However, identification
of the patient at higher risk of cardiovascular events within this subgroup using hsCRP is now
important given that statins may prevent the occurrence of these serious cardiovascular events
(Ridker, 2008).

Secondary prevention: Secondary prevention trials indicate that “statin” therapy reduces
mortality, major coronary events, coronary artery procedures, and stroke. The Heart Protection
Study proved that lowering serum cholesterol levels reduces the rate of major vascular events
among high-risk individuals with documented vascular disease (CHD, cerebrovascular,
peripheral vascular) or diabetes regardless of initial cholesterol concentrations. PROVE IT is a
randomized, double-blind trial evaluating hospitalized patients with acute coronary syndrome to
determine the effects of intense LDL-C lowering therapy. Four thousand patients with an LDL-C
levels of 106 mg/dL were randomized to pravastatin 40 mg daily or atorvastatin 80 mg daily.
After 2 years, the combined cardiovascular endpoint (death, MI, unstable angina requiring
hospitalization, revascularization and stroke) was ~26% in the pravastatin patients (median LDL-
C 95 mg/dL) and ~22% in the atorvastatin treated patients (median LDL-C 62 mg/dL).

LaRosa and colleagues assessed the efficacy and safety of lowering LDL cholesterol <100 mg/dL
in patients with stable coronary heart disease (LaRosa, 2005). Ten thousand and one patients
with baseline LDL levels <130 mg/dL were randomized to atorvastatin 10 mg or 80 mg daily and
followed for a median of 4.9 years. The primary endpoint was the occurrence of the first major
cardiovascular event (death from CVD, MI, resuscitation after cardiac arrest, or stroke). A
primary event occurred in 434 patients (8.7%) receiving 80 mg daily (mean LDL 77 mg/dL) and
548 patients (10.9%) receiving 10 mg dose (mean LDL 101 mg/dL) (95% CI, 0.69-0.89; p
<0.001). There was no mortality difference between the two treatment groups.

In addition to the ability of HMG-CoA reductase inhibitors to decrease levels of high-sensitivity

C-reactive protein (hs-CRP), they also possess pleiotropic properties including improved
endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of
platelet aggregation, and anticoagulant effects. These nonlipid effects may be beneficial when
HMG-CoA reductase inhibitors are introduced early in the management of acute coronary
syndromes (de Denus, 2002).

Myopathy: Currently-marketed HMG-CoA reductase inhibitors appear to have a similar

potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The
factors that increase risk include advanced age (especially >80 years of age), women more
frequently than men, small body frame, frailty, multisystem disease (eg, chronic renal
insufficiency especially due to diabetes), multiple medications, drug interactions (use with
caution or avoid). The combination of a HMG-CoA reductase inhibitor plus nicotinic acid seems
to carry a lower risk of myopathy than does a HMG-CoA reductase inhibitor plus a fibrate. Other
medications, when used concurrently, may enhance the risk of myopathy associated with statins;
these include drugs that inhibit CYP3A4 isoenzymes (lovastatin, simvastatin, atorvastatin) or
CYP2C9 isoenzymes (fluvastatin). HMG-CoA reductase inhibitors may exacerbate exercise-
induced skeletal muscle injury. Many experts favor getting a baseline creatine kinase (CK)
measurement before initiating therapy (asymptomatic CK elevations are common). Obtain a CK
measurement if patient complains of muscle soreness, tenderness, or pain.

Anesthesia and Critical Care Concerns/Other Considerations

Myopathy: Currently-marketed HMG-CoA reductase inhibitors appear to have a similar

potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The
factors that increase risk include advanced age (especially >80 years), gender (occurs in women
more frequently than men), small body frame, frailty, multisystem disease (eg, chronic renal
insufficiency especially due to diabetes), multiple medications, and drug interactions (use with
caution or avoid).

Based on current research, HMG-CoA reductase inhibitors should be continued in the

perioperative period. Postoperative discontinuation of statin therapy is associated with an
increased risk of cardiac morbidity and mortality