Minocin Injection

Name: Minocin Injection

Clinical pharmacology

Following a single dose of Minocin 200 mg administered intravenously to 10 healthy male subjects, serum concentrations of minocycline ranged from 2.52 to 6.63 mcg/mL (average 4.18 mcg/mL) at the end of infusion and 0.82 to 2.64 mcg/mL (average 1.38 mcg/mL) after 12 hours. In a group of 5 healthy male subjects, serum concentrations of minocycline ranged from 1.4 to1.8 mcg/mL at the end of the dosing interval following administration of Minocin 100 mg every 12 hours for three days. When Minocin 200 mg once daily was administered for three days, serum concentrations of minocycline were approximately 1 mcg/mL at 24 hours. The serum elimination half-life of minocycline following administration of either Minocin 100 mg every 12 hours or 200 mg once daily was not significantly different and ranged from 15 to 23 hours.

The serum elimination half-life of minocycline ranged from 11 to 16 hours in subjects with hepatic impairment (n=7) and 18 to 69 hours in subjects with renal impairment (n=5). In comparison, the serum elimination half-life of minocycline ranged from 11 to 17 hours following a single dose of oral minocycline 200 mg in healthy subjects (n=12).

Microbiology

Mechanism of Action

The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including minocycline, have a similar antimicrobial spectrum of activity against a wide range of Gram-positive and Gram-negative bacteria. Cross-resistance of these bacteria to tetracyclines is common.

List of Microorganisms

Minocycline has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Gram-positive Bacteria

Bacillus anthracis
Listeria monocytogenes

Staphylococcus aureus

Streptococcus pneumoniae

Gram-negative Bacteria

Bartonella bacilliformis
Brucella
species
Klebsiella granulomatis

Campylobacter fetus

Francisella tularensis

Vibrio cholerae

Yersinia pestis

Acinetobacter
species
Enterobacter aerogenes

Escherichia coli

Haemophilus influenzae

Klebsiella
species
Neisseria meningitidis

Shigella
species

Other Microorganisms

Actinomyces species
Borrelia recurrentis

Chlamydophila psittaci

Chlamydia trachomatis

Clostridium
species
Entamoeba
species
Fusobacterium nucleatum
subspecies fusiforme
Mycobacterium marinum

Mycoplasma pneumoniae

Propionibacterium acnes

Rickettsiae
Treponema pallidum
subspecies pallidum
Treponema pallidum
subspecies pertenue
Ureaplasma urealyticum

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tetracycline or minocycline powder.1,2 The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method.2,3 This procedure uses paper disks impregnated with 30 mcg tetracycline or 30 mcg minocycline to test the susceptibility of microorganisms to minocycline. The disk diffusion interpretive criteria are provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Minocycline and Tetracycline

Species Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL)
S I R S I R S I R
Enterobacteriaceaea
  Minocycline ≤ 4 8 ≥ 16 ≥ 16 13 - 15 ≤ 12      
  Tetracycline ≤ 4 8 ≥ 16 ≥ 15 12 -14 ≤ 11      
Acinetobactera
  Minocycline ≤ 4 8 ≥ 16 ≥ 16 13 - 15 ≤ 12      
  Tetracycline ≤ 4 8 ≥ 16 ≥ 15 12 -14 ≤ 11      
Haemophilus influenzae
  Tetracycline ≤ 2 4 ≥ 8 ≥ 29 26 -28 ≤ 25      
Streptococcus pneumoniae
  Tetracycline ≤ 1 2 ≥ 4 ≥ 28 25 -27 ≤ 24      
Staphylococcus aureusa
  Minocycline ≤ 4 8 ≥ 16 ≥ 19 15 - 18 ≤ 14      
  Tetracycline A 4 8 ≥ 16 ≥ 19 15 - 18 ≤ 14      
Vibrio choleraea
  Minocycline ≤ 4 8 ≥ 16 ≥ 16 13 - 15 ≤ 12      
  Tetracycline ≤ 4 8 ≥ 16 ≥ 19 15 - 18 ≤ 14      
Neisseria meningitidisb
  Minocycline - - - ≥ 26 - - ≤ 2 - -
Bacillus anthracisb
  Tetracycline ≤ 1 - -            
Francisella tularensisb
  Tetracycline ≤ 4 - -            
Yersinia pestis
  Tetracycline ≤ 4 8 ≥ 16            
aOrganisms that are susceptible to tetracycline are also considered susceptible to minocycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to minocycline.
bThe current absence of resistance isolates precludes defining any result other than “susceptible”. If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.

A report of “Susceptible” indicates that the antimicrobial drug is likely to inhibit growth of the microorganism if the antimicrobial compound reaches the concentrations usually achievable at the site of infection. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial drug is not likely to inhibit growth of the microorganism, if the antimicrobial drug reaches the concentrations usually achievable at the site of infection; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test1,2,3. Standard tetracycline (class compound) or minocycline powder should provide the following range of MIC values noted in Table 2. For the disc diffusion technique, using the 30 mcg tetracycline or 30 mcg minocycline disk, the criteria in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Minocycline and Tetracycline

Species Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL)
Enterococcus faecalis ATCC 29212
  Minocycline 1 - 4 -- --
  Tetracycline 8 - 32 -- --
Escherichia coli ATCC 25922
  Minocycline 0.25 - 1 19 -25 --
  Tetracycline 0.5 - 2 18 -25 --
Haemophilus influenzae ATCC 49247
  Tetracycline 4 -32 14 -22 --
Neisseria gonorrhoeae ATCC 49226
  Tetracycline -- 30 -42 0.25 - 1
Staphylococcus aureus ATCC 25923
  Minocycline   25 - 30 --
  Tetracycline   24 -30 --
Staphylococcus aureus ATCC 29213
  Minocycline 0.06 - 0.5   --
  Tetracycline 0.12 - 1   --
Streptococcus pneumoniae ATCC 49619
  Tetracycline 0.06 - 0.5 27 -31 --

Animal Pharmacology And Toxicology

Minocycline hydrochloride has been observed to cause a dark discoloration of the thyroid in experimental animals (rats, minipigs, dogs, and monkeys). In the rat, chronic treatment with minocycline hydrochloride has resulted in goiter accompanied by elevated radioactive iodine uptake and evidence of thyroid tumor production. Minocycline hydrochloride has also been found to produce thyroid hyperplasia in rats and dogs.

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REFERENCES

1. Clinical and Laboratory Standards (CLSI). Methods for Dilution Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Ninth Edition. CLSI document M07-A9 [2012]. Clinical and Laboratory Standards, 940 West Valley Rd., Suite 2500, Wayne, PA 19087-1898.

2. Clinical and Laboratory Standards (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard-Eleventh Edition. CLSI document M02-A11 [2012]. Clinical and Laboratory Standards, 940 West Valley Rd., Suite 2500, Wayne, PA 19087-1898.

3. Clinical and Laboratory Standards (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement. CLSI document M100S24 [2014]. Clinical and Laboratory Standards, 940 West Valley Rd., Suite 2500, Wayne, PA 19087-1898.

Contraindications

This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines or to any of the components of the product formulation.

Warnings

Tooth Development
MINOCIN, like other tetracycline-class antibacterials, can cause fetal harm when administered to a pregnant woman. If any tetracycline is used during pregnancy, or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown).

This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Tetracycline drugs, therefore, should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.

Skeletal Development
All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has been noted in animals treated early in pregnancy.

Dermatologic Reaction
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) including fatal cases have been reported with minocycline use. If this syndrome is recognized, the drug should be discontinued immediately.

Anti‑anabolic Action
The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis. Under such conditions, monitoring of creatinine and BUN is recommended, and the total daily dosage should not exceed 200 mg in 24 hours (See DOSAGE AND ADMINISTRATION). If renal impairment exists, even usual oral or parenteral doses may lead to systemic accumulation of the drug and possible liver toxicity.

Photosensitivity
Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. This has been reported with minocycline.

Central Nervous System Effects
Central nervous system side effects including light-headedness, dizziness or vertigo have been reported. Patients who experience these symptoms should be cautioned about driving vehicles or using hazardous machinery while on minocycline therapy. These symptoms may disappear during therapy and usually disappear rapidly when the drug is discontinued.

Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MINOCIN®, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Intracranial Hypertension
Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including Minocin. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and Minocin should be avoided because isotretinoin is also known to cause pseudotumor cerebri.

Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize.

Adverse Reactions

The following adverse reactions have been observed in patients receiving tetracyclines.

Body as a whole: Fever, and discoloration of secretions.

Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, dyspepsia, stomatitis, glossitis, dysphagia, enamel hypoplasia, enterocolitis, pseudomembranous colitis, pancreatitis, inflammatory lesions (with monilial overgrowth) in the oral and anogenital regions. These reactions have been caused by both the oral and parenteral administration of tetracyclines.

Genitourinary: Vulvovaginitis.

Hepatic toxicity: Hyperbilirubinemia, hepatic cholestasis, increases in liver enzymes, fatal hepatic failure, and jaundice. Hepatitis, including autoimmune hepatitis, and liver failure have been reported (See PRECAUTIONS).

Skin: Alopecia, erythema nodosum, hyperpigmentation of nails, pruritus, toxic epidermal necrolysis, and vasculitis, maculopapular and erythematous rashes. Exfoliative dermatitis has been reported. Fixed drug eruptions have been reported. Lesions occurring on the glans penis have caused balanitis. Erythema multiforme and Stevens-Johnson syndrome have been reported. Photosensitivity is discussed above (See WARNINGS). Pigmentation of the skin and mucous membranes has been reported.

Local Reactions: Injection site erythema and injection site pain.

Respiratory: Cough, dyspnea, bronchospasm, exacerbation of asthma, and pneumonitis.

Renal toxicity: Interstitial nephritis. Elevations in BUN have been reported and are apparently dose related (See WARNINGS). Acute renal failure has been reported.

Musculoskeletal: Arthralgia, arthritis, bone discoloration, myalgia, joint stiffness, and joint swelling.

Hypersensitivity reactions: Urticaria, angioneurotic edema, polyarthralgia, anaphylaxis/anaphylactoid reaction (including shock and fatalities), anaphylactoid purpura, myocarditis, pericarditis, exacerbation of systemic lupus erythematosus, and pulmonary infiltrates with eosinophilia have been reported. A lupus-like syndrome and serum sickness-like reactions also have been reported.

Blood: Agranulocytosis, hemolytic anemia, thrombocytopenia, leukopenia, neutropenia, pancytopenia, and eosinophilia have been reported.

Central Nervous System: Convulsions, dizziness, hypesthesia, paresthesia, sedation, and vertigo. Pseudotumor cerebri (benign intracranial hypertension) in adults and bulging fontanels in infants (See PRECAUTIONS - General). Headache has also been reported.

Other: Thyroid cancer has been reported in the post-marketing setting in association with minocycline products. When minocycline therapy is given over prolonged periods, monitoring for signs of thyroid cancer should be considered. When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. Cases of abnormal thyroid function have been reported.

Tooth discoloration in pediatric patients less than 8 years of age (See WARNINGS) and in adults has been reported.

Oral cavity discoloration (including tongue, lip, and gum) have been reported.

Tinnitus and decreased hearing have been reported in patients on MINOCIN® (minocycline for injection).

The following syndromes have been reported. In some cases involving these syndromes, death has been reported. As with other serious adverse reactions, if any of these syndromes are recognized, the drug should be discontinued immediately:

Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, and pericarditis. Fever and lymphadenopathy may be present.

Lupus-like syndrome consisting of positive antinuclear antibody; arthralgia, arthritis, joint stiffness, or joint swelling; and one or more of the following: fever, myalgia, hepatitis, rash, and vasculitis.

Serum sickness-like syndrome consisting of fever; urticaria or rash; and arthralgia, arthritis, joint stiffness, or joint swelling. Eosinophilia may be present.

MINOCIN® (minocycline) for Injection contains magnesium sulfate heptahydrate (See DESCRIPTION). Adverse effects that may be associated with magnesium intoxication include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and CNS depression proceeding to respiratory paralysis (See PRECAUTIONS).

Dosage and administration

THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF MINOCYCLINE DIFFERS FROM THAT OF THE OTHER TETRACYCLINES. EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS.

Note: Rapid administration is to be avoided. Parenteral therapy is indicated only when oral therapy is not adequate or tolerated. Oral therapy should be instituted as soon as possible. If intravenous therapy is given over prolonged periods of time, thrombophlebitis may result.

For Pediatric Patients above 8 years of Age

Usual pediatric dose: Initial dose of 4 mg/kg, then 2 mg/kg administered over 60 minutes every 12 hours, not to exceed the usual adult dose.

Adults

Usual adult dose: Initial dose of 200 mg, then 100 mg administered over 60 minutes every 12 hours and should not exceed 400 mg in 24 hours.

The lyophilized powder should be reconstituted with 5 mL Sterile Water for Injection USP and immediately further diluted in 100 mL to 1,000 mL with Sodium Chloride Injection USP, Dextrose Injection USP, or Dextrose and Sodium Chloride Injection USP, or in 250 mL to 1000 mL Lactated Ringer’s Injection USP, but not with other solutions containing calcium because a precipitate may form especially in neutral and alkaline solutions.

When diluted in compatible solutions, the pH usually ranges from 4.5 to 6.0.

Once diluted into an intravenous bag, MINOCIN® for Injection may be stored either at room temperature for up to 4 hours or refrigerated at 2 to 8°C (36 to 46°F) for up to 24 hours. Any unused portions must be discarded after that period.

The pharmacokinetics of minocycline in patients with renal impairment (CLCR <80 mL/min) have not been fully characterized. Current data are insufficient to determine if a dosage adjustment is warranted. The total daily dosage should not exceed 200 mg in 24 hours in patients with renal impairment. However, due to the anti-anabolic effect of tetracyclines, BUN and creatinine should be monitored (See WARNINGS). Because MINOCIN (minocycline) for Injection contains magnesium sulfate heptahydrate, serum levels of magnesium should be monitored in patients with renal impairment (See DESCRIPTION, PRECAUTIONS).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Incompatibilities

Additives or other medications should not be added to MINOCIN single-use vials or infused simultaneously through the same intravenous line including Y-connectors. If the same intravenous line is used for sequential infusion of additional medications, the line should be flushed before and after infusion of MINOCIN with Sodium Chloride Injection USP, Dextrose Injection USP, Dextrose and Sodium Chloride Injection USP, or Lactated Ringer’s Injection USP.

How is Minocin Injection Supplied

MINOCIN® (minocycline) for Injection is supplied as 100 mg single-use vials of sterile lyophilized powder.

      NDC  65293-014-01: 100 mg single-use vial
      NDC 65293-014-10: units of 10 x 1 single-use 100 mg vials

Store at Controlled Room Temperature 20° to 25°C (68° to 77°F).

For the Consumer

Applies to minocycline: oral capsule, oral capsule extended release, oral suspension, oral tablet, oral tablet extended release

Other dosage forms:

  • intravenous powder for solution

Along with its needed effects, minocycline (the active ingredient contained in Minocin for Injection) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking minocycline:

Incidence not known
  • Black, tarry stools
  • blistering, peeling, or loosening of the skin
  • blood in the urine or stools
  • blurred or double vision
  • bulging soft spot on the head of an infant
  • chest pain, possibly moving to the left arm, neck, or shoulder
  • confusion
  • diarrhea
  • dizziness or lightheadedness
  • eye pain
  • fast heartbeat
  • general feeling of discomfort or illness
  • general tiredness and weakness
  • hives, itching, or skin rash
  • joint or muscle pain
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • loss of appetite
  • nausea or vomiting
  • red skin lesions, often with a purple center
  • severe headache
  • severe stomach pain
  • sores, ulcers, or white spots on the lips or in the mouth
  • troubled breathing
  • unusual bleeding or bruising
  • upper right abdominal or stomach pain
  • yellow eyes and skin

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

Less common
  • Continuing ringing or buzzing or other unexplained noise in the ears
  • difficulty with moving
  • hearing loss
  • hives or welts
  • muscle stiffness
  • redness of the skin
  • sleepiness or unusual drowsiness
Incidence not known
  • Bloating
  • discoloration of the tooth
  • increased sensitivity of the skin to sunlight
  • indigestion
  • severe sunburn

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