DIVAINE Injection (Minocycline)

Table of Content

Over the last three decades, Acinetobacter has transformed from a pathogen of questionable clinical significance to one of the most virulent, multidrug-resistant pathogenic organism in the intensive care unit. The increasing incidence of carbapenem resistance in Acinetobacter baumannii and other gram-negative bacteria leaves almost no cure for the ‘bad bugs’. Increase in drug resistance among pathogens as well as lack of development of new antibiotics has focused attention on the potential use of older antibiotics.

Minocycline intravenous is an old antibiotic, approved by the US FDA for the treatment of minocycline-susceptible Acinetobacter infections. Minocycline as compared with doxycycline (another second-generation tetracycline) demonstrates better in vitro activity against A. baumannii and Enterobacteriaceae and shows greater lipophilicity owing to better tissue penetration. Tigecycline, a derivative of minocycline, does not achieve sufficient blood levels to reliably treat bacteraemia and there is an increased mortality risk associated with its use especially in VAP.

Minocycline has enhanced lipophilic properties over other tetracyclines owing to excellent blood and tissue penetration. It inhibits bacterial protein synthesis and the long half-life of minocycline makes it a long-acting agent within the class. Minocycline in combination with colistin or carbapenems shows synergistic and bactericidal activity against MDR Acinetobacter. Due to the high bioavailability of oral formulation of minocycline, it offers an attractive feature for the clinician to switch from I.V. to oral route.

The recommended dosage for DIVAINE (Minocycline) I.V. is 200 mg as loading dose followed by 100 mg bid. No dosage adjustment is required for patients with renal impairment.

Composition

DIVAINE I.V.

Each vial contains:

Minocycline Hydrochloride USP equivalent to Minocycline ............................100 mg

Dosage Form

Sterile freeze-dried powder for reconstitution

Pharmacology

Pharmacodynamics

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.

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 section:

Gram-positive Bacteria

Because many isolates of the following Gram-positive bacteria have been shown to be resistant to tetracyclines, culture and susceptibility testing are especially recommended.

Bacillus anthracis

Listeria monocytogenes

Staphylococcus aureus

Streptococcus pneumoniae

Gram-negative Bacteria

Bartonella bacilliformis

Brucella species

Klebsiella (Calymmatobacterium) 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

Chlamydia psittaci

Chlamydia trachomatis

Clostridium species

Entamoeba species

Fusobacterium nucleatum subspecies fusiforme

Mycobacterium marinum

Mycoplasma pneumoniae

Propionibacterium acnes

Rickettsiae

Treponema pallidum subspecies pallidum1

Treponema pallidum subspecies pertenue1

Ureaplasma urealyticum

Pharmacokinetics

Following a single dose of minocycline 200 mg I.V. administered 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 to 1.8 mcg/mL at the end of the dosing interval following administration of minocycline 100 mg every 12 hours for three days. When minocycline 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 minocycline 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).

Indications

DIVAINE I.V. is indicated in the treatment of the following infections due to susceptible isolates of the designated bacteria:

  • Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsial pox and tick fevers caused by rickettsiae
  • Respiratory tract infections caused by Mycoplasma pneumonia
  • Lymphogranuloma venereum caused by Chlamydia trachomatis
  • Psittacosis (Ornithosis) due to Chlamydia psittaci
  • Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated, as judged by immunofluorescence
  • Inclusion conjunctivitis caused by Chlamydia trachomatis
  • Nongonococcal urethritis, endocervical, or rectal infections in adults caused by Ureaplasma urealyticum or Chlamydia trachomatis
  • Relapsing fever due to Borrelia recurrentis
  • Plague due to Yersinia pestis
  • Tularemia due to Francisella tularensis
  • Cholera caused by Vibrio cholera
  • Campylobacter fetus infections caused by Campylobacter fetus
  • Brucellosis due to Brucella species (in conjunction with streptomycin)
  • Bartonellosis due to Bartonella bacilliformis
  • Granuloma inguinale caused by Klebsiella (Calymmatobacterium) granulomatis

Minocycline is indicated for the treatment of infections caused by the following Gram-negative bacteria when bacteriologic testing indicates appropriate susceptibility to the drug:

  • Enterobacter aerogenes
  • Escherichia coli
  • Shigella species
  • Acinetobacter species
  • Respiratory tract infections caused by Haemophilus influenzae
  • Respiratory tract and urinary tract infections caused by Klebsiella species

DIVAINE I.V. is indicated for the treatment of infections caused by the following Gram positive bacteria when bacteriologic testing indicates appropriate susceptibility to the drug:

  • Upper respiratory tract infections caused by Streptococcus pneumonia
  • Skin and skin structure infections caused by Staphylococcus aureus

(Note: Minocycline is not the drug of choice in the treatment of any type of staphylococcal infection.)

When penicillin is contraindicated, minocycline is an alternative drug in the treatment of the following infections:

  • Meningitis due to Neisseria meningitidis
  • Syphilis caused by Treponema pallidum subspecies pallidum
  • Yaws caused by Treponema pallidum subspecies pertenue
  • Listeriosis due to Listeria monocytogenes
  • Anthrax due to Bacillus anthracis
  • Vincent’s infection caused by Fusobacterium fusiforme
  • Actinomycosis caused by Actinomyces israelii
  • Infections caused by Clostridium species

In acute intestinal amoebiasis, minocycline may be a useful adjunct to amoebicides.

In severe acne, minocycline may be useful adjunctive therapy.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of minocycline injection and other antibacterial drugs, minocycline injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Dosage and Administration

Dosage

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 I.V. therapy is given over prolonged periods of time, thrombophlebitis may result.

Adults

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

Renal Impairment

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 AND PRECAUTIONS).

Paediatric Patients (above 8 years of age)

Usual Paediatric Dose: Initial dose of 4 mg/kg, then 2 mg/kg administered over 60 min every 12 hours; should not exceed the usual adult dose.

Geriatric Patients

Clinical studies of I.V. minocycline did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy (see WARNINGS AND PRECAUTIONSDOSAGE AND ADMINISTRATION).

Method of Preparation and Administration

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 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 further diluted in 100 mL to 1,000 mL of compatible solutions (except Lactated Ringer’s), the pH usually ranges from 2.5 to 4.0. The pH of DIVAINE I.V. 100 mg in Lactated Ringer’s 250 mL to 1,000 mL usually ranges from 4.5 to 6.0.

Compatible Diluents: Sodium Chloride Injection, USP, Dextrose Injection, USP, and Lactated Ringer’s Injection, USP.

Final dilutions should be administered immediately, but product and diluents are compatible at room temperature for 24 hours without a significant loss of potency. Any unused portions must be discarded after that period.

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

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 and Precautions

General

Warnings

Minocycline, like other tetracycline-class antibiotics, can cause foetal 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‑grey‑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.

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 6 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 foetal tissues, and can have toxic effects on the developing foetus (often related to retardation of skeletal development). Evidence of embryotoxicity has been noted in animals treated early in pregnancy.

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.

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

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

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

Precautions

As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted.

Pseudotumour cerebri (benign intracranial hypertension) in adults has been associated with the use of tetracyclines. The usual clinical manifestations are headache and blurred vision. Bulging fontanels have been associated with the use of tetracyclines in infants. While both of these conditions and related symptoms usually resolve soon after discontinuation of the tetracycline, the possibility for permanent sequelae exists.

Hepatotoxicity has been reported with minocycline; therefore, minocycline should be used with caution in patients with hepatic dysfunction and in conjunction with other hepatotoxic drugs.

Incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy when indicated.

Prescribing minocycline injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information for Patients

Diarrhoea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin.

The concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity.

Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective.

Administration of isotretinoin should be avoided shortly before, during, and shortly after minocycline therapy. Each drug alone has been associated with pseudotumour cerebri (see WARNINGS AND PRECAUTIONS, Precautions).

Increased risk of ergotism when ergot alkaloids or their derivatives are given with tetracyclines.

Renal Impairment

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 AND PRECAUTIONS, Warnings).

Pregnancy

Teratogenic Effects: Pregnancy Category D (see WARNINGS AND PRECAUTIONS, Warnings)

There are no adequate and well-controlled studies on the use of minocycline in pregnant women. Minocycline, like other tetracycline‑class antibiotics, crosses the placenta and may cause foetal harm when administered to a pregnant woman. Rare spontaneous reports of congenital anomalies including limb reduction have been reported in post-marketing experience. Only limited information is available regarding these reports; therefore, no conclusion on causal association can be established. If minocycline is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus.

Nonteratogenic Effects (see WARNINGS AND PRECAUTIONS, Warnings).

Lactation

Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tetracyclines, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother (see WARNINGS AND PRECAUTIONS, Warnings).

Paediatric Use

Minocycline is not recommended for use in children below 8 years of age unless the expected benefits of therapy outweigh the risks (see WARNINGS AND PRECAUTIONS, Warnings).

Geriatric Use

Clinical studies of intravenous minocycline did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see WARNINGS AND PRECAUTIONSDOSAGE AND ADMINISTRATION).

DIVAINE I.V. (sterile minocycline hydrochloride, USP) does not contain sodium                                                                                                                                               

Undesirable Effects

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

Body as a Whole: Fever, and discolouration of secretions.

Gastrointestinal: Anorexia, nausea, vomiting, diarrohea, 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: Hyperbilirubinaemia, hepatic cholestasis, increases in liver enzymes, fatal hepatic failure, and jaundice. Hepatitis, including autoimmune hepatitis, and liver failure have been reported (See WARNINGS AND 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 AND PRECAUTIONS). Pigmentation of the skin and mucous membranes has been reported.

Local Reactions: Injection site erythema and injection site pain.

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

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

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

Hypersensitivity Reactions: Urticaria, angioneurotic oedema, 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, haemolytic anaemia, thrombocytopenia, leucopenia, neutropenia, pancytopenia, and eosinophilia have been reported.

Central Nervous System: Convulsions, dizziness, hypoesthesia, paraesthesia, sedation, and vertigo. Pseudotumour cerebri (benign intracranial hypertension) in adults and bulging fontanels in infants (see WARNINGS AND 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 discolouration of the thyroid gland. Cases of abnormal thyroid function have been reported.

Tooth discolouration in paediatric patients less than 8 years of age (see WARNINGS AND PRECAUTIONS, Warnings) and in adults has been reported.

Oral cavity discolouration (including tongue, lips, and gums) have been reported.

Tinnitus and decreased hearing have been reported in patients on 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.

Overdosage

The adverse events more commonly seen in overdose are dizziness, nausea and vomiting.

No specific antidote for minocycline is known.

In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures. Minocycline is not removed in significant quantities by haemodialysis or peritoneal dialysis.

Incompatibility

DIVAINE I.V. should not be mixed before or during administration with any solutions containing the following: adrenocorticotropic hormone (ACTH), aminophylline, amobarbital sodium,amphotericin B, bicarbonate infusion mixtures, calcium gluconate or chloride, carbenicillin, cephalothin sodium, cefazolin sodium, chloramphenicol succinate, colistin sulphate, heparin sodium, hydrocortisone sodium succinate, iodine sodium, methicillin sodium, novobiocin, penicillin, pentobarbital, phenytoin sodium, polymyxin, prochlorperazine, sodium ascorbate, sulphadiazine, sulphisoxazole, thiopental sodium, vitamin K (sodium bisulphate or sodium salt), whole blood.

Additives or other medications should not be added to DIVAINE 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 DIVAINE with Sodium Chloride Injection USP, Dextrose Injection USP, Dextrose and Sodium Chloride Injection USP, or Lactated Ringer’s Injection USP.

Storage and Handling Instructions

Before Opening

Store below 25° C. Protect from light.

Reconstituted Solutions

Infusion or Admixture solution is stable at room temperature for 24 hr.

Packaging Information

Divaine I.V.: Vial of 8 ml

Last Updated: Nov 2015
Last Reviewed: Nov 2015