THERAPEUTIC CLASSIFICATION

Antibiotic

ACTION, CLINICAL PHARMACOLOGY

The mode of action of lincomycin hydrochloride is the inhibition of protein synthesis by the inhibition of the binding of aminoacyl sRNA to the messenger ribosome complex at the 50S ribosomal unit.

INDICATIONS AND CLINICAL USES

LINCOCIN (lincomycin hydrochloride) is indicated in the treatment of serious infections due to sensitive gram positive organisms (staphylococci, including penicillinase-producing staphylococci, streptococci and pneumococci) when the patient is intolerant of, or the organism resistant to other appropriate antibiotics. LINCOCIN is indicated in the treatment of osteomyelitis, when the causative organism has been found to be sensitive to this antibiotic.

CONTRAINDICATIONS

As with all drugs, the use of LINCOCIN (lincomycin hydrochloride) is contraindicated in patients previously found to be hypersensitive to the drug or patients who have previously been found hypersensitive to clindamycin (Dalacin C) or to any other component of the product. LINCOCIN should not be given to persons with known pre-existing monilial infections. Until further clinical experience is obtained, LINCOCIN is not indicated in the newborn.

WARNINGS

-associated disease (CDAD) has been reported with use of many antibacterial agents, including LINCOCIN ( lincomycin hydrochloride). CDAD may range in severity from mild diarrhoea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhoea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy. If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases. (see ADVERSE REACTIONS ) LINCOCIN should not be administered undiluted intravenously. All intravenous doses of LINCOCIN should be given by infusion over a period of 30 to 120 minutes. Cases of cardiopulmonary arrest have been reported during the treatment of severe endocarditis when large intravenous doses (over 4 grams) were given rapidly without dilution. These reactions do not occur when the drug is diluted as noted under DOSAGE AND ADMINISTRATION. This product contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.

PRECAUTIONS

GENERAL:

LINCOCIN (lincomycin hydrochloride) should be used with caution in those patients with a history of gastro-intestinal disease, specifically colitis. LINCOCIN is not indicated for use in the treatment of meningitis as the levels within the cerebral spinal fluid do not reach an adequate concentration to combat this infection. No serious renal or neurologic abnormalities have been reported to date. No ototoxicity has been demonstrated in any of a large number of patients treated with LINCOCIN.

USE IN OBSTETRICS AND NURSING MOTHERS:

No adverse effects on survival of offspring from birth to weaning were seen in studies performed in rats using oral doses of lincomycin up to 1000mg/kg (7.5 times the maximum human dose of 8g/day). No teratogenic effects were seen in a study conducted in rats treated with more than 55 times the highest recommended adult human dose of 8g/day. In humans, lincomycin crosses the placenta and results in cord serum levels about 25% of the maternal serum levels. No significant accumulation occurs in the amniotic fluid. Limited experience with 322 women receiving LINCOCIN orally at a dosage of 500 mg four times per day for seven days during pregnancy revealed no ill effect in the mother or the fetus. One hundred and ten of these patients were treated in the first trimester of pregnancy, 105 in the second trimester and 107 in the third trimester. All were suffering from cervicitis and/or vaginitis of bacterial origin in conjunction with their pregnancy. One hundred and twelve of the children, ages 61/2 to 71/2 years, from these patients have been examined and compared with a control group of 65 children born at the same time in the same hospital. LINCOCIN treatment did not result in any drug related abnormalities (physical, dental or developmental) when compared with the control group. LINCOCIN has been reported in breast milk at concentrations of 0.5 - 2.4 mg/mL. However, the use of lincomycin in pregnant and/or breast-feeding women should involve careful consideration of expected benefits and possible risks.

PATIENTS WITH SPECIAL DISEASES AND CONDITIONS:

The serum half-life of LINCOCIN is increased in those patients with impaired renal or hepatic function. Therefore, consideration should be given to reducing the frequency of administration in these patients. Since adequate data are not yet available in patients with pre-existing endocrine or metabolic diseases, its use in such patients is not recommended at this time unless special clinical circumstances so indicate. Efficacy of LINCOCIN in the prophylactic treatment of rheumatic fever has not been established.

DRUG INTERACTIONS:

studies have shown antagonistic activity between LINCOCIN and erythromycin; therefore, these agents should not be used concurrently.

Because LINCOCIN has been shown to have neuromuscular blocking properties which may enhance the action of other neuromuscular blocking agents, it should be used with caution in patients receiving such agents.

LABORATORY TESTS:

The use of antibiotics occasionally results in overgrowth of non-susceptible organisms -- particularly yeasts. Should superinfections occur, appropriate measures should be taken. No direct relationship of the drug to liver disease has been established. However, it is recommended that all patients receiving treatment for longer than one or two weeks have liver and kidney function tests performed. If abnormal tests appear, the drug should be discontinued unless, in the opinion of the physician, the drug should be continued for the treatment of a serious infection. During clinical studies of LINCOCIN in the therapy of infectious disease, a few cases of neutropenia and/or leukopenia were reported. No cases of irreversible toxicity to the hematopoietic system have been reported; however, it is recommended that blood counts be obtained early and repeated periodically during the course of LINCOCIN therapy.

ADVERSE REACTIONS

The following adverse reactions have been reported with the use of LINCOCIN (lincomycin hydrochloride):

Gastrointestinal - Nausea, vomiting, esophagitis, colitis, persistent diarrhoea and abdominal distress. Clotridium difficile-associated disease has been observed and the syndrome has manifested as a spectrum of symptoms from watery to severe diarrhoea, fever, abdominal cramps and leucocytosis. This may be accompanied by the passage of blood and mucous with resultant peritonitis, shock and toxic megacolon when the offending antibiotic is not discontinued and/or the condition treated). (see WARNINGS).
Hematopoietic - Neutropenia, leukopenia, agranulocytosis, and thrombocytopenic purpura have been reported. There have been rare reports of aplastic anemia and pancytopenia in which lincomycin could not be ruled out as the causative agent.
Hypersensitivity Reactions - Hypersensitivity reactions such as angioneurotic edema, serum sickness and anaphylaxis have been reported, some of these in patients sensitive to penicillin. Rare instances of erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with LINCOCIN administration.
Skin and Mucous Membranes - Pruritus, skin rashes, urticaria, vaginitis, and rare instances of exfoliative and vesiculobullous dermatitis have been reported.
Liver - Jaundice and abnormal liver function tests (particularly elevation of serum transaminase) have been observed during lincomycin therapy.
Cardiovascular - Instances of hypotension following parenteral administration have been reported, particularly after too rapid administration.

Rare instances of cardiopulmonary arrest have been reported after too rapid intravenous administration. (See Dosage and Administration section).

Local Reactions - Local irritation, pain, induration, and sterile abscess formation have been seen with IM injection. Thrombophlebitis has been reported with IV injection. These reactions can be minimized by deep IM injection and avoidance of indwelling intravenous catheters.

SYMPTOMS AND TREATMENT OF OVERDOSAGE:

No cases of large overdosage have been reported. It would be expected however that should overdosage occur, gastrointestinal side effects, including abdominal pain, nausea, vomiting and diarrhea, might be seen. Overdosage should be treated with simple gastric lavage. No specific antidote is known. Hemodialysis or peritoneal dialysis does not effectively remove lincomycin from the blood.

DOSAGE AND ADMINISTRATION

* * All doses may be increased in more severe infections. Doses as high as 8.4 grams per day, for seven days, in four divided doses of 2100 mg in an infusion of 250 mL, of normal saline, over a period of 120 minutes, were well tolerated in normal volunteers.

In b-hemolytic streptococcal infections, continue treatment for at least 10 days to diminish the likelihood of subsequent rheumatic fever or glomerulonephritis. When therapy with lincomycin is required in individuals with severe impairment of renal function, an appropriate dose is 25% to 30% of that recommended for patients with normally functioning kidneys.

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE:

Chemical Name: D-erythro-a-galacto-Octopyranoside, methyl 6, 8-dideoxy-6- [[(1-methyl-4-propyl-2-pyrrolidinyl) carbonyl] amino]-1- thio-monohydrochloride, monohydrate, (2S-trans).

DESCRIPTION

: Lincomycin, an antibiotic produced by Streptomyces lincolnensis var. lincolnensis, is chemically distinct from other clinically available antibiotics except its semi-synthetic derivative clindamycin (Dalacin C) and is isolated as a white crystalline solid. Lincomycin hydrochloride is stable in the dry state and in aqueous solution for at least 24 months. It is readily soluble in water at room temperature in concentrations up to 500 mg/mL. Physical stability of aqueous solutions can be maintained at drug concentrations up to 345 mg/mL at temperatures as low as 4 oC. The solubility in 95 percent ethanol is 80 mg/mL.

RECONSTITUTED SOLUTIONS:

LINCOCIN (600 mg - 2 mL and 1800 mg - 6 mL) was found to be compatible with 500 mL of the following solutions for a period of 24 hours at room temperature: 5% Dextrose in Water 10% Dextrose in Saline 5% Dextrose in Saline Invert sugar 10% 10% Dextrose in Water Polysal M with 5% dextrose Ringer's Solution Sodium lactate 1/6 molar Compatibility was determined by a study which indicated no appreciable change in the pH of the resultant mixture and no loss of potency of the LINCOCIN when diluted as indicated above.

Incompatibilities

When combined with lincomycin in an infusion solution, novobiocin, kanamycin, and phenytoin are each physically incompatible with lincomycin. This list may not be all-inclusive due to the multiple factors influencing drug compatibility data.

Stability and Storage recommendations: Store at room temperature (15 -30 oC), protect from light.

AVAILABILITY OF DOSAGE FORM

- Each mL containing LINCOCIN (lincomycin hydrochloride monohydrate) equivalent to lincomycin base 300 mg; also Benzyl Alcohol, 9.45 mg; Water for Injection, q.s. - supplied in 2 mL.

- 500 mg, each capsule containing LINCOCIN (lincomycin hydrochloride monohydrate) equivalent to lincomycin base 500 mg, supplied in bottles of 100 capsules.

MICROBIOLOGY

In vitro studies indicate that the spectrum of activity includes Micrococcus (Staphylococcus) aureus, Staphylococcus albus, 8-hemolytic Streptococcus, Streptococcus viridans, Streptococcus pneumoniae, Clostridium tetani, Clostridium perfringens and Corynebacterium diphtheriae. Minimum inhibitory concentrations for these organisms are listed in Table I.

Minimum Inhibitory Concentrations (M.I.C. 's) In Vitro of Organisms Sensitive to LINCOCIN (lincomycin hydrochloride)

This drug is not active against most strains of Streptococcus faecalis, nor against Neisseria gonorrhoea, Hemophilus influenzae (with the 2 mg disk), or other gram-negative organisms or yeasts. LINCOCIN may or may not be bactericidal depending on the serum level attained and the sensitivity of the organism present. LINCOCIN resistance development by staphylococci is slow and stepwise rather than rapid and streptomycin-like. LINCOCIN participates in the dissociated cross-resistance phenomenon with erythromycin. LINCOCIN is not cross-resistant with penicillin, ampicillin, erythromycin, tetracycline, or streptomycin. It is however cross-resistant with clindamycin. Animal studies on the etiology of antibiotic-associated colitis and the protective effect of vancomycin has suggested a toxin(s) produced by Clostridia as the causative agent. Studies in hamsters have shown that oral vancomycin was protective against clindamycin-induced enterocolitis when administered concurrently with, or prior to, the antibiotic challenge. Vancomycin produced a marked decrease in the colonic Clostridia counts suggesting that its antimicrobial action was responsible for its protective effect. This was supported by the finding that in vitro, vancomycin did not decrease the cytotoxic activity of an isolated toxin associated with antibiotic-induced enterocolitis in hamsters. In rabbits, vancomycin administered concurrently with clindamycin was protective against enterocolitis and resulted in a greatly lower fecal Clostridia count. Extracts from the stools of these rabbits were not lethal to mice. Analysis of the feces of patients with pseudomembranous colitis has shown the presence of a neutralizable toxin and Clostridia species (most frequently C. difficile). Almost all strains of C. difficile tested were sensitive to vancomycin with minimum inhibitory concentrations ranging from 0.2 to 16 mg/mL (Table II).

When patients with pseudomembranous colitis were treated with oral vancomycin 125 to 500 mg four times daily, fecal vancomycin concentrations greatly exceeded the MIC's for C. difficile.

PHARMACOLOGY

Clinical Absorption

Lincomycin is absorbed rapidly after oral administration, reaching peak levels in two to four hours. Levels above the minimum inhibitory concentration for most gram-positive organisms are maintained for six to eight hours. Intramuscular administration of lincomycin produces peak serum levels in 30 minutes with detectable levels persisting for 24 hours after a 600 mg dose. Intravenous infusions of lincomycin over a two hour interval yield therapeutic levels for 14 hours (see TABLE III)

Average Serum Levels in mg/mL of Lincomycin After Single Dose Administration in Normal Volunteers

The biological half-life after oral, intramuscular or intravenous administration is 5.4 +- 1.0 hours.

Urinary Excretion

The urinary excretion of lincomycin varies depending on the dosage used and the route of administration (SeeTableIV).

Range and Average 24-hour Urinary Recovery of Lincomycin After a Single Dose in Normal Volunteers

*Expressed as a percentage of the administration dose, 10 patients in each group.

Biliary Excretion

The bile is an important route of excretion of lincomycin as can be seen in the results tabulated in Table V.

Lincomycin Levels in Tissues and Body Fluids

Lincomycin penetrates most body tissues and fluids to a varying degree, depending on the dosage and route of administration. Table VI represents a compilation of data available in this regard.

The absorption of lincomycin administered orally is somewhat suppressed when given in the presence of cyclamates or cyclamate-containing foods or beverage.

TOXICOLOGY

The acute LD50 intraperitoneally in mice is 1000 mg/kg and orally in rats is >4000 mg/kg. Lincomycin was well tolerated orally in rats and dogs at doses up to 300 mg/kg/day for periods up to one year. Parenteral dosages of up to 60 mg/kg/day for 30 days subcutaneously in the rat and intramuscularly in the dog produced no significant systemic effects or pathological findings at necropsy. Lincomycin at a daily dose level of 75 mg/kg subcutaneously was injected into mature male and female rats during a prebreeding period of 60 days and throughout two mating cycles (84 days). No evidence was obtained that lincomycin exerted any effect on breeding performance and no drug-induced anomalies were discovered in the young. Similarly no evidence was obtained that lincomycin, when given in sustained parenteral dosage of 50 mg/kg daily to pregnant bitches, produced a teratogenic effect of the canine embryo. The subcutaneous LD50 value in the newborn rat was determined to be 783 mg/kg. Newborn rats and canine pups have tolerated multiple doses of 30 - 90 mg/kg/day of the drug without evidence of ill effects.

	INTRMUSCULAR (Sterile Solution)	INTRAVENOUS (Sterile Solution)
Adults	600 mg (2mL) every 24 hours	600 mg (2mL) every 8 to 12 * * hours. Administer as infusion in 250 mL or more of 5% glucose in water or normal saline over a period of 30 to 120 mins.
Severe Infections	600 mg (2mL) every 12 hours
Children *	10 mg/kg every 24 hours	10 to 20 mg/kg/day in two or three doses at 8 to 12 hour intervals. Administer as infusion diluted as for adults.
Severe Infections	10 mg/kg every 12 hours

ORGANISM	M.I.C. (m/mL)	Reference
Staphylococcus aureus	0.12 - 2.0	(16)
Staphylococcus albus	0.8 - 1.5	( 9)
8-Hemolytic streptococcus	0.12 - 2.0	(16)
Streptococcus viridans	0.12 - 0.5	(16)
Streptococcus pneumoniae	0.12 - 1.0	(16)
Clostridium tetani & perfringens	0.36 - 1.4	(15)
Corynebacterium diphtheriae	0.4	( 9)

# Strains	M.I.C. (mg/mL)	Reference
39	<= 4	10
10	0.5 - 4	3
15	0.2 -1.6	8
37	0.5 - 16	5
17	< 1	6

			Time After Medication In Hours
DOSAGE	ROUTE	0.5	2	4	6	8	12	24
500 mg	Oral	-	5.3	2.4	1.7	1.3	0.3	-
1000 mg	Oral	-	6.72	3.01	2.19	1.61	0.84	-
300 mg	I.M.	15.0	10.2	7.4	4.1	2.1	0.7	0
600 mg	I.M.	18.5	10.5	5.5	4.9	4.2	1.3	0.3
600 mg	I.V.	20.9	11.2	6.4	3.7	2.2	1.1	0

DOSAGE	ROUTE	RANGE *	AVERAGE *
500 mg	Oral	1.8 to 13.7	6.17
1000 mg	Oral	1.7 to 27.0	9.49
300 mg	I.M.	5.57 to 16.89	10.48
600 mg	I.M.	1.82 to 24.80	10.30
600 mg	I.V.	4.9 to 23.3	15.1

	SINGLE I.V. DOSE 600 mg		SINGLE ORAL DOSE 1000 mg
TIME AFTER MEDICATION	SERUM *	BILE * *	SERUM *	BILE * *
0.5 hours	8.8	-	-	-
1 hour	-	67.0	-	-
2 hours	5.2	8.0	2.8	-
3 hours	-	-	-	1.0
4 hours	3.8	3.8	1.8	1.15
5 hours	-	7.0	-	-
6 hours	3.8	2.8	1.1	2.1
7 hours	-	1.2	-	-
8 hours	3.8	1.5	1.1	-
9 hours	-	2.4	-	-
10 hours	-	1.3	-	-
12 hours	0.9	-	0	17.0
14 hours	-	-	-	42.0
24 hours	0	0	0	0

TISSUE OR BODY FLUID	LINCOMYCIN DOSAGE AND ROUTE OF ADMINISTRATION	RANGE OF VALUES *
Appendix	500 mg q6h for 3 days orally	0.9-13.5
Bile	500 mg q6h for 3 days orally	5.2-44.7
Breast	500 mg q6h for 3 days orally	<0.4- 1.7
Bronchus	500 mg q6h for 3 days orally	1.7
Gall Bladder	500 mg q6h for 3 days orally	0.9- 5.9
Lung	500 mg q6h for 3 days orally	1.5- 1.8
Muscle	500 mg q6h for 3 days orally	<0.6- 3.4
Omentum	500 mg q6h for 3 days orally	<0.4- 1.9
Pleural Fluid	500 mg q6h for 3 days orally	1.9- 3.6
Tonsil	500 mg q6h for 3 days orally	0.9-11.0
Amniotic Fluid	600 mg I.M. Single Dose	1.5- 6.9
Human Milk	500 mg q6h for 12 Doses	0.5- 1.8
Spinal Fluid (normal volunteers)	600 mg I.M. Single Dose	0.7- 1.15
Spinal Fluid (pneumococcal meningitis)	1200 mg I.V. q4h	20.0 * *
Joint Fluid	600 mg I.M. q6h	4.3-20.0
Aqueous Humor (non-inflamed eyes)	600 mg I.M. q4h	<0.5- 2.0
Aqueous Humor (inflamed eye)	600 mg I.M. q4h	21.0 * *
Bone	600 mg I.M. q6h	2.2- 6.6