Dalacin C 150/Sterile Solution

Cap: Clindamycin hydrochloride; Soln for inj: Clindamycin phosphate.

Active Ingredient: clindamycin hydrochloride or phosphate.
Capsules: Clindamycin hydrochloride is the hydrated hydrochloride salt of clindamycin. Each capsule contains clindamycin hydrochloride equivalent to 150 mg of clindamycin.
Solution for injection: Clindamycin phosphate is a water-soluble ester of clindamycin and phosphoric acid. Each mL contains the equivalent of 150 mg clindamycin, 0.5 mg disodium edetate and 9.45 mg benzyl alcohol added as preservative in each mL.
Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin.
Excipients/Inactive Ingredients: Capsules: 150 mg capsule: Maize starch, talc, vegetable magnesium stearate, lactose monohydrate.
Solution for injection: Benzyl alcohol, sodium hydroxide, disodium edetate, water for injections.

Pharmacology: Pharmacodynamics: Mechanism of action: Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis. It binds to the 50S ribosomal subunit and affects both ribosome assembly and the translation process. Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin. At usual doses, clindamycin exhibits bacteriostatic activity in vitro.
Pharmacodynamic effects: Efficacy is related to the time period over which the agent level is above the minimum inhibitory concentration (MIC) of the pathogen (%T/MIC).
Resistance: Resistance to clindamycin is most often due to mutations at the rRNA antibiotic binding site or methylation of specific nucleotides in the 23S RNA of the 50S ribosomal subunit. These alterations can determine in vitro cross resistance to macrolides and streptogramins B (MLS_B phenotype). Resistance is occasionally due to alterations in ribosomal proteins. Resistance to clindamycin may be inducible by macrolides in macrolide-resistant bacterial isolates. Inducible resistance can be demonstrated with a disk test (D-zone test) or in broth. Less frequently encountered resistance mechanisms involve modification of the antibiotic and active efflux. There is complete cross resistance between clindamycin and lincomycin. As with many antibiotics, the incidence of resistance varies with the bacterial species and the geographical area. The incidence of resistance to clindamycin is higher among methicillin-resistant staphylococcal isolates and penicillin-resistant pneumococcal isolates than among organisms susceptible to these agents.
Antimicrobial activity: Clindamycin has been shown to have in vitro activity against most isolates of the following organisms: Aerobic bacteria: Gram-positive bacteria: Staphylococcus aureus (methicillin-susceptible isolates); Coagulase-negative staphylococci (methicillin-susceptible isolates); Streptococcus pneumoniae (penicillin-susceptible isolates); Beta-hemolytic streptococci groups A, B, C, and G; Viridans group streptococci; Corynebacterium spp.
Gram-negative bacteria: Chlamydia trachomatis.
Anaerobic bacteria: Gram-positive bacteria: Actinomyces spp.; Clostridium spp. (except Clostridium difficile); Eggerthella (Eubacterium) spp.; Peptococcus spp.; Peptostreptococcus spp. (Finegoldia magna, Micromonas micros); Propionibacterium acnes.
Gram-negative bacteria: Bacteroides spp.; Fusobacterium spp.; Gardnerella vaginalis; Prevotella spp.
Fungi: Pneumocystis jirovecii.
Protozoans: Toxoplasma gondii; Plasmodium falciparum.
Breakpoints: The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Particularly in severe infections or therapy failure microbiological diagnosis with verification of the pathogen and its susceptibility to clindamycin is recommended.
Resistance is usually defined by susceptibility interpretive criteria (breakpoints) established by Clinical and Laboratory Standards Institute (CLSI) or European Committee on Antimicrobial Susceptibility Testing (EUCAST) for systemically administered antibiotics.
Clinical and Laboratory Standards Institute (CLSI) breakpoints for relevant organisms are listed as follows. (See Table 1.)

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A report of "Susceptible" (S) indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" (I) 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 that prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" (R) indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the usually achievable concentrations; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard clindamycin powder should provide the MIC ranges in Table 2. For the disk diffusion technique using the 2 mcg clindamycin disk the criteria provided in Table 2 should be achieved. (See Table 2.)

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The European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints are presented as follows. (See Table 3.)

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EUCAST QC ranges for MIC and disk zone determinations are in the table as follows. (See Table 4.)

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Pharmacokinetics: Serum level studies with a 150 mg oral dose of clindamycin hydrochloride in 24 normal adult volunteers showed that clindamycin was rapidly absorbed after oral administration. An average peak serum level of 2.50 mcg/mL was reached in 45 minutes; serum levels averaged 1.51 mcg/mL at 3 hours and 0.70 mcg/mL at 6 hours. Absorption of an oral dose is virtually complete (90%), and the concomitant administration of food does not appreciably modify the serum concentrations; serum levels have been uniform and predictable from person to person and dose to dose. Serum level studies following multiple doses of clindamycin hydrochloride for up to 14 days show no evidence of accumulation or altered metabolism of drug. Serum half-life of clindamycin is increased slightly in patients with markedly reduced renal function. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Concentrations of clindamycin in the serum increased linearly with increased dose. Serum levels exceed the MIC (minimum inhibitory concentration) for most indicated organisms for at least six hours following administration of the usually recommended doses. Clindamycin is widely distributed in body fluids and tissues (including bones). In vitro studies in human liver and intestinal microsomes indicated that clindamycin is predominantly oxidized by CYP3A4, with minor contribution from CYP3A5, to form clindamycin sulfoxide and a minor metabolite, N-desmethylclindamycin. The average biological half-life is 2.4 hours. Approximately 10% of the bioactivity is excreted in the urine and 3.6% in the feces; the remainder is excreted as bioinactive metabolites. Doses of up to 2 grams of clindamycin per day for 14 days have been well tolerated by healthy volunteers, except that the incidence of gastrointestinal side effects is greater with the higher doses. No significant levels of clindamycin are attained in the cerebrospinal fluid, even in the presence of inflamed meninges. Pharmacokinetic studies in elderly volunteers (61-79 years) and younger adults (18-39 years) indicate that age alone does not alter clindamycin pharmacokinetics (clearance, elimination half-life, volume of distribution, and area under the serum concentration time curve) after IV administration of clindamycin phosphate. After oral administration of clindamycin hydrochloride, elimination half-life is increased to approximately 4.0 hours (range 3.4 - 5.1 h) in the elderly compared to 3.2 hours (range 2.1 - 4.2 h) in younger adults. The extent of absorption, however, is not different between age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function.
Obese Pediatric Patients Aged 2 to Less than 18 Years and Obese Adults Aged 18 to 20 Years: An analysis of pharmacokinetic data in obese pediatric patients aged 2 to less than 18 years and obese adults aged 18 to 20 years demonstrated that clindamycin clearance and volume of distribution normalized by total body weight are comparable regardless of obesity.
Toxicology: Preclinical Safety Data: Carcinogenesis: Long term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential.
Mutagenesis: Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative.
Impairment of Fertility: Fertility studies in rats treated orally with up to 300 mg/kg/day (approximately 1.1 times the highest recommended adult human dose based on mg/m²) revealed no effects on fertility or mating ability.
In oral embryo fetal development studies in rats and subcutaneous embryo fetal development studies in rats and rabbits, no developmental toxicity was observed except at doses that produced maternal toxicity.

Clindamycin has been shown to be effective in the treatment of the following infections when caused by susceptible anaerobic bacteria; susceptible strains of gram positive aerobic bacteria such as streptococci, staphylococci and pneumococci; and susceptible strains of Chlamydia trachomatis.
(a) Upper respiratory infections including tonsillitis, pharyngitis, sinusitis, otitis media and scarlet fever.
(b) Lower respiratory infections including bronchitis, pneumonia, empyema and lung abscess.
(c) Skin and soft tissue infections including acne, furuncles, cellulitis, impetigo, abscesses, and wound infections, specific skin and soft tissue infections caused by susceptible organisms like erysipelas and paronychia (panaritium).
(d) Bone and joint infections including osteomyelitis and septic arthritis.
(e) Gynecological infections including endometritis, cellulitis, vaginal cuff infection and tubo-ovarian abscess, salpingitis, and pelvic inflammatory disease when given in conjunction with an antibiotic of appropriate gram negative spectrum. In cases of cervicitis due to Chlamydia trachomatis, single drug therapy with clindamycin has been shown to be effective in eradicating the organism.
(f) Intra-abdominal infections including peritonitis and abdominal abscess when given in conjunction with an antibiotic of appropriate gram negative aerobic spectrum.
(g) Septicemia and endocarditis - The effectiveness of clindamycin in the treatment of selected cases of endocarditis has been documented when clindamycin is determined to be bactericidal to the infecting organism by in vitro testing of appropriate achievable serum concentrations.
(h) Dental infections such as periodontal abscess and periodontitis.
(i) Toxoplasmic encephalitis in patients with AIDS. In patients who are intolerant to conventional treatment, clindamycin in combination with pyrimethamine has been shown to be efficacious.
(j) Pneumocystis jiroveci (previously classified as Pneumocystis carinii) pneumonia in patients with AIDS. In patients who are intolerant to, or do not respond adequately to conventional treatment, clindamycin may be used in combination with primaquine.
Clindamycin phosphate, when used concurrently with an aminoglycoside antibiotic such as gentamicin or tobramycin, has been shown to be effective in preventing peritonitis or intra-abdominal abscess after bowel perforation and bacterial contamination secondary to trauma.
In-vitro susceptibility to clindamycin has been shown for the following organisms: B. melaninogenicus, B.disiens, B. bivius, Peptostreptococcus spp., G. vaginalis, M. mulieris, M. curtisii, and Mycoplasma hominis.

Dosage in Adults: Clindamycin phosphate IM administration should be used undiluted.
Clindamycin phosphate IV administration should be diluted (see Special Precautions for Disposal and Other Handling under Cautions for Usage).
Clindamycin phosphate (IM or IV administration): The usual daily adult dosage of clindamycin phosphate for infections of the intra-abdominal area, female pelvis, and other complicated or serious infections is 2400-2700 mg given in 2, 3, or 4 equal doses. Less complicated infections due to more susceptible microorganisms may respond to lower doses such as 1200-1800 mg/day administered in 3 or 4 equal doses.
Doses of up to 4800 mg daily have been used successfully.
Single IM doses of greater than 600 mg are not recommended.
Clindamycin hydrochloride capsules (oral administration): 600-1800 mg/day divided in 2, 3 or 4 equal doses. To avoid the possibility of esophageal irritation, clindamycin HCl capsules should be taken with a full glass of water.
Dosage in Children (from 2 years of age): Clindamycin should be dosed based on total body weight regardless of obesity.
Clindamycin phosphate (IM or IV administration): 20-40 mg/kg/day in 3 or 4 equal doses.
Clindamycin hydrochloride capsules (oral administration) for children who are able to swallow capsules: To avoid the possibility of esophageal irritation, clindamycin HCl capsules should be taken with a full glass of water. Clindamycin capsules are not suitable for children who are unable to swallow them whole.
Doses of 8-25 mg/kg/day in 3 or 4 equal doses.
Dosage in Elderly: Pharmacokinetic studies with clindamycin have shown no clinically important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration. Therefore, dosage adjustments are not necessary in the elderly with normal hepatic function and normal (age-adjusted) renal function (see Pharmacology: Pharmacokinetics under Actions).
Dosage in Renal Impairment: Clindamycin dosage modification is not necessary in patients with renal insufficiency.
Dosage in Hepatic Impairment: Clindamycin dosage modification is not necessary in patients with hepatic insufficiency.
Dosage in Specific Indications: (a) Treatment of Beta-Hemolytic Streptococcal Infections: Refer to the dosage recommendations previously mentioned. Treatment should be continued for at least 10 days.
(b) Inpatient Treatment of Pelvic Inflammatory Disease: Clindamycin phosphate 900 mg (IV) every 8 hours daily plus an antibiotic with an appropriate gram-negative aerobic spectrum administered IV, e.g., gentamicin 2.0 mg/kg followed by 1.5 mg/kg every 8 hours daily in patients with normal renal function. Continue (IV) drugs for at least 4 days and at least 48 hours after the patient improves. Then continue oral clindamycin hydrochloride 450-600 mg q6h daily to complete 10-14 days total therapy.
(c) Treatment of Chlamydia trachomatis Cervicitis: Clindamycin hydrochloride capsules orally 450 mg 4 times daily for 10-14 days.
(d) Treatment of Toxoplasmic Encephalitis in Patients with AIDS: Clindamycin phosphate IV or clindamycin hydrochloride orally 600-1200 mg every 6 hours for 2 weeks followed by 300-600 mg orally every 6 hours. The usual total duration of therapy is 8 to 10 weeks. The dose of pyrimethamine is 25 to 75 mg orally each day for 8 to 10 weeks. Folinic acid 10 to 20 mg/day should be given with higher doses of pyrimethamine.
(e) Treatment of Pneumocystis jiroveci (previously classified as Pneumocystis carinii) Pneumonia in Patients with AIDS: Clindamycin phosphate IV 600 to 900 mg every 6 hours or 900 mg IV every 8 hours or clindamycin hydrochloride 300 to 450 mg orally every 6 hours for 21 days; and Primaquine 15 to 30 mg dose orally once daily for 21 days.
(f) Treatment of Acute Streptococcal Tonsillitis/Pharyngitis: Clindamycin hydrochloride capsules 300 mg orally twice daily for 10 days.

Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum.

Clindamycin is contraindicated in patients previously found to be sensitive to clindamycin or lincomycin or to any component of the formulation.

Clindamycin therapy has been associated with severe colitis which may end fatally.
It should be reserved for serious infections where less toxic antimicrobial agents are inappropriate.
It should not be used in patients with nonbacterial infections, such as most upper respiratory tract infections.
Clindamycin phosphate injectable formulation contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with a fatal "Gasping Syndrome" in premature infants. Its use should be avoided in children under 2 years of age. Clindamycin is contraindicated in newborns.

Severe hypersensitivity reactions, including severe skin reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving clindamycin therapy. If a hypersensitivity or severe skin reaction occurs, clindamycin should be discontinued and appropriate therapy should be initiated (see Contraindications and Adverse Reactions).
The clindamycin phosphate injectable formulation contains benzyl alcohol. The preservative benzyl alcohol has been associated with serious adverse events, including the "gasping syndrome", and death in pediatric patients. Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome", the minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the liver and kidneys' capacity to detoxify the chemical. Premature and low birth weight infants may be more likely to develop toxicity. Its use should be avoided in children under 2 years of age.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clindamycin, and may range in severity from mild to life-threatening. Therefore, it is important to consider the diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis". After the primary diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate-to-severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin, 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 antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
Since clindamycin does not diffuse adequately into cerebrospinal fluid, the drug should not be used in the treatment of meningitis.
If therapy is prolonged, liver and kidney function tests should be performed.
Clindamycin is potentially nephrotoxic. Acute kidney injury including acute renal failure has been reported. Therefore, monitoring of renal function should be considered during therapy of patients with pre-existing renal dysfunction or taking concomitant nephrotoxic drugs and monitoring of renal function should be performed if therapy is prolonged.
The use of clindamycin phosphate may result in overgrowth of non-susceptible organisms, particularly yeasts.
Clindamycin phosphate should not be injected intravenously undiluted as a bolus, but should be infused over at least 10-60 minutes as directed in Dosage & Administration.
Effects on Ability to Drive and Use Machines: The effect of clindamycin on the ability to drive or operate machinery has not been systematically evaluated.

Use in Pregnancy: Benzyl alcohol can cross the placenta. See Precautions.
Oral and subcutaneous reproductive toxicity studies in rats and rabbits revealed no evidence of impaired fertility or harm to the fetus due to clindamycin, except at doses that caused maternal toxicity. Animal reproduction studies are not always predictive of human response.
Clindamycin crosses the placenta in humans. After multiple doses, amniotic fluid concentrations were approximately 30% of maternal blood concentrations.
In clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters has not been associated with an increased frequency of congenital abnormalities. There are no adequate and well-controlled studies in pregnant women during the first trimester of pregnancy.
Clindamycin should be used in pregnancy only if clearly needed.
Use in Nursing Mothers: Clindamycin has been reported to appear in human breast milk in ranges from <0.5 to 3.8 μg/mL.
Clindamycin has the potential to cause adverse effects on the breastfed infant's gastrointestinal flora such as diarrhoea or blood in the stool, or rash. If oral or intravenous clindamycin is required by a nursing mother, it is not a reason to discontinue breastfeeding, but an alternate drug may be preferred. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for clindamycin and any potential adverse effects on the breastfed child from clindamycin or from the underlying maternal condition.

ADRs by SOC and CIOMS frequency category listed in order of decreasing medical seriousness within each frequency category and SOC. (See Table 5.)

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Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents.
Clindamycin is metabolized predominantly by CYP3A4, and to a lesser extent by CYP3A5, to the major metabolite clindamycin sulfoxide and minor metabolite N-desmethylclindamycin. Therefore, inhibitors of CYP3A4 and CYP3A5 may reduce clindamycin clearance and inducers of these isoenzymes may increase clindamycin clearance. In the presence of strong CYP3A4 inducers such as rifampicin, monitor for loss of effectiveness.
In vitro studies indicate that clindamycin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2E1 or CYP2D6 and only moderately inhibits CYP3A4. Therefore, clinically important interactions between clindamycin and co-administered drugs metabolized by these CYP enzymes are unlikely.

Incompatibilities: When combined with clindamycin phosphate in an infusion solution, ampicillin, phenytoin sodium, barbiturates, aminophylline, calcium gluconate, magnesium sulfate, ceftriaxone sodium, and ciprofloxacin are each physically incompatible with clindamycin phosphate.
Special Precautions for Disposal and Other Handling: Capsule: Not applicable.
Solution for injection: Dilution for IV use and IV infusion rates: The concentration of clindamycin in diluent for infusion should not exceed 18 mg per mL and INFUSION RATES SHOULD NOT EXCEED 30 MG PER MINUTE. The usual infusion rates are as follows: (see Table 6.)

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Capsules: 150 mg capsule: Store below 30°C.
Solution for injection: Store at 2°C to 8°C (Refrigerate. Do not freeze).

Other Antibiotics

J01FF01 - clindamycin ; Belongs to the class of lincosamides. Used in the systemic treatment of infections.

B