Product Monograph - Dalacin C Phosphate
Recent Major Label Changes
| 7 Warnings and Precautions, Immune | 2026-08 |
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Table Of Contents
Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.
Recent Major Label Changes .................................................................................................. 2
Table Of Contents .................................................................................................................. 2
Part 1: Healthcare Professional Information........................................................................... 4
1 Indications .................................................................................................................. 4
1.1 Pediatrics......................................................................................................... 5
1.2 Geriatrics ......................................................................................................... 5
2 Contraindications ....................................................................................................... 5
4 Dosage and Administration ........................................................................................ 5
4.1 Dosing Considerations...................................................................................... 5
4.2 Recommended Dose and Dosage Adjustment ................................................... 6
4.3 Reconstitution ................................................................................................. 7
4.4 Administration ................................................................................................. 8
4.5 Missed Dose .................................................................................................... 9
5 Overdose .................................................................................................................... 9
6 Dosage Forms, Strengths, Composition and Packaging................................................ 9
7 Warnings and Precautions ........................................................................................ 10
General ..................................................................................................................... 10
Gastrointestinal......................................................................................................... 10
Hematologic.............................................................................................................. 10
Hepatic/Biliary/Pancreatic ......................................................................................... 11
Immune .................................................................................................................... 11
Monitoring and Laboratory Tests ............................................................................... 11
Renal ........................................................................................................................ 11
Sensitivity/Resistance................................................................................................ 12
7.1 Special Populations ........................................................................................ 12
7.1.1 Pregnancy .................................................................................................. 12
7.1.2 Breastfeeding............................................................................................. 12
7.1.3 Pediatrics ................................................................................................... 12
7.1.4 Geriatrics ................................................................................................... 13
8 Adverse Reactions .................................................................................................... 13
8.2 Clinical Trial Adverse Reactions ...................................................................... 13
8.3 Less Common Clinical Trial Adverse Reactions ................................................ 14
8.5 Post-Market Adverse Reactions ...................................................................... 14
9 Drug Interactions ...................................................................................................... 15
9.2 Drug Interactions Overview ............................................................................ 15
9.4 Drug-Drug Interactions................................................................................... 16
9.5 Drug-Food Interactions .................................................................................. 16
9.6 Drug-Herb Interactions................................................................................... 17
9.7 Drug-Laboratory Test Interactions .................................................................. 17
10 Clinical Pharmacology ............................................................................................... 17
10.1 Mechanism of Action ..................................................................................... 17
10.2 Pharmacodynamics ........................................................................................ 17
10.3 Pharmacokinetics........................................................................................... 17
11 Storage, Stability and Disposal.................................................................................. 20
12 Special Handling Instructions .................................................................................... 20
Part 2: Scientific Information ............................................................................................... 21
13 Pharmaceutical Information ..................................................................................... 21
14 Clinical Trials............................................................................................................. 21
15 Microbiology ............................................................................................................ 21
16 Non-Clinical Toxicology............................................................................................. 28
Patient Medication Information........................................................................................... 31
Part 1: Healthcare Professional Information
1 Indications
DALACIN C PHOSPHATE (clindamycin phosphate) is indicated for the treatment of serious infections due to susceptible anaerobic bacteria, such as Bacteroides species, Peptostreptococcus, anaerobic streptococci, Clostridium species and microaerophilic streptococci.
DALACIN C PHOSPHATE is also indicated for the treatment of serious infections due to susceptible strains of gram positive aerobic bacteria (staphylococci, including penicillinase-producing staphylococci, streptococci and pneumococci) as well as in the treatment of Chlamydia trachomatis, when the patient is intolerant of, or the organism is resistant to other appropriate antibiotics.
Because of the risk of Clostridium difficile-associated disease (CDAD) as described in 7 Warnings and Precautions, before selecting clindamycin the health professional should consider the nature of the infection and the suitability of alternative therapy.
DALACIN C PHOSPHATE is indicated for the treatment of the following serious infections when caused by susceptible strains of the designated organisms in the conditions listed below:
- Lower respiratory infections including pneumonia, empyema, and lung abscess when caused by anaerobes, Streptococcus pneumoniae, other streptococci (except Enterococcus faecalis) and Staphylococcus aureus.
- Skin and skin structure infections including cellulitis, abscesses, and wound infections when caused by Streptococcus pyogenes, Staphylococcus aureus and anaerobes.
- Gynecological infections including endometritis, pelvic cellulitis, vaginal cuff infections, non-gonococcal tubo-ovarian abscess, salpingitis, and pelvic inflammatory disease when caused by susceptible anaerobes or Chlamydia trachomatis. Clindamycin should be given in conjunction with an antibiotic of appropriate gram negative aerobic spectrum.
- Intra-abdominal infections including peritonitis and abdominal abscess when caused by susceptible anaerobes. Clindamycin should be given in conjunction with an antibiotic of appropriate gram negative aerobic spectrum.
- Septicemia caused by Staphylococcus aureus, streptococci (except Enterococcus faecalis) and susceptible anaerobes, where the bactericidal efficacy of clindamycin against the infecting organism has been determined in vitro at achievable serum levels.
- Bone and joint infections including osteomyelitis and septic arthritis when caused by sensitive strains of Staphylococcus aureus and anaerobes.
- Pneumocystis jiroveci pneumonia in patients with AIDS. Clindamycin in combination with primaquine may be used in patients who are intolerant to, or fail to respond to conventional therapy.
DALACIN C PHOSPHATE is not indicated in the treatment of meningitis since it penetrates poorly into cerebrospinal fluid, even in the presence of inflamed meninges.
Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to clindamycin.
Indicated surgical procedures and drainage should be performed in conjunction with antibiotic therapy.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of DALACIN C PHOSPHATE and other antibacterial drugs, DALACIN C PHOSPHATE should be used only to treat 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.
1.1 Pediatrics
Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of DALACIN C PHOSPHATE in pediatric patients has been established. Therefore, Health Canada has authorized an indication for pediatric use. It is not known if use of clindamycin in the pediatric population is associated with differences in safety or effectiveness compared with adult patients.
1.2 Geriatrics
Geriatrics (>65 years of age): Insufficient data are available to Health Canada. Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients.
2 Contraindications
DALACIN C PHOSPHATE (clindamycin phosphate) is contraindicated in patients with a known hypersensitivity to preparations containing clindamycin or lincomycin or to any ingredient in the formulation or component of the formulation. For a complete listing, see 6 Dosage Forms, Strengths, Composition and Packaging.
4 Dosage and Administration
4.1 Dosing Considerations
DALACIN C PHOSPHATE dose modification may not be necessary in patients with renal disease. DALACIN C PHOSPHATE dosage reduction in liver disease is not generally considered necessary.
Dosage adjustments are not necessary in the elderly with normal hepatic function and normal (age-adjusted) renal function.
Dosage and route of administration should be determined by the severity of the infection, the condition of the patient and the susceptibility of the causative microorganisms.
In cases of β-hemolytic streptococcal infections, treatment should be continued for at least 10 days.
4.2 Recommended Dose and Dosage Adjustment
Adults
The usual daily adult dosage of DALACIN C PHOSPHATE (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 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 without adverse effects. Single intramuscular doses of greater than 600 mg are not recommended.
Pelvic Inflammatory Disease
DALACIN C PHOSPHATE 900 mg (IV) every 8 hours plus an antibiotic with appropriate gram negative aerobic spectrum administered IV. Treatment with intravenous drugs should continue for at least 48 hours after the patient demonstrates significant clinical improvement. Then continue with appropriate oral therapy to complete 10-14 days total therapy.
Pneumocystis jiroveci pneumonia in patients with AIDS
DALACIN C PHOSPHATE 600-900 mg (IV) every 6 hours or 900 mg (IV) every 8 hours in combination with oral daily dose of 15-30 mg of primaquine. Alternatively, clindamycin hydrochloride 300-450 mg may be given orally every 6 hours in combination with 15-30 mg of primaquine for 21 days. If patients should develop serious hematologic adverse effects, reducing the dosage regimen of primaquine and/or DALACIN C PHOSPHATE should be considered.
Children over one month of age (IM or IV Administration)
Clindamycin should be dosed based on total body weight regardless of obesity.
20-40 mg/kg/day in 3 or 4 equal doses. The higher doses would be used for more severe infections.
Neonates under one month of age (IM or IV Administration)
10-20 mg/kg/day in 3 or 4 equal doses. The lower dosage may be adequate for small prematures.
| Table 1 – IM or IV Administration in Neonates | |||||||
| Weight | Age | Dose | Route | ||||
| < 2 kg | 0-7 days | 5 mg/kg q12h | IV | ||||
| < 2 kg | 8-30 days | 5 mg/kg q8h | IV | ||||
| ≥ 2 kg | 0-7 days | 5 mg/kg q8h | IV | ||||
| ≥ 2 kg | 8-30 days | 5 mg/kg q6h | IV | ||||
NOTE: DALACIN C PHOSPHATE injections should be administered with caution to newborn infants less than 30 days of age. This product contains benzyl alcohol which has been associated with the fatal “gasping syndrome” in newborn infants. Preterm and low-birth weight infants may be more likely to develop toxicity (see 7.1.3 Pediatrics).
4.3 Reconstitution
Dilution for IV Use and Infusion Rates
DALACIN C PHOSPHATE must be diluted prior to intravenous administration (see Compatibility with other products for a listing of infusion solutions). The concentration in diluent for infusion should not exceed 18 mg/mL. Infusion rates should NOT EXCEED 30 MG PER MINUTE as indicated below:
| Table 2 - Dilution and infusion rates | ||
| Dose (mg) | Diluent (mL) | Time (minutes) |
| 300 | 50 | 10 |
| 600 | 50 | 20 |
| 900 | 100 | 30 |
| 1200 | 100 | 45 |
Administration of more than 1200 mg in a single 1-hour infusion is not recommended.
Alternatively, the drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV infusion as follows:
| Table 3 – Infusion rates per clindamycin levels | ||
| To maintain serum clindamycin levels | Rapid infusion rate | Maintenance infusion rate |
| Above 4 mcg/mL | 10 mg/min. for 30 min. | 0.75 mg/min. |
| Above 5 mcg/mL | 15 mg/min. for 30 min. | 1.00 mg/min. |
| Above 6 mcg/mL | 20 mg/min. for 30 min. | 1.25 mg/min. |
Compatibility with other products
DALACIN C PHOSPHATE was found to be compatible over a period of 24 hours when 4 mL (600 mg) of DALACIN C PHOSPHATE was diluted with 1000 mL of the following commonly used infusion solutions;
Sodium chloride injection
Dextrose 5% in water
Dextrose 5% in saline
Dextrose 5% in Ringer's Solution
Dextrose 5% in half-strength saline plus 40 mEq potassium chloride
Dextrose 2 1/2% in Lactated Ringer's Solution (Hartmann's Solution)
DALACIN C PHOSPHATE was not stable when added to Dextrose 5% in water plus vitamins. Although DALACIN C PHOSPHATE is compatible with Dextrose 5% in water, it is not recommended that DALACIN C PHOSPHATE be mixed with any infusion solutions containing B vitamins.
DALACIN C PHOSPHATE has been shown to be compatible with gentamycin sulfate, tobramycin sulfate and amikacin sulfate. However, a precipitate has been observed when DALACIN C PHOSPHATE and gentamicin are drawn undiluted into the same syringe before subsequent dilution. This precipitate appears to be a zinc-clindamycin complex which results from the zinc content of some gentamicin products. The particle size of the insoluble material is very small and disappears when the admixture is shaken. To avoid this problem, do not mix DALACIN C PHOSPHATE and gentamicin sulfate prior to dilution. Rather, dilute one drug or the other, agitate the solution and then add the second antibiotic.
Incompatibility with other products
When combined with DALACIN C PHOSPHATE in an infusion solution, ampicillin, phenytoin sodium, barbiturates, aminophyllin, calcium gluconate, magnesium sulfate, ceftriaxone sodium, and ciprofloxacin are each physically incompatible with clindamycin phosphate.
4.4 Administration
Injection site irritation can be minimized by deep IM injection and avoidance of indwelling intravenous catheters.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.
IM Administration
DALACIN C PHOSPHATE should be used undiluted.
IV Administration
DALACIN C PHOSPHATE should be diluted.
4.5 Missed Dose
If a dose is missed, it should be taken as soon as remembered unless it is almost time for the next dose. The dose should not be doubled to make up for a missed dose.
5 Overdose
Reported cases of overdosage with DALACIN C PHOSPHATE (clindamycin phosphate) have occurred very infrequently. The majority of these reports have involved infants and young children ranging in age from one day to three years. In this age group, doses as high as 2.4 grams have been used intravenously in 36 hours without observation of adverse reactions. Cardio-respiratory arrest and hypotension have been seen with rapid intravenous administration Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. No specific antidote is known. The serum elimination half-life of clindamycin is about 3 hours in adults and 2.5 hours in pediatric patients.
| For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669). |
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6 Dosage Forms, Strengths, Composition and Packaging
Table 4 – Dosage Forms, Strengths, Composition and Packaging
Each mL of undiluted DALACIN C PHOSPHATE (clindamycin phosphate) contains clindamycin phosphate equivalent to 150 mg of clindamycin base, benzyl alcohol 9 mg, disodium edetate 0.5 mg and water for injection q.s.
When necessary, the pH is adjusted with sodium hydroxide and/or hydrochloric acid to maintain a pH range of 5.5 to 7.0.
DALACIN C PHOSPHATE (clindamycin phosphate) is available in 2 mL, 4 mL and 6 mL vials.
Pharmacy Bulk Vial
DALACIN C PHOSPHATE is also available in a 60 mL Pharmacy Bulk Vial. The availability of the Pharmacy Bulk Vial is limited to hospitals with a pharmacy based IV admixture program. The Pharmacy Bulk Vial is intended for single puncture, multiple dispensing for intravenous use only.
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
| Intramuscular, Intravenous | Solution; clindamycin phosphate equivalent to 150 mg/mL of clindamycin base | 9 mg/mL Benzyl alcohol, disodium edetate, hydrochloric acid, sodium hydroxide |
7 Warnings and Precautions
General
DALACIN C PHOSPHATE must be diluted for intravenous administration. It should not be injected undiluted as an intravenous bolus (see 4 Dosage and Administration).
The use of antibiotics occasionally results in overgrowth of non-susceptible organisms, particularly yeasts. Should superinfections occur, appropriate measures should be taken as dictated by the clinical situation.
Care should be exercised when treating patients with multiple medications (see 9 Drug Interactions).
Gastrointestinal
DALACIN C PHOSPHATE should be prescribed with caution in patients with a history of gastrointestinal disease, particularly colitis, inflammatory bowel disease (including regional enteritis and ulcerative colitis), or a history of antibiotic-associated colitis (including pseudomembranous colitis).
If diarrhea occurs during treatment, this antibiotic should be discontinued.
Clostridium difficile-associated disease (CDAD)
Clostridium difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including DALACIN C PHOSPHATE (clindamycin phosphate). CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, 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 8 Adverse Reactions).
Hematologic
In patients with G-6-PD deficiency, the combination of clindamycin with primaquine may cause hemolytic reactions. Reference should also be made to the primaquine Product Monograph for other possible risk groups for other hematologic reactions (see 8 Adverse Reactions).
If patients should develop serious hematologic adverse effects, reducing the dosage regimen of primaquine and/or DALACIN C PHOSPHATE should be considered (see 4 Dosage and Administration).
Hepatic/Biliary/Pancreatic
In patients with moderate to severe liver disease, prolongation of the half-life of clindamycin has been found. However, it was postulated from studies that when given every eight hours, accumulation of clindamycin should rarely occur. Therefore, dosage reduction in liver disease is not generally considered necessary. Periodic liver enzyme determinations should be made when treating patients with severe liver disease (see 10 Clinical Pharmacology).
Immune
DALACIN C PHOSPHATE (clindamycin phosphate) should be prescribed with caution in atopic individuals.
Serious hypersensitivity reactions, including anaphylactoid reactions, severe skin reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS), and dermatological reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP) and Kounis syndrome have been reported in patients on clindamycin therapy. If a hypersensitivity reaction occurs clindamycin should be discontinued and appropriate therapy should be initiated (see 2 Contraindications, 8 Adverse Reactions).
Monitoring and Laboratory Tests
Periodic liver and kidney function tests and blood counts should be performed during prolonged therapy when treating patients with severe liver disease.
Routine blood examinations should be done during therapy with primaquine to monitor potential hematologic toxicities.
Serum assays for active clindamycin require an inhibitor to prevent in vitro hydrolysis of clindamycin phosphate.
Renal
DALACIN C PHOSPHATE dose modification may not be necessary in patients with renal disease. The serum half-life of clindamycin is increased slightly in patients with markedly reduced renal function.
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.
Sensitivity/Resistance
Development of drug-resistant bacteria
Prescribing DALACIN C PHOSPHATE in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.
7.1 Special Populations
7.1.1 Pregnancy
There are no adequate and well-controlled studies in pregnant women. Safety for use in pregnancy has not been established.
Clindamycin should not be used in pregnancy unless clearly needed and unless the expected benefits to the mother outweigh any potential risks to the fetus. Clindamycin crosses the placenta in humans. After multiple doses, amniotic fluid concentrations were approximately 30% of maternal blood concentrations. Clindamycin was widely distributed in fetal tissues with the highest concentration found in liver.
Clindamycin phosphate injectable formulation contains benzyl alcohol. The preservative benzyl alcohol can cross the placenta (see 7 Warnings and Precautions).
Reproduction studies have been performed in rats and mice using subcutaneous and oral doses of clindamycin ranging from 20 to 600 mg/kg/day and have revealed no evidence of impaired fertility or harm to the fetus due to clindamycin except at doses that caused maternal toxicity. In one mouse strain, cleft palates were observed in treated fetuses; this response was not produced in other mouse strains or in other species, and therefore may be a strain specific effect. 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.
7.1.2 Breastfeeding
Clindamycin has been reported to appear in human breast milk in ranges from <0.5 to 3.8 mcg/mL.
Clindamycin has the potential to cause adverse effects on the breastfed infant’s gastrointestinal flora such as diarrhea or blood in the stool, or rash. Because of the potential for serious adverse reactions in nursing infants, if clindamycin is required by a nursing mother, it is not a reason to discontinue breastfeeding, but an alternate drug may be preferred. If DALACIN C PHOSPHATE is used by a nursing mother, monitor the infant for possible adverse effects on the gastrointestinal flora, such as diarrhea, candidiasis (thrush, diaper rash) or blood in the stool indicating possible antibiotic-associated colitis.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DALACIN C PHOSPHATE and any potential adverse effects on the breastfed child from DALACIN C PHOSPHATE or from the underlying maternal condition.
7.1.3 Pediatrics
Benzyl Alcohol Toxicity
DALACIN C 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. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis and gasping respirations) has been reported in preterm and low birth weight newborns. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia and cardiovascular collapse.
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 hepatic and renal capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity.
Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. When DALACIN C PHOSPHATE is administered to the pediatric population (birth to 16 years) appropriate monitoring of organ system functions is desirable.
7.1.4 Geriatrics
Geriatrics (> 60 years of age): Experience has demonstrated that antibiotic-associated colitis may occur more frequently and with increased severity among elderly (> 60 years) and debilitated patients. These patients should be carefully monitored for the development of diarrhea.
8 Adverse Reactions
8.2 Clinical Trial Adverse Reactions
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
Adverse drug reaction frequencies for the three clindamycin formulations (clindamycin capsules, clindamycin granules for oral solution and clindamycin injection) are based on the clinical data sources from the original drug submission and on the total number of patients enrolled in the clinical trials (N=1787).
Adverse drug reactions that were considered causally related to clindamycin and observed in ≥ 1% of patients are presented below in Table 1. They are listed according to MedDRA system organ class.
Table 5. Adverse Drug Reactions Occurring in ≥ 1% of Patients treated with clindamycin within the Original Clinical Trials
Adverse Reaction System Organ Class / Preferred Term | clindamycin Total N=17871 n (%) |
| Gastrointestinal disorders | |
| Diarrhea | 26 (1.45) |
| Investigations | |
| Liver function test abnormal | 66 (3.7) |
| Skin and subcutaneous tissue disorders | |
| Rash maculopapular | 21 (1.18) |
1clindamycin hydrochloride capsules N=851; clindamycin granules for oral solution N=340; clindamycin phosphate injection N=596
8.3 Less Common Clinical Trial Adverse Reactions
Less common adverse drug reactions that were considered causally related to clindamycin and observed in < 1% of patients are listed below.
Blood and lymphatic system disorders: Eosinophilia.
Gastrointestinal disorders: Nausea, abdominal pain and vomiting.
General disorders and administration site conditions: Local irritation, pain, abscess formation have been seen with IM injection.
Nervous system disorders: Dysgeusia.
Skin and subcutaneous tissue disorders: Urticaria, erythema multiforme and pruritus.
8.5 Post-Market Adverse Reactions
Additional adverse events which have been reported in temporal association with DALACIN C formulations (clindamycin capsules, clindamycin granules for oral solution and clindamycin injection) since market introduction are listed below. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be established.
Blood and lymphatic system disorders: Agranulocytosis, leucopenia, neutropenia and thrombocytopenia. In clindamycin/primaquine combination studies, serious hematologic toxicities (grade III, grade IV neutropenia or anemia, platelet counts < 50 x 109/L, or methemoglobin levels of 15% or greater) have been observed.
Cardiac disorders: Cardio-respiratory arrest and hypotension have been seen with rapid intravenous administration (see 4 Dosage and Administration).
Gastrointestinal disorders: Colitis and pseudomembranous colitis. Clostridium difficile-associated disease (CDAD) has been observed and may manifest as a range of symptoms varying from watery diarrhea to fatal colitis, the onset of which may occur during or after antibacterial treatment (see 7 Warnings and Precautions). Esophagitis and esophageal ulcer have been reported with the oral formulations.
General disorders and administration site conditions: Injection site irritation, thrombophlebitis. These reactions can be minimized by deep IM injection and avoidance of indwelling intravenous catheters.
Hepatobiliary disorders: Jaundice.
Immune system disorders: Generalized mild to moderate morbilliform-like skin rashes, anaphylactic shock, anaphylactoid reactions, anaphylactic reactions, hypersensitivity, and drug reaction with eosinophilia and systemic symptoms (DRESS), Kounis syndrome.
Infections and infestations: Clostridium difficile colitis.
Musculoskeletal: Polyarthritis.
Renal and urinary disorders: Renal dysfunction as evidenced by azotemia, oliguria and/or proteinuria. Acute kidney injury including acute renal failure has been reported. (see 7 Warnings and Precautions)
Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), erythema multiforme, dermatitis exfoliative, dermatitis bullous, cutaneous vasculitis, dermatitis vesiculobullous, rash morbilliform, symmetrical drug-related intertriginous and flexural exanthema, vaginal infection, vaginitis, acute generalized exanthematous pustulosis (AGEP), angioedema.
Vascular disorders: Thrombophlebitis has been seen with rapid intravenous administration (see 4 Dosage and Administration).
9 Drug Interactions
9.2 Drug Interactions Overview
Clindamycin is metabolized predominantly by CYP3A4, and to a lesser extent 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 rifampin, 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.
Clindamycin has been shown to have neuromuscular blocking properties and potential antagonism with erythromycin and aminoglycosides (see Table 6).
In a clindamycin/primaquine combination study, serious hematologic toxicity has been observed, but the contribution of clindamycin, if any, is unknown (see 8 Adverse Reactions).
For other physicochemical interactions, please see to compatibility / incompatibility information in section 4 Dosage and Administration.
9.4 Drug-Drug Interactions
The drugs listed in the table below are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction.
| Table 6 - Established or Potential Drug-Drug Interactions | |||||||
| Proper name | Ref | Effect | Clinical comment | ||||
Neuromuscular blocking agents Examples include: atracurium, doxacurium, pancuronium, vecuronium | CS | Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. | Use with caution in patients receiving these agents concurrently. | ||||
| Aminoglycosides | T | Clindamycin is reported to antagonize bactericidal activity of aminoglycosides in vitro. In vivo antagonism has not been demonstrated. | |||||
| Erythromycin | T | Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Clindamycin and erythromycin may compete for the same protein binding site in bacteria. | Due to possible clinical significance the two drugs should not be administered concurrently. | ||||
| Inhibitors of CYP3A4, CYP3A5 | T | Clearance of clindamycin may be reduced. | |||||
| Inducers of CYP3A4, CYP3A5 | T | Clearance of clindamycin may be increased. | Monitor for loss of effectiveness. | ||||
| Strong inducers of CYP3A4 such as rifampin | CS and CT | Rifampin appears to dramatically decrease the serum clindamycin concentration. | Serum clindamycin levels and effectiveness should be carefully monitored. A clinically relevant effect of clindamycin on rifampin concentrations is not expected. | ||||
Legend: CS = Case Study; CT = Clinical Trial; T = Theoretical
9.5 Drug-Food Interactions
Interactions with food have not been established.
9.6 Drug-Herb Interactions
Efficacy of clindamycin should be closely monitored in patients using concomitant St. John’s Wort, a CYP3A4 inducer.
9.7 Drug-Laboratory Test Interactions
Interactions between clindamycin and laboratory tests have not been studied.
10 Clinical Pharmacology
10.1 Mechanism of Action
Following parenteral administration, biologically inactive clindamycin phosphate is rapidly hydrolyzed in plasma to active clindamycin. 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. At usual doses, clindamycin exhibits bacteriostatic activity in vitro.
Clindamycin is primarily bacteriostatic, but may be bactericidal at high concentrations. The mechanism of action of clindamycin in combination with primaquine on Pneumocystis jiroveci is not known.
10.2 Pharmacodynamics
(see 15 Microbiology)
10.3 Pharmacokinetics
Absorption:
An equilibrium state is reached by the third dose. After intramuscular injection, peak serum levels of clindamycin are reached within 3 hours in adults and 1 hour in pediatric patients. Peak serum levels of clindamycin are achieved immediately after the end of a short-term (10 to 45 minutes) intravenous infusion.
Distribution:
Clindamycin binds primarily to alpha-1-acid glycoprotein. Protein binding is concentration dependent, ranging from 60% to 94% at therapeutic serum concentrations.
Clindamycin is distributed into body fluids and tissues including bone, synovial fluid, bile and pleural fluid. Significant levels of clindamycin are not reached in cerebrospinal fluid even in the presence of inflamed meninges. Clindamycin does not cross the blood-brain barrier even in the presence of inflamed meninges. Clindamycin readily crosses the placenta and is distributed into breast milk.
Table 7 records tissue and body fluid levels of clindamycin base following administration of clindamycin phosphate in adult patients undergoing surgical procedures.
| Table 7: Clindamycin concentrations in Tissues and Fluids | ||
| Specimen | Dosage of clindamycin phosphate | Tissue or Fluid Level |
| Bone | IM 300 mg every 8 hours | 6.4 mcg/g |
| Bone | IM 600 mg every 8 hours | 1.44 mcg/g |
| Bone | IV 600 mg every 8 hours | 0.75 mcg/g |
| Bone Marrow | IM 600 mg every 8 hours | 10.83 mcg/g |
| Bile | IV 300 mg every 6 hours | 2.70 mcg/g |
| Synovial Fluid | IM 300 mg every 8 hours | 4.87 mcg/mL |
| Synovial Fluid | IM 150 mg every 12 hours | 15.6 mcg/mL |
| Pleural Fluid | IV 450 mg every 8 hours | 3.65 mcg/mL |
| Table 8- Average Peak Serum Concentrations After Dosing with Clindamycin Phosphate | ||
| Clindamycin Phosphate Dosage Regimen | Clindamycin mcg/mL | Clindamycin Phosphate mcg/mL |
| Healthy Adult Male (Post Equilibrium) | ||
| 300 mg IV in 10 min., q8h | 7 | 15 |
| 600 mg IV in 20 min., q8h | 10 | 23 |
| 900 mg IV in 30 min., q12h | 11 | 29 |
| 1200 mg IV in 45 min., q12h | 14 | 49 |
| 300 mg IM q8h | 6 | 3 |
| 600 mg IM q12h * | 9 | 3 |
| Children (first dose)* | ||
| 5-7 mg/kg IV in 1 hour | 10 | |
| 3-5 mg/kg IM | 4 | |
| 5-7 mg/kg IM | 8 | |
* Data in this group from patients being treated for infection
Metabolism:
In vitro studies in human liver and intestinal microsomes indicate clindamycin is predominantly oxidized by CYP3A4, with minor contribution from CYP3A5, to form clindamycin sulfoxide and a minor metabolite, N-desmethylclindamycin.
Elimination:
Approximately 10% of the microbiologically active form is excreted in the urine and about 4% in the feces. The remainder is excreted as biologically inactive metabolites.
Clindamycin phosphate disappears rapidly from the serum; the average elimination half-life is 6 minutes following IM or IV administration in adults. The serum elimination half-life of clindamycin is about 3 hours in adults and 2.5 hours in pediatric patients.
Special Populations and Conditions
Geriatrics:
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.
Hepatic Impairment:
Six patients with impaired liver function had a mean serum elimination half-life of 4.5 hours (range 4.2 to 7.0 hours).
Renal Impairment:
Four patients with impaired renal function had a mean serum elimination half-life of 3.0 hours (range 1.7 to 5.6 hours).
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.
11 Storage, Stability and Disposal
Store DALACIN C PHOSPHATE at controlled room temperature (15 to 30°C). When diluted as recommended, DALACIN C PHOSPHATE is stable for 24 hours.
12 Special Handling Instructions
There are no special handling instructions.
Part 2: Scientific Information
13 Pharmaceutical Information
Drug Substance
Proper name: clindamycin phosphate
Chemical name:
- 1) L-threo-α-D-galacto-Octopyranoside, methyl 7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]amino]-1-thio-, 2-(dihydrogen phosphate), (2S-trans)-;
- 2) Methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pryrrolidinecarboxamido)-1-thio-L-threo-α-D-galacto-octopyranoside 2-(dihydrogen phosphate);
- 3) 7-(S)-Chloro-7-deoxylincomycin 2-phosphate.
Molecular formula and molecular mass: C18H34ClN2O8PS, 505
Structural formula:
Physicochemical properties: Clindamycin phosphate is a water soluble ester of clindamycin and phosphoric acid. It is a white to off-white crystalline hygroscopic powder that is odourless or nearly odourless. It has a pH of 3.5 to 4.5 and melts with decomposition at about 175°C. The partition coefficient is 0.03.
14 Clinical Trials
The authorized indications were based on safety and efficacy clinical trials which were conducted with DALACIN C PHOSPHATE.
15 Microbiology
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
Development of resistance to clindamycin by staphylococci is slow and stepwise rather than rapid and streptomycin-like. Clindamycin, like lincomycin, participates in the dissociated cross-resistance phenomenon with erythromycin. Clindamycin is not cross-resistant with penicillin, ampicillin, tetracycline or streptomycin. There is complete cross resistance between clindamycin and lincomycin.
Resistance to clindamycin may occur by one of several mechanisms. Resistance does not appear to be caused by reduced drug uptake but rather is generally due to alterations in the bacterial target site (50S ribosomal subunit). 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 (MLSB 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. 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. Some veterinary isolates of streptococci may enzymatically inactivate clindamycin by adenylation. Plasmid-mediated transferable resistance to clindamycin (and erythromycin) in B. fragilis was reported in 1979. Despite the existence of multiple resistance mechanisms, the reported incidence of clindamycin resistance in the B. fragilis group has remained relatively low (averaging 5.3% from 1970-1987 in over 7,600 isolates). Susceptibility of isolates to clindamycin should be assessed by individual MIC determinations.
Susceptibility Test Methods
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.
In order to assess the significance of in vitro antibiotic activity against bacterial species, it is necessary to compare the organism's minimum inhibitory concentration (MIC) to the defined susceptibility interpretive breakpoints for the antibiotic. Table 9 identifies the currently-accepted NCCLS (1990) MIC interpretative breakpoints for clindamycin.
Clinical and Laboratory Standards Institute (CLSI) breakpoints for relevant organisms are listed below.
| Table 9. CLSI Susceptibility Interpretive Criteria for Clindamycin | ||||||
|---|---|---|---|---|---|---|
| Pathogen | ||||||
| Minimal Inhibitory Concentrations (MIC in mcg/mL) | Disk Diffusion (Zone Diameters in mm)a | |||||
| Staphylococcus spp. | S ≤ 0.5 | I 1–2 | R ≥4 | S ≥21 | I 15–20 | R ≤14 |
Streptococcus pneumoniae and other Streptococcus spp. | ≤0.25 | 0.5 | ≥1 | ≥19 | 16–18 | ≤15 |
| Anaerobic Bacteriab | ≤2 | 4 | ≥8 | NA | NA | NA |
NA = not applicable
aDisk content 2 micrograms of clindamycin
bMIC ranges for anaerobes are based on agar dilution methodology
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.
The reported clindamycin MIC90 value (i.e., the concentration of clindamycin that inhibits 90% of test isolates) was utilized as the most descriptive measure of clindamycin activity. Where the data from more than one study are summarized, the weighted average MIC90 value was calculated to account for differences in the number of strains in each study.
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 10. For the disk diffusion technique using the 2 mcg clindamycin disk the criteria provided in Table 10 should be achieved.
| Table 10. CLSI Acceptable Quality Control (QC) Ranges for Clindamycin to be Used in Validation of Susceptibility Test Results | ||||||||
| QC Strain | Minimum Inhibitory Concentration Range (mcg/mL) | Disk Diffusion Range (Zone Diameters in mm) | ||||||
Staphylococcus aureus ATCC 29213 | 0.06–0.25 | NA | ||||||
Staphylococcus aureus ATCC 25923 | NA | 24–30 | ||||||
Streptococcus pneumoniae ATCC 49619 | 0.03–0.12 | 19–25 | ||||||
Bacteroides fragilis ATCC 25285 | 0.5–2a | NA | ||||||
Bacteroides thetaiotaomicron ATCC 29741 | 2–8a | NA | ||||||
Eggerthella lenta ATCC 43055 | 0.06–0.25a | NA | ||||||
NA=Not applicable. ATCC® is a registered trademark of the American Type Culture Collection aMIC ranges for anaerobes are based on agar dilution methodology. | ||||||||
The European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints are presented below.
| Table 11. EUCAST Susceptibility Interpretive Criteria for Clindamycin | |||||||||
MIC breakpoints (mg/L) | Zone diameter breakpoints (mm)a | ||||||||
| Organism | S ≤ | R > | S ≥ | R < | |||||
| Staphylococcus spp. | 0.25 | 0.5 | 22 | 19 | |||||
Streptococcus Groups A, B, C and G | 0.5 | 0.5 | 17 | 17 | |||||
| Streptococcus pneumoniae | 0.5 | 0.5 | 19 | 19 | |||||
| Viridans group streptococci | 0.5 | 0.5 | 19 | 19 | |||||
| Gram-positive anaerobes | 4 | 4 | NA | NA | |||||
| Gram-negative anaerobes | 4 | 4 | NA | NA | |||||
| Corynebacterium spp. | 0.5 | 0.5 | 20 | 20 | |||||
aDisk content 2 µg of clindamycin NA=not applicable; S=susceptible; R=resistant | |||||||||
EUCAST QC ranges for MIC and disk zone determinations are in the table below.
| Table 12. EUCAST Acceptable Quality Control (QC) Ranges for Clindamycin to be Used in Validation of Susceptibility Test Results | |||||
| QC Strain | Minimum Inhibitory Concentration Range (mcg/mL) | Disk Diffusion Range (Zone Diameters in mm) | |||
Staphylococcus aureus ATCC 29213 | 0.06–0.25 | 23-29 | |||
Streptococcus pneumoniae ATCC 49619 | 0.03–0.125 | 22-28 | |||
| ATCC® is a registered trademark of the American Type Culture Collection | |||||
Antimicrobial Activity
The in vitro susceptibility of clinical isolates to clindamycin is presented in Table 13 (gram-positive aerobic bacteria), Table 14 (gram-negative aerobic bacteria), Table 15 (gram-positive anaerobic bacteria), Table 16 (gram-negative anaerobic bacteria) and Table 17 (Chlamydia spp and Mycoplasma spp).
| Table 13: In vitro activity of clindamycin against gram-positive aerobic bacteriaa | |||
| Organism | Nb | MIC90 Rangec | MIC90d |
| Bacillus cereus | 46 | 1 | 1 |
| Corynebacterium diphtheriae | 192 | 0.1 | 0.1 |
| Listeria monocytogenes | 218 | 1-8 | 2.22 |
| Staphylococcus aureus (methicillin-susceptible) | 286 | 0.12-2 | 0.50 |
| Staphylococcus saprophyticus | 57 | 0.12-0.25 | 0.16 |
| Streptococcus agalactia | 59 | ≤ 0.06-0.50 | 0.15 |
| Streptococcus bovis | 22 | 0.04 | 0.04 |
| Streptococcus pneumonia (penicillin-susceptible) | 660 | 0.03-0.25 | 0.23 |
| Streptococcus pyogenes | 141 | 0.13-0.25 | 0.08 |
| Streptococcus spp, Group B | 38 | ≤ 0.12-0.25 | 0.15 |
| Streptococcus spp, Group C | 30 | ≤ 0.12-0.50 | 0.22 |
| Streptococcus spp, Group G | 34 | 0.06-0.50 | 0.31 |
| Streptococcus spp, viridans Group (penicillin-susceptible) | 67 | ≤ 0.06-1.6 | 0.53 |
a clinical efficacy has not been established for some of these species
b N, total number of isolates
c Range of reported MIC90 values
d MIC90 for single study or weighted average MIC90 for two or more studies
| Table 14: In vitro activity of clindamycin against gram-negative aerobic bacteriaa | |||
| Organism | Nb | MIC90 Rangec | MIC90d |
| Campylobacter jejuni | 449 | 0.39-8 | 1.7 |
| Campylobacter fetus | 41 | 1-1.6 | 1.2 |
| Campylobacter coli | 31 | 0.50 | 0.50 |
| Gardnerella vaginalis | 156 | ≤ 0.06-0.39 | 0.3 |
| Helicobacter pylori | 47 | 2-3.1 | 2.6 |
| Neisseria gonorrhoeae (β-lactamase-negative) | 77 | 4 | 4 |
| Neisseria gonorrhoeae (β-lactamase-positive) | 54 | 2 | 2 |
a clinical efficacy has not been established for some of these species
b N, total number of isolates
c Range of reported MIC90 values
d MIC90 for single study or weighted average MIC90 for two or more studies
| Table 15: In vitro activity of clindamycin against gram-positive anaerobic bacteriaa | ||||||||||||||||
| Organism | Nb | MIC90 Rangec | MIC90d | |||||||||||||
| Actinomyces israelii | 46 | 0.12 | 0.12 | |||||||||||||
| Actinomyces spp | 38 | 0.50-1 | 0.8 | |||||||||||||
| Clostridium botulinum | 224 | 4 | 4 | |||||||||||||
| Clostridium difficile | 191 | 4->256 | 57.7 | |||||||||||||
| Clostridium novyi | 18 | 2 | 2 | |||||||||||||
| Clostridium perfringens | 386 | 0.25-8 | 3.4 | |||||||||||||
| Clostridium ramosum | 98 | 4-12.5 | 8.3 | |||||||||||||
| Eubacterium spp | 45 | 0.4-2 | 1.1 | |||||||||||||
| Lactobacillus spp | 88 | 0.50-1 | 0.8 | |||||||||||||
| Peptostreptococcus anaerobes | 283 | 0.25-0.50 | 0.4 | |||||||||||||
| Peptostreptococcus asaccharolyticus | 268 | 0.25-2 | 1.5 | |||||||||||||
| Peptostreptococcus magnus | 90 | 2 | 2 | |||||||||||||
| Peptostreptococcus prevotii | 87 | 0.12-4 | 2.9 | |||||||||||||
| Peptostreptococcus tetradius | 28 | 0.5 | 0.5 | |||||||||||||
| Anaerobic gram-positive cocci | 247 | 0.5-1 | 0.9 | |||||||||||||
| Propionibacterium acnes | 267 | 0.10-0.25 | 0.2 | |||||||||||||
| Propionibacterium spp | 71 | 0.12-0.20 | 0.16 | |||||||||||||
a clinical efficacy has not been established for some of these species
b N, total number of isolates
c Range of reported MIC90 values
d MIC90 for single study or weighted average MIC90 for two or more studies
| Table 16: In vitro activity of clindamycin against gram-negative anaerobic bacteriaa | |||||||||||||
| Organism | Nb | MIC90 Rangec | MIC90d | ||||||||||
| Bacteroides fragilis group | 4,284 | 0.5-8 | 2.45 | ||||||||||
| Bacteroides fragilis | 2,002 | ≤ 0.20-4 | 2.22 | ||||||||||
| Bacteroides melaninogenicus | 224 | ≤ 0.03-0.50 | 0.07 | ||||||||||
| Bacteroides spp | 141 | ≤ 0.06-0.50 | 0.31 | ||||||||||
| Bacteroides bivius | 155 | ≤ 0.03-
|
| ||||||||||
| Bacteroides disiens | 33 | ≤ 0.03-
|
| ||||||||||
| Fusobacterium spp | 330 | ≤ 0.10-2 | 0.85 | ||||||||||
| Mobiluncus mulieris | 10 | 0.06 | 0.06 | ||||||||||
| Mobiluncus curtisii | 12 | 0.12 | 0.12 | ||||||||||
| Veillonella spp | 38 | 0.06-0.25 | 0.20 | ||||||||||
a clinical efficacy has not been established for some of these species
b N, total number of isolates
c Range of reported MIC90 values
d MIC90 for single study or weighted average MIC90 for two or more studies
Clindamycin has demonstrated in vitro activity against Chlamydia trachomatis and Mycoplasma spp (see Table 17). For Chlamydia trachomatis, the MIC90 for clindamycin is reached at 2.3 µg/mL; in vitro synergism with gentamicin has also been demonstrated.
| Table 17: In vitro activity of clindamycin against Chlamydia spp and Mycoplasma spp a | ||||||||||||
| Organism | Nb | MIC90 Rangec | MIC90d | |||||||||
| Chlamydia trachomatis | 84 | 0.5-5.9 | 2.3 | |||||||||
| Mycoplasma hominis | 106 | 0.25-0.8 | 0.58 | |||||||||
| Mycoplasma pneumoniae | 9 | 4 | 4 | |||||||||
a clinical efficacy has not been established for some of these species
b N, total number of isolates
c Range of reported MIC90 values
d MIC90 for single study or weighted average MIC90 for two or more studies
The in vitro activity of clindamycin in combination with primaquine has not been determined.
16 Non-Clinical Toxicology
General Toxicology:
Acute Toxicity
The results of LD50 studies are shown in Table 18:
| Table 18: LD50 Results | ||
| Species | Route | LD50 (mg/kg) |
| Adult Mouse | IP | 1145 |
| Adult Mouse | IV | 855 |
| Adult Rat | SC | >2000 |
| Adult Rat | PO | 1832 |
| Newborn Rat | SC | 179 |
Table 19 and 20 summarize toxicity and teratology studies.
Carcinogenicity: Long term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential.
| Table 19 - TOXICITY STUDIES | |||||
| Type of Study | Species | Route | Dose mg/kg/d | Duration | Conclusions |
| Tolerance | Rabbit N=3 | im | 100,200, 300 mg | single dose | Slight to moderate local irritation |
| Tolerance | Rat N=10 | sc | 120 | 6 days | Local evidence of multiple epidermal breakdown with scab formation over the injection site was present in most rats. No systemic evidence of drug effect was detected at necropsy. Organ weights were not significantly different from control animals and likewise no significant deviations of hematologic data were noted among treated animals. |
| Tolerance | Dog N=3 | im | 60 | 6 days | These doses were well tolerated by the dogs. Serum transaminase values were elevated terminally with SGOT values increasing in advance of SGPT values, suggesting that the source of these changes was the injected muscles. No other evidence of treatment-related changes was noted in terminal hemograms, blood chemistry values |
| and urinalyses. Gross pathological changes were confined to the injection sites where there were signs of slight hemorrhage and edema. | |||||
| Subacute Toxicity | Rat N=10 | sc | 30,60,90 | 1 month | No drug-related systemic effects were observed. Local inflammatory changes were seen at all three dose levels with focal necrosis of the subcutaneous tissues and overlying epidermis seen in the 60 and 90 mg/kg groups. |
| Subacute Toxicity | Dog N=9 | im | 30,60,90 | 1 month | Under the conditions of this study, clindamycin phosphate was found to be mildly to moderately irritating. Elevations of SGOT and SGPT were noted in these dogs and were thought to be due to muscle damage caused by the injections. Other blood evaluations and liver function tests were in the normal range. A slight dose-related increase in liver weight was indicated on the basis of per cent of body weight, but no morphologic evidence of drug effect on the liver was obtained. |
| Subacute Toxicity | Dog N=8 | iv | 60,120 | 1 month | No drug related effects were observed in any of the animals during or after the intravenous administrations. In particular, there was no evidence of drug-induced hemolysis or drug-related changes in the cephalic veins on both gross and microscopic examination. |
| Table 20 - TERATOLOGY STUDIES | ||||
| Species | Route | Dose mg/kg/day | Duration | Conclusions |
| Rat | sc | 0, 100, 180 | gestation days 6-15 | not teratogenic |
| Mouse | sc 2 strains | 100, 180 | gestation days 6-15 | A low incidence of cleft palate occurred in one strain in the initial experiment and as a result, the study was repeated twice with no abnormalities noted. The study in the second strain of mice was completely within normal limits. |
| Rat | po | 100, 300 | No biologically significant effect on the reproductive parameters studied was noted. Pups from treated females were slightly lighter at birth and weaning but post-natal survival was not affected by this slight weight reduction. None of the pups which were dead at birth, died before weaning, or were sacrificed at weaning, exhibited significant morphologic abnormalities. | |
Genotoxicity: Clindamycin phosphate did not show evidence of mutagenicity when tested in the Ames Assay (Salmonella/Microsome Test) or the Micronucleus Test.
Reproductive and Developmental Toxicology:
Teratogenic and Reproductive Studies in the Rat and Rabbit
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.
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.