Clindamycin Phosphate/ Tretinoin

Registered South African indications:

• Acne vulgaris

Contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to lincomycin
• Pregnancy 
• Women planning a pregnancy
• Women of childbearing potential not on effective contraception (South African manufacturer recommendations)
• Breastfeeding (South African manufacturer recommendations)
• Regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis
• Personal or familial history of skin cancer
• History of acute eczemas, rosacea and perioral dermatitis
• Pustular and deep cystic nodular acne varieties (acne conglobata and acne fulminans)

Cautions

• 1 month after discontinuation of treatment in women of childbearing potential (South African manufacturer recommendations)
• Women of childbearing potential not on effective contraception and for 1 month after discontinuation of treatment (International manufacturer recommendations)
• Breastfeeding (International manufacturer recommendations)
• Renal impairment
• Hepatic impairment
• Elderly
• Mild acne vulgaris
• Contact with the mouth, eyes and mucous membranes and with abraded or eczematous skin
• Application to sensitive areas of skin
• Use of more than the recommended amount or too frequent application
• Atopic subjects
• Application at the same time as other topical preparations (including cosmetics)
• Use of medicated cleansers and scrubbing solutions 
• Abrasive soaps, soaps and cosmetics as well as spices or lime
• Patients with sunburn
• Considerable sun exposure
• Inherent sensitivity to the sun
• Use of sun lamps or sun beds
• Prolonged use
• Coadministration with oral and topical antibiotics, particularly if chemically different
• Coadministration with keratolytic agents such as sulphur, salicylic acid, benzoyl peroxide or resorcinol and chemical abrasives

Forms avail. in SA and covered in this monograph: gel

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Acne vulgaris - moderate severity
- When comedones, papules and pustules are present

• Topical (gel): Apply small quantity to the affected area, dly at bedtime

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Consideration should be given to official guidance on the appropriate use of antibacterial agents and acne treatment

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Adhere to the principles of antibiotic stewardship

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Clindamycin phosphate/ tretinoin is not for oral, ophthalmic, intranasal or intravaginal use. Clindamycin phosphate/ tretinoin is not recommended in treatment of mild acne vulgaris

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Application: Once daily at bedtime, the entire face should be washed with mild soap and dried. A pea-sized amount of medication should be squeezed onto one fingertip, dot onto the chin; cheeks, nose, and forehead, then gently rub over the entire face

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Treatment with clindamycin phosphate/ tretinoin should not exceed 12 weeks of continuous use without careful evaluation. It should be noted that therapeutic improvement may not be observed for several weeks after starting treatment. The safety and efficacy of repeated treatment courses with clindamycin phosphate/ tretinoin have not been established

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In case of a missed dose of clindamycin phosphate/ tretinoin, the patient should wait for the next dose at the usual time. Patients should not double the dose to make up for the forgotten dose

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Method of administration: Clindamycin phosphate/ tretinoin is indicated for external (dermatological) use only. The application of clindamycin phosphate/ tretinoin should avoid eyes, eyelids, lips and nostrils. After the application the patient should wash hands

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International manufacturer recommendations

Acne vulgaris
- When comedones, papules and pustules are present

• Topical (gel): Apply small quantity to the affected area, dly at bedtime

---

Consideration should be given to official guidance on the appropriate use of antibacterial agents and acne treatment

---

Clindamycin phosphate/ tretinoin is not for oral, ophthalmic, intranasal or intravaginal use. Clindamycin phosphate/ tretinoin is not recommended in treatment of mild acne vulgaris

---

Application: Once daily at bedtime, the entire face should be washed with mild soap and dried. A pea-sized amount of medication should be squeezed onto one fingertip, dot onto the chin, cheeks, nose, and forehead; then gently rub over the entire face

---

Treatment with clindamycin phosphate/ tretinoin should not exceed 12 weeks of continuous use without careful evaluation. It should be noted that therapeutic improvement may not be observed for several weeks after starting treatment

---

In case of a missed dose of clindamycin phosphate/ tretinoin, the patient should wait for the next dose at the usual time. Patients should not double the dose to make up for the forgotten dose

---

Method of administration: Clindamycin phosphate/ tretinoin is indicated for external (dermatological) use only. The application of clindamycin phosphate/ tretinoin should avoid eyes, eyelids, lips and nostrils. After the application the patient should wash hands

Paed. forms avail. in SA and covered in this monograph: gel

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Acne vulgaris - moderate severity
- When comedones, papules and pustules are present

• Younger than 12 years old: Not established for use
• 12 years and older: See adult dosage

International manufacturer recommendations

Acne vulgaris
- When comedones, papules and pustules are present

• Younger than 12 years old: Not established for use
• 12 years and older: See adult dosage

Pregnancy
South African manufacturer recommendations

• Contraindicated
• Clindamycin phosphate/ tretinoin is contraindicated in pregnancy, or in women planning a pregnancy
• If clindamycin phosphate/ tretinoin is used during pregnancy, or if the patient becomes pregnant while using clindamycin phosphate/ tretinoin, treatment should be discontinued, and counselling of the patient and partner should be done
• Clindamycin: Safety of clindamycin in pregnancy has not been established. Clindamycin was not teratogenic in reproduction studies in rats and mice, using subcutaneous and oral doses of clindamycin
• Tretinoin: Tretinoin is teratogenic and orally administered retinoids have been associated with congenital abnormalities. Topically administered retinoids, such as tretinoin are assumed to result into low systemic exposure to tretinoin and its metabolites. However, because the level of systemic exposure to tretinoin and/or its metabolites that is teratogenic is unknown, teratogenicity due to topical application of tretinoin cannot be excluded. Factors such as damaged skin, and/or excessive use may result in increased systemic exposure to tretinoin
• Clindamycin phosphate/ tretinoin should be prescribed to women of childbearing potential only if effective contraception was started at least one month before treatment and a laboratory pregnancy test performed 24 hours before initiation of treatment, was reported as negative. Effective contraception should be continued during treatment and for 1 month after discontinuation of treatment. Male partners of women of childbearing potential on treatment with clindamycin phosphate/ tretinoin, should use barrier contraception (e.g. condom) with sexual intercourse and continue to do so, until one month after the treatment was completed. Their female partners should be on effective contraception until one month after completion of treatment

International manufacturer recommendations

• Contraindicated
• Clindamycin phosphate/ tretinoin is contraindicated in pregnancy, or in women planning a pregnancy. If the product is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued
• Clindamycin: A limited number of pregnancies exposed in the first trimester to clindamycin indicate no adverse effects of clindamycin on pregnancy or on the health of the foetus/newborn child. Clindamycin was not teratogenic in reproduction studies in rats and mice, using subcutaneous and oral doses of clindamycin
• Tretinoin: Orally administered retinoids have been associated with congenital abnormalities. When used in accordance with the prescribing information, topically administered retinoids are generally assumed to result into low systemic exposure due to minimal dermal absorption. However, there could be individual factors (e.g. damaged skin barrier, excessive use) that contribute to an increased systemic exposure
• Clindamycin phosphate/ tretinoin should be given to women of childbearing potential only if effective contraception is used during treatment and for 1 month after discontinuation of treatment

Breastfeeding
South African manufacturer recommendations

• Contraindicated 
• Women should not breastfeed their babies if they are on treatment with clindamycin phosphate/ tretinoin. Both retinoids, such as tretinoin, their metabolites and clindamycin cross into breastmilk

International manufacturer recommendations

• Caution; not recommended 
• It is not known whether tretinoin and clindamycin are secreted in breast milk following the use of clindamycin phosphate/ tretinoin. Oral and parenteral administration of clindamycin has been reported to result in the appearance of clindamycin in breast milk. It is known that orally administered retinoids and their metabolites are secreted in breast milk. Therefore, clindamycin phosphate/ tretinoin should not be used in women who are breastfeeding

Fertility 

• There are no available data on fertility on clindamycin phosphate/ tretinoin. Clindamycin: Reproduction studies in rats and mice, using subcutaneous and oral doses of clindamycin, revealed no evidence of impaired fertility. Tretinoin: Systemically administered tretinoin severely affects fertility. Available data regarding fertility after topical administration in humans are limited and a negative effect on fertility cannot be excluded

Renal Impairment 

• Caution; no information available 
  In view of the low systemic exposure to clindamycin and tretinoin following topical administration of clindamycin phosphate/ tretinoin, moderate renal impairment is not expected to result in systemic exposure of clinical concern. However, clindamycin and tretinoin serum concentrations have not been studied in patients with renal disease following topical administration. Individual decisions are advisable in severe cases 

Hepatic Impairment

• Caution; no information available 
  In view of the low systemic exposure to clindamycin and tretinoin following topical administration of clindamycin phosphate/ tretinoin, moderate hepatic impairment is not expected to result in systemic exposure of clinical concern. However, clindamycin and tretinoin serum concentrations have not been studied in patients with hepatic disease following topical administration. Individual decisions are advisable in severe cases 

Elderly 

• Caution; no information available 

Drugs in Sport

• Permitted - No warnings 

Central Nervous System Disorders

• Headache

Gastrointestinal Disorders 

• Gastroenteritis
• Nausea

Endocrine and Metabolic Disorders 

• Hypothyroidism

Skin and Subcutaneous Tissue Disorders 

• Acne
• Dry skin
• Erythema
• Seborrhoea
• Photosensitivity reaction
• Pruritus
• Rash
  - Exfoliative rash
  - Macular rash
• Skin exfoliation
• Sunburn
• Dermatitis
• Herpes simplex
• Skin bleeding
• Burning sensation
• Skin depigmentation
• Skin irritation
• Application site reactions
  - Burning
  - Dermatitis
  - Dryness
  - Erythema
  - Irritation
  - Swelling
  - Erosion
  - Discolouration
  - Pruritus
  - Desquamation

Immune, Blood and Lymphatic System Disorders 

• Hypersensitivity

Sensory Disorders 

• Eye irritation 

Others

• Feeling hot
• Pain

• Medicated soaps and cleansers that have a strong drying effect
• Corticosteroids
• Erythromycin
• Metronidazole
• Aminoglycosides 
• Neuromuscular blocking agents
• Vitamin K antagonists
• Warfarin

Other interactions

• Products with high concentrations of alcohol
• Astringents

None routine.  Specific cases may require

• Prothrombin time (PT) 
• International normalised ratio (INR)
  (See additional prescribing points) 

Antibiotic-associated colitis

• Antibiotic-associated colitis (also known as clostridium difficile-associated colitis (CDAD)) has been reported with the use of topical clindamycin as contained in clindamycin phosphate/ tretinoin. If prolonged or significant diarrhoea occurs or the patient suffers from abdominal cramps, treatment with clindamycin phosphate/ tretinoin should be discontinued immediately, as the symptoms may indicate antibiotic-associated colitis
• Suitable diagnostic methods, such as the determination of clostridium difficile and toxin and, if necessary, colonoscopy should be employed and treatment options for colitis considered

Monitoring considerations when coadministered with vitamin K antagonists 

• Increases in the prothrombin time (PT) and international normalised ratio (INR) and/or bleeding, have been reported in patients treated with clindamycin as contained in clindamycin phosphate/ tretinoin in combination with a vitamin K antagonist (e.g. warfarin). Coagulation tests (PT and INR), should therefore, be frequently monitored in patients treated with vitamin K antagonists

Clindamycin phosphate/ tretinoin is the combination of two active substances, which act through different mechanisms of action.
Clindamycin: Clindamycin is a semisynthetic derivative of the parent compound lincomycin that is produced by Streptomyces lincolnensis and is predominantly bacteriostatic. Clindamycin binds to the 50S ribosomal subunits of susceptible bacteria and prevents elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing bacterial protein synthesis. Although clindamycin phosphate is inactive in-vitro, rapid in-vivo hydrolysis converts this compound to the antibacterial active clindamycin. Clindamycin has been shown to have in vitro activity against Cutibacterium acnes (Propionibacterium acnes), one pathophysiological factor that influence the development of acne vulgaris. Clindamycin also exerts an anti-inflammatory effect on the acne vulgaris lesions.
Tretinoin: Topical tretinoin has both comedolytic and anti-inflammatory effects. Tretinoin decreases cohesiveness of follicular epithelial cells resulting in decreased microcomedone formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells, causing extrusion of the comedones. The comedolytic activity is related to a normalisation of the desquamation of the follicular epithelium. Tretinoin exerts anti-inflammatory effect via suppression of toll-like receptors (TLRs). Combination of clindamycin and tretinoin, as in clindamycin phosphate/ tretinoin, combines the individual actions of both active components and when applied together, tretinoin increases the penetration of clindamycin. Combination therapy with clindamycin phosphate/ tretinoin targets multiple pathogenic factors: abnormal follicular keratinization, P.acnes proliferation, inflammation and increased sebum production.

COMBINATION PREPARATIONS 

Clindamycin Phosphate/ Tretinoin

Gel (per g) 10mg/0.25mg

• Treclin Gel (Mylan) originator