Clindamycin/Niacinamide/Tretinoin/Azelaic

Clindamycin is a lincosamide antibiotic and is not a controlled substance. FDA-approved products include oral capsules (Cleocin HCl), oral solution (Cleocin Pediatric), intravenous and intramuscular injection (Cleocin Phosphate), topical gel, lotion, solution and foam (Cleocin T, Clindagel, Evoclin), vaginal cream and ovules (Cleocin, Clindesse), and fixed topical combinations with benzoyl peroxide, tretinoin or adapalene/benzoyl peroxide. Compounding pharmacies use clindamycin phosphate in topical preparations.

• Oral and injectable: serious infections caused by susceptible anaerobic bacteria and susceptible streptococci, pneumococci and staphylococci, reserved for patients in whom less toxic antibiotics are inappropriate. Labeled injectable uses include lower respiratory tract, skin and skin structure, gynecologic, intra-abdominal, and bone and joint infections and septicemia.
• Topical: acne vulgaris, alone or in fixed combination with benzoyl peroxide or tretinoin. Acne guidelines advise against topical clindamycin monotherapy and pair it with benzoyl peroxide to limit bacterial resistance.
• Vaginal: bacterial vaginosis.
• Prescribers also use compounded topical clindamycin in combination preparations for acne.

Clindamycin binds the 23S rRNA of the bacterial 50S ribosomal subunit and inhibits protein synthesis. It is usually bacteriostatic and can be bactericidal at higher concentrations against some organisms. It reduces Cutibacterium acnes in the follicle and the free fatty acids it produces. Cross-resistance occurs with macrolides through ribosomal methylation (erm genes).

Oral clindamycin hydrochloride is about 90% absorbed, with peak serum levels about 45 to 60 minutes after a dose; food does not meaningfully reduce it. It distributes widely, including into bone, but not into cerebrospinal fluid. It is metabolized in the liver mainly by CYP3A4 to clindamycin sulfoxide and N-desmethylclindamycin and excreted in urine and feces. The half-life is about 2.4 to 3 hours in adults and longer in older adults. Topical clindamycin phosphate is hydrolyzed in the skin to active clindamycin; systemic absorption is low, and vaginal products are absorbed more.

• Hypersensitivity to clindamycin or lincomycin.
• Topical and vaginal products: history of regional enteritis, ulcerative colitis or antibiotic-associated colitis.

• Diarrhea and colitis: severe diarrhea and C. difficile colitis have been reported with oral, injectable, topical and vaginal clindamycin. Stop clindamycin and evaluate if significant diarrhea occurs.
• Serious skin and hypersensitivity reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, acute generalized exanthematous pustulosis and anaphylaxis have been reported with systemic use.
• Acute kidney injury and hepatotoxicity have been reported with systemic use; monitor in prolonged therapy or at-risk patients.
• Overgrowth of nonsusceptible organisms, including yeast, can occur.
• Injectable products containing benzyl alcohol carry a risk of gasping syndrome in neonates; some capsule strengths contain tartrazine.
• Topical use: dryness, irritation and peeling; avoid the eyes and mucous membranes.

• Neuromuscular blocking agents: clindamycin can enhance neuromuscular blockade.
• Erythromycin and other macrolides: antagonism at the ribosomal binding site; avoid combining, including topical erythromycin products.
• Strong CYP3A4 inducers (for example rifampin) can lower clindamycin levels; strong CYP3A4 inhibitors can raise them.
• Topical: cumulative irritation with other drying, peeling or abrasive acne products.

Systemic: diarrhea, nausea, vomiting, abdominal pain, metallic taste, esophagitis with capsules, rash, pruritus, transient liver enzyme elevation and, less often, C. difficile colitis and severe skin reactions. Topical: dryness, erythema, burning, itching, peeling, oily skin, and rarely diarrhea or colitis. Vaginal: vulvovaginal candidiasis and irritation.

Clindamycin crosses the placenta. Systemic use in the second and third trimesters has not been associated with an increased frequency of congenital abnormalities; first-trimester data are more limited. Clindamycin passes into human milk and may cause diarrhea, candidiasis or bloody stools in the infant; monitor the infant. Topical use produces low systemic exposure.

• Diarrhea or abdominal cramping during and up to two months after therapy.
• Liver and kidney function and complete blood count during prolonged systemic therapy.
• Skin reactions and hypersensitivity.
• Topical use: local tolerability and treatment response per prescriber.

• Cleocin HCl (clindamycin hydrochloride) capsules Prescribing Information, Pfizer.
• Cleocin Phosphate (clindamycin injection) Prescribing Information, Pfizer.
• Cleocin T (clindamycin phosphate) topical Prescribing Information, Pfizer.
• American Academy of Dermatology, Guidelines of care for the management of acne vulgaris (2024).

Niacinamide, also called nicotinamide, is the amide form of vitamin B3. It is sold as a dietary supplement and is widely used in cosmetic skin products. It is distinct from niacin (nicotinic acid), which is FDA-approved for dyslipidemia and causes flushing. Lake Hills Pharmacy uses niacinamide bulk substance in compounded topical preparations.

As a vitamin, nicotinamide is used to prevent and treat niacin deficiency (pellagra). Prescribers use topical niacinamide in compounded dermatology preparations for acne, rosacea, hyperpigmentation and skin barrier support, and oral nicotinamide in patients at high risk of nonmelanoma skin cancer.

Niacinamide is a precursor of NAD+ and NADP+, cofactors for cellular redox reactions, energy metabolism and DNA repair. In skin it reduces transfer of melanosomes from melanocytes to keratinocytes, increases synthesis of ceramides and other stratum corneum lipids to strengthen the barrier and reduce water loss, and has anti-inflammatory effects, including reduced cytokine release and neutrophil chemotaxis. It may also reduce sebum production. It does not cause the prostaglandin-mediated flushing seen with niacin.

Orally, niacinamide is rapidly absorbed and widely distributed. It is metabolized in the liver, chiefly to N-methylnicotinamide and pyridone derivatives, which are excreted in the urine; more unchanged drug appears in the urine at high doses. Topically, it penetrates the stratum corneum, and systemic exposure from topical use is small relative to dietary intake.

• Hypersensitivity to niacinamide or any component of the preparation.

• Topical: irritation, burning and itching can occur. In some formulations niacinamide can hydrolyze to nicotinic acid, which may cause transient flushing or redness.
• Oral high doses (grams per day): liver toxicity has been reported at very high doses; use caution in liver disease. Gastrointestinal upset is common at high doses.
• Thrombocytopenia has been reported with oral nicotinamide in patients on dialysis.

• Oral nicotinamide may raise concentrations of carbamazepine and primidone by reducing their clearance.
• No clinically relevant interactions are known for topical use.

Topical: mild burning, stinging, itching, redness and dryness; contact dermatitis is uncommon. Oral: nausea, diarrhea, flatulence, dizziness, headache and rash; liver enzyme elevation at very high doses.

Nicotinamide is a normal nutrient, and topical use is not expected to raise systemic exposure meaningfully above dietary intake. Safety of high-dose oral supplementation in pregnancy and lactation has not been established.

Topical: skin tolerability and clinical response. High-dose oral use: periodic liver tests, and blood counts in patients on dialysis.

• Martindale: The Complete Drug Reference, nicotinamide monograph.
• Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline, Institute of Medicine (National Academies).
• Niacin Fact Sheet for Health Professionals, NIH Office of Dietary Supplements.

Tretinoin (all-trans retinoic acid) is a retinoid. FDA-approved topical products include Retin-A cream and gel, Renova emollient cream, Atralin gel, Altreno lotion and Tri-Luma cream (with hydroquinone and fluocinolone). Oral tretinoin capsules are approved for acute promyelocytic leukemia. Lake Hills Pharmacy compounds topical tretinoin preparations as a 503A pharmacy on patient-specific prescriptions.

• Topical (Retin-A, Atralin, Altreno): acne vulgaris.
• Topical (Renova 0.02% and 0.05%): adjunct for mitigation of fine facial wrinkling, mottled hyperpigmentation and roughness associated with chronic sun exposure, with sun avoidance.
• Topical (Tri-Luma): short-term treatment of moderate to severe facial melasma, in combination.
• Oral capsules: induction of remission in acute promyelocytic leukemia (APL) with the t(15;17) translocation or PML/RARA gene.
• Prescribers use compounded topical tretinoin, alone or with other agents, for acne, photoaging and hyperpigmentation.

Tretinoin binds nuclear retinoic acid receptors (RAR-alpha, beta, gamma), altering gene transcription. In skin it increases epidermal cell turnover, reduces cohesion of follicular keratinocytes, normalizes follicular keratinization and promotes dispersion of melanin granules. In APL it induces differentiation of leukemic promyelocytes.

Topical: systemic absorption is minimal, and plasma retinoid levels stay within the endogenous range in labeled studies. Oral: peak levels occur in 1 to 2 hours, elimination half-life is short (about 0.5 to 2 hours), and metabolism through CYP26 and CYP3A4 induces its own clearance with continued dosing.

• Hypersensitivity to tretinoin, other retinoids or any component of the preparation (oral capsules: also parabens).

• Topical: local irritation (erythema, peeling, dryness, burning) is common; reduce frequency or stop if severe. Avoid eyes, mouth, nasal folds and mucous membranes, and do not apply to eczematous, sunburned or broken skin.
• Photosensitivity: minimize sun and UV exposure and use sunscreen and protective clothing. Weather extremes such as wind or cold may increase irritation.
• Oral: leukocytosis, pseudotumor cerebri (risk rises with tetracyclines), hyperlipidemia, elevated liver enzymes, and thrombosis risk.

• Topical: additive irritation with keratolytics (salicylic acid, sulfur, resorcinol), astringents, alcohol-containing products and abrasive cleansers; benzoyl peroxide can degrade some tretinoin formulations. Use caution with photosensitizing drugs such as thiazides, tetracyclines, fluoroquinolones, phenothiazines and sulfonamides.
• Oral: CYP3A4 inhibitors and inducers alter exposure; antifibrinolytics such as tranexamic acid increase thrombotic risk; tetracyclines increase the risk of pseudotumor cerebri; avoid vitamin A supplements.

Topical: erythema, peeling, dryness, burning, stinging, pruritus, temporary hyper- or hypopigmentation and photosensitivity. Oral: headache, fever, dry skin and mucous membranes, bone pain, nausea, hyperlipidemia, liver enzyme elevation and differentiation syndrome.

Oral tretinoin causes fetal harm and requires pregnancy exclusion and contraception. Topical tretinoin labeling reports limited human data; systemic absorption is low, but isolated reports of birth defects exist and many prescribers avoid topical retinoids in pregnancy. It is not known whether topical tretinoin passes into breast milk; oral labeling advises against breastfeeding during treatment and for 1 week after the last dose.

Topical: skin tolerability and photosensitivity at intervals set by the prescriber; confirm pregnancy status and plans. Oral: complete blood counts, coagulation, lipids, liver tests, pregnancy testing and signs of differentiation syndrome.

• Retin-A (tretinoin) Cream and Gel Prescribing Information.
• Renova (tretinoin) Cream 0.02% Prescribing Information.
• Tri-Luma (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) Cream Prescribing Information, Galderma Laboratories.
• Tretinoin Capsules, 10 mg, Prescribing Information (generic labeling).
• Lexicomp Drug Information, Wolters Kluwer.

Azelaic acid is a saturated nine-carbon dicarboxylic acid that occurs naturally in wheat, rye and barley and is produced by the skin yeast Malassezia. US products are Finacea Gel 15% (and generic azelaic acid gel 15%), Finacea Foam 15% and Azelex Cream 20%. Lake Hills Pharmacy uses azelaic acid in compounded topical preparations.

• Finacea Gel 15% and Foam 15%: topical treatment of the inflammatory papules and pustules of mild to moderate rosacea.
• Azelex Cream 20%: topical treatment of mild to moderate inflammatory acne vulgaris.
• Prescribers use compounded azelaic acid, alone or combined with other agents, for acne, rosacea, melasma, post-inflammatory hyperpigmentation and other hyperpigmentation disorders.

Azelaic acid has several actions: it is antibacterial against Cutibacterium acnes and Staphylococcus epidermidis by inhibiting microbial protein synthesis; it normalizes keratinization and reduces follicular hyperkeratosis; it reduces reactive oxygen species from neutrophils and dampens the kallikrein-cathelicidin pathway implicated in rosacea; and it competitively inhibits tyrosinase and has an antiproliferative effect on hyperactive melanocytes, with little effect on normal melanocytes. The exact mechanism in rosacea is not fully known.

A small fraction, a few percent, of a topical dose is absorbed through the skin. Absorbed azelaic acid is excreted mainly unchanged in the urine, with some undergoing beta-oxidation. Its apparent half-life after topical application is longer than after oral dosing because absorption is rate-limiting. Plasma levels after topical use remain within the range seen from normal dietary intake.

Azelex Cream labeling contraindicates use in patients with hypersensitivity to any of its components; Finacea labeling lists no contraindications. Compounded preparations should not be used in patients with hypersensitivity to azelaic acid or any component.

• Skin reactions: burning, stinging, itching, dryness and erythema are common, mostly early in treatment; stop if severe or persistent.
• Hypopigmentation has been reported; monitor patients with darker complexions for early signs.
• Avoid contact with the eyes, mouth and other mucous membranes; rinse with water if contact occurs.
• Worsening of asthma has been reported in patients using azelaic acid products.
• Finacea Foam contains a flammable propellant; avoid fire, flame and smoking during and right after application.

No formal interaction studies exist and no clinically relevant systemic interactions are expected with topical use. Irritation can be additive with retinoids, benzoyl peroxide, abrasive or drying cleansers and alcohol-containing products.

Burning, stinging, tingling, itching, dryness, erythema, scaling and contact dermatitis. Less often: hypopigmentation, hypersensitivity reactions including angioedema and urticaria, eye irritation after accidental contact, and worsening of asthma.

Systemic absorption after topical use is minimal. In animal studies, oral doses far above human topical exposure caused embryotoxicity only at maternally toxic levels, with no teratogenicity. Human data are limited. Azelaic acid is not expected to raise milk levels meaningfully above those from diet after topical use; avoid application to the breast area while nursing.

Tolerability and skin irritation, pigmentary changes in patients with darker skin, asthma symptoms in patients with asthma, and clinical response at follow-up.

• Finacea (azelaic acid) Gel 15% Prescribing Information, LEO Pharma.
• Finacea (azelaic acid) Foam 15% Prescribing Information, LEO Pharma.
• Azelex (azelaic acid) Cream 20% Prescribing Information.
• Guidelines of Care for the Management of Acne Vulgaris (2024), American Academy of Dermatology.