Minocycline Hydrochloride

(BANM, rINNM)
Synonyms: Hidrocloruro de minociclina; Minociklin-hidroklorid; Minociklino hidrochloridas; Minocycline, chlorhydrate de; Minocyclini hydrochloridum; Minocyklin-hydrochlorid; Minocyklinhydroklorid; Minocykliny chlorowodorek; Minosykliinihydrokloridi.
Cyrillic synonym: Миноциклина Гидрохлорид.

💊 Chemical information

Chemical formula: C23H27N3O7,HCl = 493.9.
CAS — 13614-98-7.
ATC — A01AB23; J01AA08.
ATC Vet — QA01AB23; QJ01AA08.

Pharmacopoeias.

In Eur., Jpn, and US.

Ph. Eur. 6.2

(Minocycline Hydrochloride Dihydrate). A yellow, hygroscopic, crystalline powder. Sparingly soluble in water; slightly soluble in alcohol. It dissolves in solutions of alkali hydroxides and carbonates. A 1% solution in water has a pH of 3.5 to 4.5. Store in airtight containers. Protect from light.

USP 31

(Minocycline Hydrochloride). A yellow crystalline powder. Sparingly soluble in water; slightly soluble in alcohol; practically insoluble in chloroform and in ether; soluble in solutions of alkali hydroxides and carbonates. pH of a solution in water containing the equivalent of minocycline 1% is between 3.5 and 4.5. Store in airtight containers. Protect from light.

Incompatibility.

Preparations of minocycline hydrochloride have an acid pH and incompatibility may reasonably be expected with alkaline preparations or with drugs unstable at low pH.

💊 Adverse Effects and Precautions

As for Tetracycline. Gastrointestinal disturbances with minocycline are reported to be less frequent than with the less well absorbed tetracyclines. Oesophageal ulceration has occurred and may be a particular problem if capsules or tablets are taken with insufficient fluid or in a recumbent posture: minocycline should be taken with at least half a glass of water, in an upright position, and well before going to bed. Vestibular adverse effects including dizziness or vertigo may occur with minocycline, particularly in women. Patients should be advised not to drive or operate machinery if affected. Tinnitus and decreased hearing have been reported rarely. There have also been reports, some fatal, of a hypersensitivity syndrome (comprising eosinophilia, fever, rash, and varying additional symptoms), a lupus-like syndrome, and a serum-sickness-like syndrome (both comprising arthralgia, fever, and joint stiffness or swelling, amongst other symptoms). Minocycline may also cause hyperpigmentation of the skin (see below). Although minocycline, unlike many tetracyclines, does not appear to accumulate in patients with renal impairment, usual doses can lead to higher serum concentrations resulting in possible liver toxicity; reduced doses and monitoring of renal function may be necessary, particularly in those with severe impairment. The BNF recommends that if treatment continues for longer than 6 months patients should be monitored every 3 months for hepatotoxicity, pigmentation, and SLE.

Incidence of adverse effects.

Severe complications have been reported in patients given minocycline for acne, including serum-sickness-like disease,1,2 lupus erythematosus,3 and hepatitis.3,4 The number of cases reported probably reflects the widespread use of this drug and the true incidence of such adverse effects is difficult to assess.5 A study of 700 patients receiving minocycline for acne revealed adverse effects in 13.6%, mostly benign.6 Gastrointestinal disturbances and vestibular disturbances were the most common, each occurring in about 2% of patients, and pigmentation in up to 4% of patients. Another problem is that of assessing the efficacy of minocycline and the incidence of severe adverse effects relative to other antibacterials commonly used in acne such as tetracycline and erythromycin. A systematic review7 suggested that the incidence of adverse effects might be greater with minocycline than with doxycycline. A retrospective analysis8 of a UK population database found that minocycline was associated with an increased risk for drug-induced lupus erythematosus; no increased risk was reported for the other tetracyclines. Other systematic reviews9,10 concluded that minocycline should not be used as a first-line oral tetracycline in patients with acne since there is no compelling evidence that it is more effective than some other tetracyclines or commonly used treatments; the risk of rare but serious adverse effects also makes it less suitable.10
1. Knowles SR, et al. Serious adverse reactions induced by minocycline: report of 13 patients and review of the literature. Arch Dermatol 1996; 132: 934–9
2. Harel L, et al. Serum-sickness-like reaction associated with minocycline therapy in adolescents. Ann Pharmacother 1996; 30: 481–3
3. Gough A, et al. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ 1996; 312: 169–72
4. Australian Adverse Drug Reactions Advisory Committee (ADRAC). Minocycline and the liver, the CNS, the skin. Aust Adverse Drug React Bull 1996; 15: 14. Also available at: http:// www.tga.gov.au/adr/aadrb/aadr9611.htm (accessed 11/08/08
5. Seukeran DC, et al. Benefit-risk assessment of acne therapies. Lancet 1997; 349: 1251–2
6. Goulden V, et al. Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol 1996; 134: 693–5
7. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther 2005; 27: 1329–42
8. Margolis DJ, et al. Association or lack of association between tetracycline class antibiotics used for acne vulgaris and lupus erythematosus. Br J Dermatol 2007; 157: 540–6
9. Garner SE, et al. Minocycline for acne vulgaris: efficacy and safety. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2003 (accessed 16/05/05)
10. McManus P, Iheanacho I. Don’t use minocycline as first line oral antibiotic in acne. BMJ 2007; 334: 154.

Effects on intracranial pressure.

Minocycline has been associated with benign intracranial hypertension; for further details, see under Tetracycline.

Effects on the liver.

A systematic review1 considered 65 published case reports of hepatitis or liver damage associated with the use of minocycline for acne, including 4 fatalities, and also data held by WHO concerning 493 reactions involving the liver in 393 patients in whom the indication for the use of minocycline was largely unspecified. Of the 65 published cases, 38 occurred in females and 61 in patients under 40 years of age. These cases appeared to be of the following types:
16 cases appeared to be attributable to a hypersensitivity reaction, with a rapid onset usually within 1 month of starting treatment and sometimes associated with eosinophilia and exfoliative dermatitis
29 cases of hepatitis (of which 20 were in females) appeared to be of an auto-immune nature, occurring after 1 year or more of therapy and sometimes associated with lupus-like symptoms
20 cases could not be definitively classified into either group The 393 patients described by the WHO data had 22 different types of hepatic reaction which could be broadly grouped into 4 categories:
hepatic dysfunction (32% of patients)
hepatitis (26%)
abnormal liver function tests (24%)
hyperbilirubinaemia or jaundice (14%) There were, in addition, several other reactions, including hepatic damage or necrosis in 11 patients and fatty liver in 7. Gender distribution was almost even. Of the 393 patients, 14 also experienced lupus-like symptoms. The outcome of the hepatic reactions was reported in less than half of the patients, although it was apparent that there had been at least 3 fatalities. Despite these findings, the reviewers concluded1 that there was no clear information regarding the absolute or relative risks of hepatitis in patients given minocycline, and that it was inappropriate to comment as to whether monitoring would be worthwhile. A study of the comparative rates of hepatitis in people exposed to minocycline compared with those who were not was required.
1. Lawrenson RA, et al. Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data. Drug Safety 2000; 23: 333–49.

Effects on the lungs.

Hypersensitivity pneumonitis, characterised by pulmonary infiltrates and eosinophilia, has been reported1-6 with minocycline. In most cases, the pneumonitis resolved after stopping minocycline but some required corticosteroid therapy; however, residual lung damage can occur. In one case6 relapsing acute respiratory failure that required mechanical ventilation was reported.
1. Guillon J-M, et al. Minocycline-induced cell-mediated hypersensitivity pneumonitis. Ann Intern Med 1992; 117: 476–81
2. Bridges AJ. Minocycline-induced pneumonia. Ann Intern Med 1993; 118: 749–50
3. Sigmann P. Minocycline-induced pneumonia. Ann Intern Med 1993; 118: 750
4. Sitbon O, et al. Minocycline pneumonitis and eosinophilia: a report on 8 patients. Arch Intern Med 1994; 154: 1633–40
5. Dykhuizen RS, et al. Minocycline and pulmonary eosinophilia. BMJ 1995; 310: 1520–1
6. Oddo M, et al. Relapsing acute respiratory failure induced by minocycline. Chest 2003; 123: 2146–8.

Hyperpigmentation.

Minocycline has been associated with pigmentation of the skin and other tissues.1-3 Three patterns of skin pigmentation have been described:1 blue-black macules occurring in areas of inflammation and scarring and possibly due to an iron chelate of minocycline within macrophages; blue-grey macules or hyperpigmentation affecting normal skin and which may be due to a breakdown product of minocycline; or a greyishbrown discoloration occurring particularly in sun-exposed areas of skin (‘muddy skin syndrome’), apparently due to melanin deposition. In general, pigmentation results from long-term use of minocycline at cumulative doses greater than 100 g; however, skin or oral mucosal pigmentation may occur regardless of dose or duration of therapy.2 Indeed, there have been reports3 of skin pigmentation developing after short-term use ranging from 3 to 28 days. Pigmentation of the skin and oral mucosa usually appears to resolve slowly on stopping the drug although recovery may be incomplete; pigmentation is often permanent when other sites are involved.2
1. Basler RSW. Minocycline-related hyperpigmentation. Arch Dermatol 1985; 121: 606–8
2. Eisen D, Hakim MD. Minocycline-induced pigmentation: incidence, prevention and management. Drug Safety 1998; 18: 431–40
3. Nakamura S, et al. Acute pigmentation due to minocycline therapy in atopic dermatitis. Br J Dermatol 2003; 148: 1073–4.

💊 Interactions

As for Tetracycline. Minocycline has a lower affinity for binding with calcium than tetracycline. Consequently its absorption is less likely to be affected by milk or food, although it is still affected by calcium-containing antacids and other divalent and trivalent cations such as aluminium, bismuth, iron, magnesium, and zinc.

💊 Antimicrobial Action

Minocycline has a spectrum of activity and mode of action similar to that of tetracycline but it is more active against many species including Staphylococcus aureus, streptococci, Neisseria meningitidis, various enterobacteria, Acinetobacter, Bacteroides, Haemophilus, Nocardia, and some mycobacteria, including M. leprae. Partial cross-resistance exists between minocycline and other tetracyclines but some strains resistant to other drugs of the group remain sensitive to minocycline, perhaps because of better cell-wall penetration.

💊 Pharmacokinetics

For the general pharmacokinetics of the tetracyclines, see Tetracycline. Minocycline is readily absorbed from the gastrointestinal tract and absorption is not significantly affected by the presence of food or moderate amounts of milk. Oral doses of 200 mg followed by 100 mg every 12 hours are reported to produce plasma concentrations of about 2 to 4 micrograms/mL. It is more lipid-soluble than doxycycline and the other tetracyclines and is widely distributed in body tissues and fluids with high concentrations being achieved in the hepatobiliary tract, lungs, sinuses and tonsils, as well as in tears, saliva, and sputum. Penetration into the CSF is relatively poor, although a higher ratio of CSF to blood concentrations has been reported with minocycline than with doxycycline. It crosses the placenta and is distributed into breast milk. About 75% of minocycline in the circulation is bound to plasma proteins. It has a low renal clearance: only about 5 to 10% of a dose is excreted in the urine and up to about 34% is excreted in the faeces. However, in contrast to most tetracyclines it appears to undergo some metabolism in the liver, mainly to 9-hydroxyminocycline. Sources differ as to whether the normal plasma half-life of 11 to 26 hours is prolonged in patients with renal impairment, with a consequent risk of accumulation; hepatic impairment does not appear to lead to accumulation. Little minocycline is removed by haemodialysis and peritoneal dialysis.
1. Saivin S, Houin G. Clinical pharmacokinetics of doxycycline and minocycline. Clin Pharmacokinet 1988; 15: 355–66.

💊 Uses and Administration

Minocycline is a tetracycline derivative with uses similar to those of tetracycline. It is also a component of multidrug regimens for the treatment of leprosy and has been used in the prophylaxis of meningococcal infection to eliminate the carrier state, but the high incidence of vestibular disturbances means that it is not the drug of choice for the latter. Minocycline is usually given orally as the hydrochloride; doses are expressed in terms of the base. Minocycline hydrochloride 108 mg is equivalent to about 100 mg of minocycline. Minocycline capsules and tablets should be taken with plenty of fluid, with the patient in an upright position, and well before going to bed. In patients in whom oral therapy is not feasible, minocycline hydrochloride has been given by slow intravenous infusion in doses equivalent to those given orally. In some countries it has also been given by intramuscular injection. The usual adult oral dose is 200 mg daily in divided doses, usually every 12 hours; an initial loading dose of 200 mg may be given. An oral dose of 50 mg twice daily or 100 mg once daily is used for the treatment of acne; alternatively, a dose of about 1 mg/kg once daily is also given as a modified-release preparation to patients weighing 45 kg and over. In asymptomatic meningococcal carriers, 100 mg has been given orally twice daily for 5 days, usually followed by a course of rifampicin. For multibacillary leprosy an oral dose of minocycline 100 mg daily with clofazimine and ofloxacin or 100 mg monthly with rifampicin and ofloxacin have been recommended by WHO as alternative multidrug therapy regimens. As an alternative regimen for patients with single-lesion paucibacillary leprosy WHO suggests a single dose of minocycline 100 mg with rifampicin and ofloxacin. For details of doses in children and adolescents, see below. For dosage recommendations in patients with renal impairment, see below. In adults with periodontitis, a modified-release subgingival gel containing minocycline hydrochloride has been inserted into the periodontal pocket as an adjunct to scaling and root planing; each cartridge contains the equivalent of 1 mg of minocycline and the total used depends on the size, shape, and number of pockets being treated. Minocycline has also been applied as a 2% gel for periodontal infections.

Administration in children.

In children, the effects on teeth should be considered and tetracyclines only used when absolutely essential. In the UK, minocycline is licensed for use in children aged 12 years and over; the usual adult dose (see above) may be given orally. However, in the USA, it may be given to those over 8 years old in usual oral doses of 4 mg/kg initially followed by 2 mg/kg every 12 hours.

Administration in renal impairment.

US licensed product information states that pharmacokinetics in patients with renal impairment have not been fully characterised and therefore recommends that no more than 200 mg in any 24-hour period should be given to these patients.

Motor neurone disease.

Minocycline is being investigated as a potential treatment for amyotrophic lateral sclerosis, a form of motor neurone disease, on the basis of its neuroprotective properties.

Movement disorders.

Minocycline is under investigation1,2for the management of Huntington’s chorea.
1. Huntington Study Group. Minocycline safety and tolerability in Huntington disease. Neurology 2004; 63: 547–9
2. Bonelli RM, et al. Neuroprotection in Huntington’s disease: a 2year study on minocycline. Int Clin Psychopharmacol 2004; 19: 337–42.

Musculoskeletal and joint disorders.

For reference to the use of minocycline in the treatment of rheumatoid arthritis, see under Tetracycline.

Skin disorders.

For reference to the use of minocycline in the treatment of various skin disorders, see under Tetracycline.

💊 Preparations

BP 2008: Minocycline Tablets; Prolonged-release Minocycline Capsules; USP 31: Minocycline for Injection; Minocycline Hydrochloride Capsules; Minocycline Hydrochloride Oral Suspension; Minocycline Hydrochloride Ta b l e t s .

Proprietary Preparations

Arg.: Acneclin; Asolmicina†; Clinax; Meibi; Minocin; Pimple; Seboclear; Austral.: Akamin; Minomycin; Austria: Auramin; Klinoc†; Minocin†; Minostad; Minotyrol†; Udima; Belg.: Klinotab; Mino-50; Minocin; Minotab; Braz.: Minoderm; Minomax†; Canad.: Enca; Minocin; Chile: Bagomicina; Minocin†; Pracne; Cz.: Skid†; Fr.: Mestacine; Minolis; Mynocine; Parocline; Yelnac†; Zacnan; Ger.: Akne-Puren†; Aknefug Mino; Aknin-Mino†; Aknosan; Klinomycin; Lederderm†; Minakne; Mino-Wolff†; Minoclir; Minoplus; Skid; Skinocyclin; Udima; Gr.: Cycline; Minocin; Hong Kong: Minaxen; Minocin; India: CNN†; Cynomycin; Indon.: Minocin; Irl.: Minocin; Minox; Israel: Minocin†; Minoclin; Ital.: Minocin; Jpn: Periocline; Malaysia: Borymycin; Minocin†; Minoclin; Mex.: Banimed; Micromycin; Minocin; Ranmino; Neth.: Aknemin; Minocin; Minotab; Peritrol; NZ: Minomycin; Minotabs; Philipp.: Minocin; Port.: Arestin; Cipancin; Minocin; Minotrex; S.Afr.: Cyclimycin; Minotabs; Triomin; Singapore: Borymycin; Minocin†; Spain: Minocin; Switz.: Aknin-N; Aknoral; Minac 50; Minocin; Thai.: Minocin†; UK: Aknemin; Blemix†; Dentomycin; Minocin; Sebomin; Sebren; USA: Arestin; Cleeravue-M; Dynacin; Minocin; Myrac; Solodyn; Venez.: Minocin†.
Published May 08, 2019.