Sulfamethoxazole/ Trimethoprim/ Isoniazid/ Pyridoxine Hydrochloride

These indications are based on manufacturer information for both originator and generic products. For product specific registered indications, please refer to product specific manufacturer information

Registered South African indications:

• Prevention and/or risk reduction of non-viral opportunistic and bacterial infections
  - Pneumocystis jirovecii pneumonia
  - Toxoplasma gondii infections
  - Isosporiasis
  - Activation of latent tuberculosis in HIV positive patients (WHO clinical stages 2; 3 or 4) on appropriate antiretroviral treatment and tuberculin sensitivity test (TST) positive but without signs, symptoms and/or diagnostic interventions indicative of active tuberculosis

Contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to isoniazid chemically related medication such as ethionamide, pyrazinamide and niacin
• Hypersensitivity to sulphonamides
• Hypersensitivity to sulphonylurea anti-diabetic and saluretic sulphonamide derivatives
• Pregnancy
• Breastfeeding
• Severe renal impairment 
• Moderate to severe hepatic impairment
  - With acute or chronic hepatic disease
• Porphyria
• Active tuberculosis
• History of drug-induced immune thrombocytopenia and in patients with documented megaloblastic anaemia due to folate deficiency
• Serious haematological disorders
• Blood dyscrasias
• Vitamin B₁₂ and folic acid deficiency
• History of gout or acute gout
• Infants <6 weeks of age
• Alcohol abuse/ alcoholism
• HIV positive patients but TST (tuberculin sensitivity test) negative and in pre-ARV treatment phase
• Coadministration with dofetilide
• Coadministration with leucovorin (follinic acid)
  (See additional prescribing points)
• Coadministration with sulfamethoxazole/ trimethoprim containing preparations
• Coadministration with tyramine and/or histamine containing food/ beverages
• Glucose-6-phosphate dehydrogenase deficiency

Cautions

• Mild to moderate renal impairment
• Mild hepatic impairment
• Elderly
• Prolonged use
• Possible folate deficiency
• Chronic alcoholics
• Anticonvulsant therapy
• Malabsorption syndrome
• Malnutrition states
• Seizure disorder
• History of psychosis
• Severe allergies
• Bronchial asthma
• Thyroid dysfunction
• AIDS
  (See additional prescribing points)
• Slow acetylators
• Slow inactivators
• Underlying disorders of potassium metabolism
• High doses of sulfamethoxazole/ trimethoprim
• Group A β-haemolytic streptococcal infections
• Risk of neuropathy or pyridoxine deficiency
• Diabetic patients
• Uraemic state
• Coadministration of agents known to induce hyperkalaemia
• Coadminstration with levodopa in conjunction with supplemental vitamins that contain >5mg pyridoxine in the daily dose
• Phenylketonuric patients not on appropriate dietary restriction
• May impair ability to drive and operate machinery

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

Infections caused by: Mycobacterium tuberculosis; Pneumocystis jirovecii pneumonia; Toxoplasma gondii

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

Prevention and/or risk reduction of non-viral opportunistic and bacterial infections
- Pneumocystis jirovecii pneumonia
- Toxoplasma gondii infections
- Isosporiasis
- Activation of latent tuberculosis in HIV positive patients (WHO clinical stages 2; 3 or 4) on appropriate antiretroviral treatment and tuberculin sensitivity test (TST) positive but without signs, symptoms and/or diagnostic interventions indicative of active tuberculosis

Sulfamethoxazole/ Trimethoprim/ Isoniazid/ Pyridoxine Hydrochloride
800/160/300/25 (mg)

• Oral (tab): ≥25kg: 1 tab, dly

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Tablets for oral administration, best taken after meals with an adequate amount of fluid

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If aluminium containing antacids are taken, they must be taken at least one hour after isoniazid

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

Infections caused by: Mycobacterium tuberculosis; Pneumocystis jirovecii pneumonia; Toxoplasma gondii

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

Prevention and/or risk reduction of non-viral opportunistic and bacterial infections
- Pneumocystis jirovecii pneumonia
- Toxoplasma gondii infections
- Isosporiasis
- Activation of latent tuberculosis in HIV positive patients (WHO clinical stages 2; 3 or 4) on appropriate antiretroviral treatment and tuberculin sensitivity test (TST) positive but without signs, symptoms and/or diagnostic interventions indicative of active tuberculosis

Sulfamethoxazole/ Trimethoprim/ Isoniazid/ Pyridoxine Hydrochloride
800/160/300/25 (mg)

• Younger than 6 weeks: Contraindicated
• Between 14-24.9kg: Oral (tab): ½ tab, dly
• ≥25kg: See adult dosage

---

Tablets for oral administration, best taken after meals with an adequate amount of fluid

---

If aluminium containing antacids are taken, they must be taken at least one hour after isoniazid

Pregnancy

• Contraindicated 
• Exposure to sulfamethoxazole/ trimethoprim during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot
• If sulfamethoxazole/ trimethoprim is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the foetus
• Sulfamethoxazole/ trimethoprim use in late pregnancy increases the risk of jaundice and kernicterus in the newborn and should not be used
• In rats, oral doses of approximately 5 and 6 times the recommended human daily dose of sulfamethoxazole/ trimethoprim based on a body surface area produced teratologic effects manifested mainly as cleft palates. In rabbit studies, an overall increase in foetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area
• It has been reported that in both rats and rabbits, isoniazid may exert an embryocidal effect when administered orally during pregnancy
• The requirement for pyridoxine appears to be increased during pregnancy

Breastfeeding

• Contraindicated 
• Sulfamethoxazole/ trimethoprim/ isoniazid/ pyridoxine hydrochloride should not be administered to mothers breastfeeding their babies
• Both trimethoprim and sulfamethoxazole, as contained in this combination preparation, pass into the breast milk and increase the risk of jaundice and kernicterus in the baby
• Isoniazid is known to pass into maternal breast milk. Mothers on treatment with sulfamethoxazole/ trimethoprim/ isoniazid/ pyridoxine hydrochloride or isoniazid should not breastfeed their babies
• The need for pyridoxine is increased during breastfeeding but despite the increased need of pyridoxine, mothers breastfeeding theirs babies should not be treated with sulfamethoxazole/ trimethoprim/ isoniazid/ pyridoxine hydrochloride
• It is not known whether pyridoxine, as contained in sulfamethoxazole/ trimethoprim/ isoniazid/ pyridoxine hydrochloride, is excreted in human milk

Fertility

• No information available

Renal Impairment

• Mild to moderate: Caution; no information available 
• Severe: Contraindicated 

Hepatic Impairment

• Mild: Caution; no dose adjustment recommended 
  (See additional prescribing points)
• Moderate to severe with acute or chronic hepatic disease: Contraindicated 

Elderly

• Caution; no dose adjustment recommended 
  There is an increased risk of severe adverse reactions in elderly patients or when complicating conditions exist, e.g. impaired renal, and/ or hepatic function, or concomitant use of other medicines in which case the risk may be related to the dosage and duration of treatment

Porphyria

• Porphyrinogenic (P) 

Drugs in Sport

• Permitted - No warnings
  (See additional prescribing points)

Central Nervous System Disorders

• Neuropathy
  - Peripheral neuropathy
  - Paraesthesia
• Aseptic meningitis
  - Meningitis-like symptoms
• Ataxia
• Seizures
• Headache
• Hallucinations
• Depression
• Apathy
• Nervousness
• Insomnia
• Dizziness
• Drowsiness
• Fatigue
• Weakness
• Toxic psychosis
• Psychotic reactions
• Memory impairment
• Toxic encephalopathy
• Atrophy
• Somnolence

Cardiovascular Disorders

• Allergic myocarditis
• QT prolongation
• Ventricular tachycardia
• Torsade de pointes

Respiratory Disorders

• Pulmonary infiltrates
• Pulmonary eosinophilia
• Eosinophilic alveolitis
• Fibrosing alveolitis
• Allergic alveolitis
• Cough
• Shortness of breath

Gastrointestinal Disorders

• Nausea and vomiting
• Stomatitis
• Glossitis
• Diarrhoea
• Pseudomembranous enterocolitis
• Clostridium difficile associated diarrhoea (CDAD)
  -  Mild diarrhoea
  - Fatal colitis
• Acute pancreatitis
• Pellagra
• Anorexia
• Abdominal pain
• Epigastric distress
• Dry mouth
• Constipation

Hepatobiliary Disorders

• Hepatic necrosis
• Fulminant hepatic necrosis
• Hepatomegaly
• Elevated transaminases
• Elevated bilirubin
  - Bilirubinaemia
  - Bilirubinuria
• Hepatotoxicity
  (See additional prescribing points)
• Hepatitis (severe and sometimes fatal)
• Cholestasis liver necrosis
• Vanishing bile duct syndrome
• Jaundice
  - Cholestatic jaundice
• Progressive liver damage

Genitourinary Disorders

• Electrolyte abnormalities
• Impaired renal function
• Tubular necrosis
• Interstitial nephritis
• Elevated blood urea
• Elevated serum creatinine
• Crystalluria
• Increased diuresis
• Toxic nephrosis
  - With oliguria and anuria
• Nephrotoxicity
  - In association with cyclosporine
• Haematuria
• Urinary retention

Endocrine and Metabolic Disorders

• Hyperkalaemia
• Hypernatraemia
• Hyponatraemia
• Hypoglycaemia
• Gynaecomastia
• Hyperglycaemia
• Metabolic acidosis
• Pyridoxine deficiency
• Low serum folic acid levels

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Lumbar pain
• Rhabdomyolysis
• Hyperreflexia

Skin and Subcutaneous Tissue Disorders

• Photosensitivity
• Erythema multiforme
• Purpura
  - Henoch–Schönlein purpura
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis (Lyell’s syndrome)
• Exfoliative dermatitis
• Pruritus
• Maculopapular rash
• Urticaria
• Rash
• Pellagra-like dermatitis in malnourished patients
• Generalised skin eruptions

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
  - Fever
  - Chills
  - Angioedema
  - Anaphylactic reactions
  - Serum sickness
  - Skin eruptions
  - Lymphadenopathy
  - Vasculitis associated with positive antinuclear antibodies
• Anaphylaxis
• Leukopenia
• Granulocytopenia
• Agranulocytosis
• Thrombocytopenia
  - Thrombotic thrombocytopenic purpura
  - Idiopathic thrombocytopenic purpura
• Fungal infections
  - Candidiasis
• Anaemia
  - Megaloblastic anaemia
  - Haemolytic anaemia
  - Autoimmune anaemia
  - Aplastic anaemia
  - Sideroblastic anaemia
• Pancytopenia
• Neutropenia
• Hypoprothrombinaemia
• Methaemoglobinaemia
• Eosinophilia
• Lupus erythematosus
  -  Systemic lupus erythematosus
• Blood dyscrasias
• Drug fever
• Generalised allergic reactions
• Periarteritis nodosa
• Lupus-like syndrome
• Rheumatoid syndrome
• Haemolysis (in certain susceptible G6PD deficient patients)

Sensory Disorders

• Conjunctival and scleral injection
• Uveitis
• Tinnitus
• Vertigo
• Optic neuritis

• Dofetilide
• Leucovorin
• Other preparations containing sulfamethoxazole/ trimethoprim
• Other preparations containing isoniazid
• Agents known to induce hyperkalaemia
• Levodopa
• Altretamine
• Oral contraceptives
• Hydralazine
• Penicillamine
• Thiazide diuretics
• Digoxin
• Warfarin
• Cyclosporin
• Methotrexate
• Tricyclic antidepressants
• Pyrimethamine
• Oral hypoglycaemics
• CYP2C8 substrates
• CYP2C9 substrates
• OCT2 substrates
• Pioglitazone
• Repaglinide
• Rosiglitazone
• Glipizide
• Glyburide
• Metformin
• Indomethacin
• Amantadine
• Zidovudine
• Lamivudine
• Angiotensin converting enzyme inhibitors
• Paracetamol
• Rifampicin
• Alfentanil
• Benzodiazepines
• Diazepam
• Anticonvulsants
• Carbamazepine
• Phenobarbitone
• Phenytoin
• Primidone
• Valproic acid
• Haloperidol
• Ketoconazole
• Theophylline
• Aluminium containing antacids
• Aluminium hydroxide
• Disulfiram
• Selective serotonin reuptake inhibitors
• Cycloserine
• Meperidine
• Enflurane
• Glucocorticosteroids
• Hepatotoxic agents
• Neurotoxic agents

Other interactions

• Alcohol
• Tyramine containing food/ beverages
• Cheese
• Red wine
• Histamine containing food/ beverages
• Diamine oxidase
• Skipjack
• Tuna
• Other tropical fish
• Test for prohibited substances
  (See additional prescribing points)
• Serum methotrexate assay using the competitive protein-binding technique when bacterial dihydrofolate reductase is used as the binding protein
• Jaffé alkaline picrate reaction assay for creatinine
• Copper sulphate urine glucose tests

• Haematological parameters
• Hepatic function
• Renal function
• Thyroid function
• Viral loads
• Ophthalmic examination
  - Ophthalmoscopy

Specific cases may require

• Blood glucose
• Full blood count
• Electrolytes
  - Serum potassium
• Serum digoxin levels
• Serum phenytoin levels
• Coagulation time
• Urinalysis
• Laboratory and relevant imaging procedures to detect opportunistic infections
  - Tuberculosis
  - Other infections

Additional observations

• Neurological examinations
• Signs of hypersensitivity

Test for prohibited substances

• Sulfamethoxazole/ trimethoprim/ isoniazid/ pyridoxine hydrochloride may lead to a positive test for prohibited substances in competitive sport activities

Clostridium difficile associated diarrhoea

• Clostridium difficile associated diarrhoea (CDAD) has been reported with use of sulfamethoxazole/ trimethoprim, and may range in severity from mild diarrhoea to fatal colitis
• Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of Clostridium difficile
• Clostridium difficile produces toxins A and B which contribute to the development of CDAD
• Hypertoxin producing strains of Clostridium difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy
• CDAD must be considered in all patients who present with diarrhoea following antibiotic use
• Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial medicines
• If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile should be discontinued
• Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of Clostridium difficile, and surgical evaluation should be instituted as clinically indicated

Coadministration with leucovorin (folinic acid) for Pneumocystis jirovecii pneumonia

• Treatment failure and excess mortality were observed when trimethoprim/ sulfamethoxazole was used coadministered with leucovorin (folinic acid) for the treatment of HIV positive patients with Pneumocystis jirovecii pneumonia (PJP) in a randomized placebo-controlled trial
• Coadministration of trimethoprim/ sulfamethoxazole and leucovorin (folinic acid) during treatment of PJP should be avoided

Use in the treatment of and prophylaxis for Pneumocystis jirovecii pneumonia in patients with Acquired Immunodeficiency Syndrome (AIDS)

• AIDS patients may not tolerate or respond to sulfamethoxazole/ trimethoprim in the same manner as non-AIDS patients
• The incidence of side effects, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with sulfamethoxazole/ trimethoprim therapy in AIDS patients who are being treated for Pneumocystis jirovecii pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of sulfamethoxazole/ trimethoprim in non-AIDS patients
• Adverse effects are generally less severe in patients receiving sulfamethoxazole/ trimethoprim for prophylaxis
• A history of mild intolerance to sulfamethoxazole/ trimethoprim in AIDS patients does not appear to predict intolerance of subsequent secondary prophylaxis. However, if a patient develops skin rash or any sign of adverse reaction, therapy with sulfamethoxazole/ trimethoprim should be re-evaluated

Hepatic impairment
Hepatotoxicity

• There is a possibility of severe and sometimes fatal hepatitis with isoniazid
• This typically occurs within the first three months of treatment but can develop late
• Transient elevation of liver enzymes occurs in 10% of patients, overt hepatitis occurs in less than 1% but may be fatal
• There is an increased risk of hepatitis in patients over 50 years, slow acetylators and those who consume alcohol daily
• Liver function tests should be performed every 3 months during treatment and isoniazid discontinued if liver enzymes are raised more than five times the normal upper limit
• Patients who develop malaise, anorexia and nausea together with raised liver enzyme levels should discontinue isoniazid promptly pending investigation

Special warning

• May affect the performance of a child and adult learning in schools and other institutions of education, learning and training

Sulfamethoxazole (SMZ) competitively inhibits the utilisation of para-aminobenzoic acid in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim (TMP) reversibly inhibits bacterial dihydrofolate reductase (DHFR), an enzyme active in the folate metabolic pathway converting dihydrofolate to tetrahydrofolate. Depending on the conditions the effect may be bactericidal. Thus trimethoprim and sulfamethoxazole block two consecutive steps in the biosynthesis of purines and therefore nucleic acids essential to many bacteria. This action produces marked potentiation of activity in vitro between the two agents. 

Isoniazid is bacteriostatic against semi-dormant bacilli and bactericidal against rapidly dividing Mycobacterium. It inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. Isoniazid depletes pyridoxine supplies by binding to pyridoxine. Pyridoxine is required by GABA transaminase and glutamic acid decarboxylase, which both synthesize GABA. Pyridoxine is converted to active forms of Vitamin B6, pyridoxal phosphate and pyridoxamine phosphate. These forms act as coenzymes in reactions of intermediary metabolism. 

Pyridoxine is converted to pyridoxal 5-phosphate in the body. Pyridoxal 5-phosphate is a coenzyme for the synthesis of amino acids, neurotransmitters (serotonin, norepinephrine), sphingolipids and aminolevulinic acid.

Spectrum of activity: Mycobacterium tuberculosis; Pneumocystis jirovecii pneumonia; Toxoplasma gondii 

COMBINATION PREPARATIONS

Sulfamethoxazole/ Trimethoprim/ Isoniazid/ Pyridoxine Hydrochloride

Tablet 800mg/160mg/300mg/25mg

• Cotrizid (Cipla Medpro)