Solonex- Co 300mg Tablet

SOLONEX CO is indicated for the prevention of active tuberculosis in adults and children 2 years of age and older presenting with:

• (1) latent tuberculosis infection (LTBI) caused by Mycobacterium tuberculosis who are at high risk of progression to tuberculosis disease (including those in close contact with active tuberculosis patients, recent conversion to a positive tuberculin skin test),
• (2) HIV-infected patients not receiving antiretroviral therapy (ART),
• (30 Patients with pulmonary fibrosis on radiograph with no signs and symptoms of TB regardless of HIV status. Active tuberculosis disease should be ruled out before initiating treatment with SOLONEX CO.

Posology

SOLONEX CO should be administered once-weekly for 12 weeks as directly observed therapy (DOT).

Adults and children 12 years and older: The recommended dose of rifapentine should be determined based on weight of the patient up to a maximum of 900 mg once weekly (see Table 1). The recommended dose of isoniazid is 15 mg/kg (rounded to the nearest 50 mg or 100 mg) up to a maximum of 900 mg once weekly for 12 weeks.

Children 2 u2013 11 years: The recommended dose of SOLONEX CO should be determined based on weight of the patient up to a maximum of 900 mg once-weekly (see Table 1). The recommended dose of isoniazid is 25 mg/kg (rounded to the nearest 50 mg or 100 mg) up to a maximum of 900 mg once-weekly for 12 weeks.

Table 1: Weight Based Dose of SOLONEX CO in the prophylactic treatment of latent Tuberculosis Infection in adults and children 2 years and older at high risk of progression to tuberculosis disease.

Weight range Rifapentine dose Isoniazid dose Number of SOLONEX CO tablets once a week for 12 weeks

• 10 u2013 14 kg 300 mg 300 mg 1
• 14,1 u2013 25 kg 450 mg 450 mg 1u00bd
• 25,1 u2013 32 kg 600 mg 600 mg 2
• 32,1 u2013 50 kg 750 mg 750 mg 2u00bd
• > 50 kg 900 mg 900 mg 3

Special populations

Paediatric patients: The youngest patient included in the clinical efficacy trial was 2 years. No data are available for patients below 2 years old.

Elderly patients (65 years of age and older): No dosage adjustment is required in the elderly, but caution should be exercised due to the possible decrease in renal and hepatic function.

Hepatic impairment: No dosage adjustment is required, however, the half-life of isoniazid may be prolonged in the presence of hepatic insufficiency. SOLONEX CO should be used with caution in patients with mild to moderate hepatic impairment. (see sections 4.3 and 4.4).

Renal impairment: No dosage adjustment is required when given to patients with mild renal failure. However, SOLONEX CO is contraindicated in patients with severe renal failure (glomerular filtration rate of less than 10 mL/minute (creatinine clearance < 30 mL/min) (See Section 4.3 and 4.4).

Method of administration

For oral use. Patients should be informed that adherence to the treatment regimen for SOLONEX CO and other substances is essential for effective treatment, and the importance of not missing any doses must be stressed. SOLONEX CO should be given with food. For patients who cannot swallow tablets, the tablets may be crushed and added to a small amount of semi-solid food, all of which should be consumed immediately (see section 5.2). Interactions with antacids have not been studied. However, in the clinical efficacy study, patients were advised to take SOLONEX CO at least 1 hour before or 2 hours after the ingestion of antacids.

SOLONEX CO is contraindicated:

• u2022 in patients with known hypersensitivity to isoniazid and rifapentine or any of the excipients listed in section 6.1.
• u2022 Hypersensitivity to ethionamide, pyrazinamide, niacin, or other chemically related compounds or to any of the excipients (see Section 6.1).
• u2022 In patients with porphyria.
• u2022 In patients with acute or chronic liver disease.
• u2022 Severe renal failure
• u2022 Alcoholism
• u2022 Seizure disorders
• u2022 Pregnancy and lactation
• u2022 HIV-infected patients on antiretroviral therapy because of potential interactions leading to loss of efficacy with protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) (See Section 4.5)

Active tuberculosis should be ruled out before initiating treatment for latent tuberculosis infection.

Hepatotoxicity

SOLONEX CO may cause serious hepatic disease/injury. Patients with abnormal liver tests and/or liver disease should only be given SOLONEX CO if no safer alternative is available, and then with caution and under strict medical supervision (see section 4.3). In such patients, careful monitoring of liver function parameters (especially serum transaminases and bilirubin) should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If there are indications of a liver reaction or of the hepatic condition worsening, SOLONEX CO should be discontinued.

Hypersensitivity and related reactions

Hypersensitivity reactions may occur in patients receiving SOLONEX CO. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations) (see section 4.8). Monitor patients receiving SOLONEX CO therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue SOLONEX CO.

Medicine interactions

Rifapentine, one of the components of SOLONEX CO is an inducer of CYP3A4 and CYP2C8/9. Concomitant use of SOLONEX CO with other medicines metabolised by any of these enzymes, such as protease inhibitors, non-nuclease-reverse transcriptase inhibitors (Efavirenz: CYP3A4 inducer and inhibitor), and hormonal contraceptives may cause a significant decrease in plasma concentrations and loss of therapeutic effect of these medicines (see sections 4.5 and 5.2). SOLONEX CO has also been shown to inhibit and to induce P-gp which could modify plasma exposure of digoxin (a P-gp substrate with narrow therapeutic index). Appropriate monitoring and dose adjustment of digoxin may be necessary in case of co-administration with rifapentine as contained in SOLONEX CO (see sections 4.5 and 5.2).

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported in association with the use of SOLONEX CO treatment regimen. Patients should be informed about the signs and symptoms of serious skin manifestations. Treatment should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Clostridium difficile -associated diarrhoea

Pseudomembranous colitis has been reported to occur with rifamycins such as in SOLONEX CO. Diarrhoea, particularly if severe and/or persistent, occurring during treatment or in the initial weeks following treatment may be symptomatic of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, SOLONEX CO should be stopped immediately and the patient treated appropriately without delay. Medicines inhibiting the peristalsis are contraindicated in this clinical situation.

Discolouration of body fluids

SOLONEX CO may produce a predominantly red-orange discolouration of body tissues and/or fluids (e.g. skin, teeth, tongue, urine, faeces, saliva, sputum, tears, sweat and cerebrospinal fluid). Contact lenses or dentures may become permanently stained. The administration of 10 mg pyridoxine daily is recommended to prevent or minimise symptoms of peripheral neuritis, as well as for those who are diabetic, alcoholic, malnourished or uraemic, infected with HIV (currently not on antiretroviral therapy). SOLONEX CO should be given with caution in patients suffering from convulsive disorders and diabetes mellitus and patients with a history of psychosis.

SOLONEX CO should be used with caution in patients with mild to moderate hepatic or renal impairment (see section 4.2) or patients taking other potentially hepatotoxic medicines. If symptoms of hepatitis deteriorate in these patients, SOLONEX CO should be discontinued immediately. Periodic eye examination during treatment is recommended.

Effect of SOLONEX CO on other medicines

- Effect on medicines metabolised by CYP3A4 and CYP2C8/9

Rifapentine as contained in SOLONEX CO is an inducer of CYP3A4 and CYP2C8/9. Therefore, SOLONEX CO may increase the metabolism of other co-administered medicines that are metabolised by these enzymes. Appropriate monitoring and dosage adjustment may be necessary if medicines metabolised by CYP3A4 or CYP2C8/9 are co-administered with SOLONEX CO. Induction of enzyme activities by SOLONEX CO occurred after the first dose of SOLONEX CO. Enzyme activities returned to baseline levels, in general, 14 days after discontinuing SOLONEX CO. Examples of such substances include:

• - Antiretroviral medicines:
• u2022 Protease inhibitors: indinavir, darunavir, lopinavir, saquinavir, ritonavir
• u2022 Non-nucleoside reverse transcriptase inhibitors: rilpivirine, efavirenz
• u2022 Nucleoside reverse transcriptase inhibitor: zidovudine
• - Antifungals: itraconazole, ketoconazole, voriconazole
• - Narcotic analgesics: methadone, alfentanil, buprenorphine
• - Hypoglycaemic medicines: repaglinide
• - Calcium channel blockers: felodipine, diltiazem, verapamil, nifedipine
• - Alpha/Beta adrenergic antagonists: alfuzosin, propranolol
• - Ergot alkaloid derivatives: ergotamine
• - Oral anti-vitamin K anticoagulant: warfarin
• - Hormonal contraceptives: oral, transdermal and implant
• - Immunosuppressants: ciclosporin, tacrolimus, sirolimus
• - Benzodiazepines: midazolam.

Inhibition of CYP450

Isoniazid, as in SOLONEX CO can inhibit the hepatic metabolism of a number of medicines, in some cases leading to increased toxicity. These include the antiepileptics carbamazepine, primidone, and phenytoin, the benzodiazepines diazepam and triazolam, and others such as warfarin and theophylline. Concomitant administration of benzodiazepines (diazepam/carbamazepine) and isoniazid, as in SOLONEX CO therapy, has been reported to result in benzodiazepine toxicity (sedation, respiratory depression, etc.). Concurrent administration of SOLONEX CO and rifampicin may lead to a higher risk of hepatotoxicity, while increased central nervous system adverse effects have occurred when SOLONEX CO is given with potentially neurotoxic medicines such as cycloserine or disulfiram. Hepatotoxic reactions have been reported when paracetamol is given concurrently with SOLONEX CO, while chronic alcoholism increases the risk of isoniazid induced hepatitis. When isoniazid, as in SOLONEX CO is given to patients receiving paraminosalicyclic acid concurrently, the plasma concentrations of isoniazid may be increased, and adverse effects are more likely to occur. Prednisolone may increase hepatic metabolism and/or excretion of SOLONEX CO. Aluminium-containing antacids may delay and decrease absorption and serum concentrations of isoniazid. It is therefore recommended that SOLONEX CO be administered at least 1 hour before taking antacids (see section 4.2). Isoniazid, as in SOLONEX CO may reduce the therapeutic effects of levodopa. Concomitant administration of isoniazid, as in SOLONEX CO with itraconazole or ketoconazole may result in significant decreases in either medicineu2019s serum concentrations, and thus therapeutic failure. Concurrent use should be well monitored, and dosage increases made if necessary. Because the clearance of isoniazid, as in SOLONEX CO was found to be doubled when zalcitabine was given in HIV-positive patients, concurrent use of isoniazid and zalcitabine should be monitored to ensure isoniazid effectiveness.

- Effect of SOLONEX CO on transporter substrates

In vitro, SOLONEX CO has been shown to inhibit and to induce P-gp which could modify plasma exposure of digoxin (P-gp substrate) (see section 5.2). Because of the narrow therapeutic index of digoxin, appropriate monitoring and dose adjustment of digoxin may be necessary in case of co-administration with SOLONEX CO.

- Effect of SOLONEX CO on antiretroviral medicines

- Protease inhibitors and non-nucleoside reverse transcriptase inhibitors

Concomitant use of rifapentine with protease inhibitors and non-nucleoside reverse transcriptase inhibitors, metabolised by CYP3A4 or CYP2C8/9, may cause a significant decrease in plasma concentrations and loss of therapeutic effect of these medicines. Concomitant use of SOLONEX CO with protease inhibitors and non-nucleoside reverse transcriptase inhibitors is contraindicated.

- Hormonal contraceptives

SOLONEX CO may reduce the effectiveness of hormonal contraceptives. Women taking oral contraception, using a transdermal patch, or other systemic hormonal contraceptives who need SOLONEX CO therapy should discuss the use of an additional non-hormonal means of contraception or the change of their contraceptive pill with their medical practitioner.

Effect of other medicines on SOLONEX CO

Potential interaction with CYP450 inducer/inhibitor medicines, as well as with transporters inhibitor/inducer medicines are not expected (see section 5.2). Since SOLONEX CO is highly bound to albumin, medicine displacement interactions with non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas and oral anticoagulants may also occur. Adverse reactions have occurred when SOLONEX CO has been given with anti-epileptics such as phenytoin, primidone, carbamazepine, and ethosuximide, with benzodiazepines, such as diazepam or triazolam, and with warfarin.

Interferences with laboratory and diagnostic tests

Therapeutic concentrations of rifampin have been shown to inhibit standard microbiological assays for serum folate and vitamin B12. Similar interferences should be considered for SOLONEX CO. Therefore, alternative assay methods should be considered.

Food interactions: Palpitations, headache, conjunctival irritation, severe flushing, tachycardia, tachypnoea, sweating and itching on the skin have been reported following ingestion of cheese, red wine, and some fish.

Pregnancy

Safety during pregnancy has not been established. SOLONEX CO is not recommended during pregnancy. Human data: Rifampicin is known to cause postnatal haemorrhages in the mother and infant when taken during the last few weeks of pregnancy. Since SOLONEX CO might have a similar effect, appropriate coagulation testing should be performed when pregnant women are inadvertently exposed to SOLONEX CO during late pregnancy. Treatment with vitamin K may be indicated.

Breastfeeding

Mothers on treatment with SOLONEX CO should not breastfeed their babies. It is not known whether SOLONEX CO is excreted in human milk. SOLONEX CO may produce a red-orange discolouration of body fluids, including breast milk.

Fertility

No data on the effect of SOLONEX CO on fertility is available.

SOLONEX CO may cause dizziness, impaired concentration, and/or drowsiness. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

Tabulated summary of adverse reactions

Rifapentine:

System organ class Frequent Less frequent Frequency unknown

Infections and infestations - Influenza pneumonia

Immune system disorders Hypersensitivity - -

Nervous system disorders - Headache -

Gastrointestinal disorders - Nausea, Upper abdominal pain Pancreatitis, oesophageal irritation

Hepatobiliary disorders - Hepatitis -

Skin and subcutaneous tissue disorders - Skin reaction Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome (see section 4.4)

Musculoskeletal and connective tissue disorders - Myalgia -

General disorders and administration site conditions - Influenza-like illness, fatigue, chills, pyrexia, asthenia -

Isoniazid:

Blood and lymphatic system disorders: - Haematological effects (various anaemias, agranulocytosis, thrombocytopenia and eosinophilia).

Immune system disorders: - Hypersensitivity reactions (fever, skin rashes, joint pain).

Metabolism and nutrition disorders: - Hyperglycaemia, metabolic acidosis.

Psychiatric disorders: - Neurotoxicity (psychotic reactions)

Nervous system disorders: Peripheral neuritis. Convulsions, hyperreflexia

Eye disorders: - Optic neuritis

Ear and labyrinth disorders: - Vertigo

Gastrointestinal disorders: Nausea, vomiting, constipation, dry mouth, gastrointestinal irritation.

Hepato-biliary disorders: Hepatitis, hepatitis prodromal symptoms (loss of appetite, nausea or vomiting, unusual tiredness or weakness), transient increases in liver enzymes.

Skin and subcutaneous tissue Skin reactions such as purpura, acneform syndrome, lupus erythematosus-like syndrome, exfoliative dermatitis, pellagra, alopecia, urticaria.

Musculoskeletal and connective tissue disorders: - - Rheumatoid syndrome

Renal and urinary disorders: - Urinary retention.

Reproductive system and breast disorders: - Gynaecomastia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

An overdose may precipitate side effects and increase the severity thereof. Symptoms of overdose u2013 include slurred speech, metabolic acidosis, hyperglycaemia, hallucinations, respiratory and CNS depression, convulsions and coma.

Treatment consists of gastric lavage following intubation (if the patient is in a coma and seen within one hour after overdose) symptomatic and supportive therapy. This includes use of large doses of pyridoxine (1:1) and anti-convulsants given intravenously u2013 to prevent and/or control convulsions, and sodium bicarbonate for metabolic acidosis. Instillation of activated charcoal slurry via naso-gastric tube into the stomach, may help adsorb any remaining medicine from the gastrointestinal tract. Forced diuresis and haemodialysis or peritoneal dialysis has been used in case isoniazid (as contained) in SOLONEX CO have been used.