Sonke Efavirenz 200 mg, 600 mg CAPSULE

SONKE EFAVIRENZ 200 capsules are indicated in combination with other antiretroviral medicines for the treatment of HIV - 1 infected adults, adolescents and children, greater than 3 years of age and 13 kg weight. SONKE EFAVIRENZ 600 tablets are indicated in combination with other antiretroviral medicines for the treatment of HIV - 1 infected adults, adolescents and children weighing greater than or equal to 40 kg.

Posology
Adults: The recommended dosage of SONKE EFAVIRENZ in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs) is 600 mg orally, once daily. In order to improve the tolerability of nervous system side effects, bed time dosing is recommended during the first two to four weeks of therapy and in patients who continue to experience these symptoms (see section 4.8).
Concomitant antiretroviral therapy
SONKE EFAVIRENZ must be given in combination with other antiretroviral medicines (see section 4.5).
Adolescents and children (17 years and younger)
The recommended dose of SONKE EFAVIRENZ in combination with a protease inhibitor and/or NRTIs for patients 17 years of age and under is described below. SONKE EFAVIRENZ should only be administered to children who are able to reliably swallow capsules or tablets. SONKE EFAVIRENZ has not been adequately studied in children under the age of 3 years or children weighing less than 13 kg. SONKE EFAVIRENZ must not be used in children less than 3 years of age or less than 13 kg weight.
Paediatric doses to be administered once daily:
Body weight (kg) SONKE EFAVIRENZ dose (mg)
13 to less than 15 200
15 to less than 20 250*
20 to less than 25 300*
25 to less than 32.5 350*
32.5 to less than 40 400
Greater than or equal to 40 600
*The formulation of SONKE EFAVIRENZ is not suitable to provide this dosage
Dose adjustment
If efavirenz is co-administered with voriconazole, the voriconazole maintenance dose must be increased to 400 mg every 12 hours and the efavirenz dose must be reduced by 50 %, i.e. to 300 mg once daily. When treatment with voriconazole is stopped, the initial dose of efavirenz should be restored. If efavirenz is co-administered with rifampicin to patients weighing 50 kg or more, an increase in the dose of efavirenz to 800 mg/day may be considered.
Special populations
Renal impairment
The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1 % of an efavirenz dose is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.
Hepatic impairment
Patients with mild liver disease may be treated with their normally recommended dose of efavirenz. Patients should be monitored carefully for dose-related adverse reactions, especially nervous system symptoms.
Paediatric population
SONKE EFAVIRENZ 600 tablets are not suitable for children weighing less than 40 kg. SONKE EFAVIRENZ 200 capsules are available for these patients.
Method of administration
SONKE EFAVIRENZ may be taken with or without food as desired. A high fat meal may increase the absorption of SONKE EFAVIRENZ and should be avoided.

• Hypersensitivity to efavirenz or to any of the excipients of SONKE EFAVIRENZ.
• Patients with severe hepatic impairment (Child Pugh Class C) (see section 4.4).
• Pregnancy and lactation (see section 4.6).
• Patients with a history of previous liver injury/failure with efavirenz-containing antiretroviral treatment (ART). (see section 4.4).
• SONKE EFAVIRENZ 200 capsules is contraindicated in children less than 3 years or weighing less than 13 kg and adults weighing less than 13 kg. SONKE EFAVIRENZ 600 tablets is contraindicated in adults and children who weigh less than 40 kg.
• SONKE EFAVIRENZ should not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil or ergot derivatives because competition for CYP3A4 by efavirenz could result in inhibition of metabolism of these medicines and create the potential for serious and/or life-threatening adverse events (e.g. cardiac dysrhythmias, prolonged sedation or respiratory depression).

Resistant human immunovirus (HIV) strains emerge rapidly when SONKE EFAVIRENZ is administered as monotherapy, therefore SONKE EFAVIRENZ must not be used as a single medicine to treat HIV or added on as a sole medicine to a failing regimen. The choice of new antiretroviral agent(s) to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance (see section 5.1). Co-administration of efavirenz with the fixed combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate is not recommended unless needed for dose adjustment (for example, with rifampicin). Coadministration of sofosbuvir/velpatasvir with efavirenz is not recommended (see section 4.5). Concomitant administration of velpatasvir/sofosbuvir/voxilaprevir with efavirenz is not recommended (see section 4.5). Coadministration of glecaprevir/pibrentasvir with efavirenz may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect. Coadministration of glecaprevir/pibrentasvir with efavirenz is not recommended (see section 4.5). Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.5). Serious nervous system and psychiatric symptoms have been reported (see Nervous system symptoms). Lipodystrophy and metabolic abnormalities Combination antiretroviral therapy has been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat, enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and elevated serum lipid and glucose levels in HIV patients. Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment. Immune Reconstitution Inflammatory Syndrome Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically, such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, cryptococcal meningitis and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Appropriate treatment of the opportunistic disease should be instituted or continued and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS. Autoimmune disorders (such as Graves' disease) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. Osteonecrosis Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (cART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement. Opportunistic infections Patients receiving SONKE EFAVIRENZ should be advised that they may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by healthcare professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done. The risk of HIV transmission to others Patients should be advised that current antiretroviral therapy, including SONKE EFAVIRENZ, does not prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed. Concomitant use When prescribing medicines concomitantly with SONKE EFAVIRENZ, medical practitioners should refer to the corresponding manufactureru2019s medicine professional information. If any antiretroviral medicine in a combination regimen is interrupted because of suspected intolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviral medicines. The antiretroviral medicines should be restarted at the same time upon resolution of the intolerance symptoms. Intermittent monotherapy and sequential reintroduction of antiretroviral medicines is not advisable because of the increased potential for selection of drug-resistant mutant virus. Skin rash Mild-to-moderate rash has been reported with SONKE EFAVIRENZ use and usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. SONKE EFAVIRENZ should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. If therapy with SONKE EFAVIRENZ is discontinued, consideration should also be given to interrupting therapy with other antiretroviral medicines to avoid development of drug resistant virus (see section 4.8). Severe rash associated with blistering, moist desquamation or ulceration has been reported in less than 1 % of patients treated with efavirenz. The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0,1 %. Experience with efavirenz in patients who discontinued other antiretroviral medicines of the NNRTI class is limited (see section 4.8). SONKE EFAVIRENZ is not recommended for patients who have had a life-threatening cutaneous reaction (e.g. Stevens-Johnson syndrome) while taking another NNRTI. Prophylaxis with appropriate antihistamines prior to initiating therapy with SONKE EFAVIRENZ in children may be considered. Nervous system symptoms Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming are frequently reported adverse reactions in patients receiving efavirenz 600 mg daily in clinical studies (see section 4.8). Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2 u2013 4 weeks. Patients should be informed that if they do occur, these common symptoms are likely to improve with continued therapy and are not predictive of subsequent onset of any of the less frequent psychiatric symptoms. Psychiatric symptoms Psychiatric adverse reactions have been reported in patients treated with efavirenz. Patients with a prior history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse reactions. In particular, severe depression was more common in those with a history of depression. There have also been post-marketing reports of severe depression, death by suicide, delusions and psychosis-like behaviour and catatonia. Patients should be advised that if they experience symptoms such as severe depression, psychosis or suicidal ideation, they should contact their doctor immediately to assess the possibility that the symptoms may be related to the use of SONKE EFAVIRENZ, and if so, to determine whether the risks of continued therapy outweigh the benefits (see section 4.8). Seizures Convulsions have been observed in adult and paediatric patients receiving efavirenz, generally in the presence of known medical history of seizures. Patients who are receiving concomitant anticonvulsant medicines primarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, may require periodic monitoring of plasma levels. In a drug interaction study, carbamazepine plasma concentrations were decreased when carbamazepine was co-administered with efavirenz (see section 4.5). Caution must be taken in any patient with a history of seizures. Effect of food The administration of efavirenz with food may increase efavirenz exposure (see section 5.2) and may lead to an increase in the frequency of adverse reactions (see section 4.8). It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime.

SONKE EFAVIRENZ is an in vivo inducer of CYP3A4, CYP2B6 and UGT1A1. Other medicines that are substrates of CYP3A4 may have decreased plasma concentrations when co-administered with SONKE EFAVIRENZ. In vitro efavirenz is also an inhibitor of CYP3A4. Theoretically, efavirenz may therefore initially increase the exposure to CYP3A4 substrates and caution is warranted for CYP3A4 substrates with narrow therapeutic index (see section 4.3). Efavirenz may be an inducer of CYP2C19 and CYP2C9; however, inhibition has also been observed in vitro and the net effect of co-administration with substrates of these enzymes is not clear (see section 5.2). Efavirenz exposure may be increased when given with medicinal products (for example, ritonavir) or food (for example, grapefruit juice) which inhibit CYP3A4 or CYP2B6 activity. Compounds or herbal preparations (for example Ginkgo biloba extracts and St. John's wort) which induce these enzymes may give rise to decreased plasma concentrations of efavirenz. Concomitant use of St. John's wort is contraindicated (see section 4.3). Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.4). Co-administration of efavirenz with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of efavirenz with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and efavirenz are administered concurrently; clinical response and/or drug levels should be monitored as appropriate. QT Prolonging Drugs Efavirenz is contraindicated with concomitant use of medicines (they may cause prolonged QTc interval and Torsade de Pointes) such as: antiarrhythmics of classes IA and III, neuroleptics and antidepressant agents, certain antibiotics including some medicines of the following classes: macrolides, fluoroquinolones, imidazole, and triazole antifungal medicines, certain non-sedating antihistaminics (terfenadine, astemizole), cisapride, flecainide, certain antimalarials and methadone (see section 4.3). Contraindications of concomitant use Efavirenz must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine), since inhibition of their metabolism may lead to serious, life-threatening events (see section 4.3). Elbasvir/grazoprevir Concomitant administration of efavirenz with elbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir. This loss is due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by CYP3A4 induction. (see section 4.3). St. Johnu2019s Wort (Hypericum perforatum) Patients on SONKE EFAVIRENZ should not concomitantly use medicines containing St. Johnu2019s Wort (Hypericum perforatum) since it may be expected to result in reduced plasma concentrations of SONKE EFAVIRENZ. This effect is due to an induction of CYP3A4 and may result in loss of therapeutic effect and development of resistance.

Women of childbearing potential should always be used in combination with other methods of contraception (e.g. oral or other hormonal contraceptives) (see section 4.5). Women of childbearing potential should undergo pregnancy testing prior to initiation of SONKE EFAVIRENZ (see section 4.3). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of efavirenz is recommended.
Pregnancy
SONKE EFAVIRENZ should not be used during pregnancy as teratogenicity has been reported. Malformations have been observed in foetuses from efavirenz-treated monkeys that received doses, which resulted in plasma concentrations similar to those in humans given 600 mg/day; therefore, pregnancy should be avoided in women receiving SONKE EFAVIRENZ. Foetal neural tube defects There have been seven retrospective reports of findings consistent with neural tube defects, including meningomyelocele, all in mothers exposed to efavirenz-containing regimens (excluding any efavirenz-containing fixed-dose combination tablets) in the first trimester. Two additional cases (1 prospective and 1 retrospective) including events consistent with neural tube defects have been reported with the fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate. A causal relationship of these events to the use of efavirenz has not been established, and the denominator is unknown. As neural tube defects occur within the first 4 weeks of foetal development (at which time neural tubes are sealed), this potential risk would concern women exposed to efavirenz during the first trimester of pregnancy.
Breastfeeding
Since animal data suggest that the substance may be passed into breast milk, mothers taking SONKE EFAVIRENZ should not breastfeed their infants (see section 4.3). It is recommended that HIV-infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV.

SONKE EFAVIRENZ 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 list of adverse reactions
MedDRA system organ class Frequency Adverse reactions
Immune system disorders Less frequent Hypersensitivity
Frequency unknown Immuno-allergic liver injury/failure
Metabolism and nutrition disorders Frequent Hypertriglyceridaemia. Less frequent Hypercholesterolaemia. Frequency unknown Weight gain and weight loss.
Psychiatric disorders Frequent Aggravated depression, emotional lability, euphoria, hallucination. Less frequent Mania, paranoia, psychosis, suicide attempt, suicide ideation, delusion, neurosis, completed suicide.
Nervous system disorders Frequent Dizziness, impaired concentration, headache, somnolence, insomnia. Less frequent Abnormal dreams, anorexia, hypoesthesia, abnormal coordination, ataxia, convulsions, paraesthesia, neuropathy, tremors, agitation, amnesia, anxiety, apathy, increased appetite, confusion, impaired coordination, impotence, decreased libido, increased libido, neuralgia, peripheral neuropathy, speech disorder, vertigo.
Eye disorders Less frequent Blurred vision.
Ear and labyrinth disorders Less frequent Tinnitus.
Cardiac disorders Less frequent Flushing, palpitations, tachycardia.
Respiratory, thoracic and mediastinal disorders Less frequent Asthma. Frequency unknown Sinusitis, dyspnoea, upper respiratory tract infections.
Gastrointestinal disorders Frequent Nausea, vomiting, diarrhoea. Less frequent Dyspepsia, abdominal pain, pancreatitis. Frequency unknown Gastritis, gastroenteritis, gastroesophageal reflux, constipation, malabsorption.
Hepatobiliary disorders Less frequent Hepatitis, hepatic enzyme increase. Frequency unknown Hepatic failure.
Skin and subcutaneous tissue disorders Frequent Rash, pruritus, increased sweating. Less frequent Eczema, skin exfoliation, alopecia, erythema multiforme, Stevens-Johnson Syndrome, urticaria, folliculitis. Frequency unknown Acne, seborrhoea, nail disorders, skin discolouration.
Musculoskeletal and connective tissue disorders Less frequent Arthralgia, myalgia. Frequency unknown Myopathy.
Reproductive system and breast disorders Less frequent Gynaecomastia.
General disorders and administration site conditions Frequent Fatigue, allergic reaction, asthenia. Less frequent Taste perversion, malaise, syncope. Frequency unknown Alcohol intolerance, hot flushes, influenza-like symptoms, pain, redistribution/accumulation of body fat.
Investigations
Laboratory abnormalities Raised liver enzyme values have occurred, particularly in patients with viral hepatitis Raised serum - cholesterol and triglyceride concentrations have been reported. Liver enzymes Elevations of AST and ALT to greater than five times the upper limit of the normal range were seen in 3 % of patients treated with 600 mg of SONKE EFAVIRENZ. Lipids Increases in total cholesterol of 10 to 20 % have been observed in some uninfected volunteers receiving SONKE EFAVIRENZ. Increases in non-fasting total cholesterol and HDL of approximately 20 % and 25 %, respectively, were observed in patients treated with efavirenz+SDV+3TC and of approximately 40 % and 35 % in patients treated with SONKE EFAVIRENZ + IDV. The effects of SONKE EFAVIRENZ on triglycerides and LDL were not well characterized. The clinical significance of these findings is unknown (see section 4.4).

In overdose, side effects will be exacerbated and exaggerated (see section 4.8). Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms and involuntary muscle contractions. Treatment of overdose with SONKE EFAVIRENZ should consist of general supportive measures, including monitoring of vital signs and observation of the patientu2019s clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with SONKE EFAVIRENZ. Since SONKE EFAVIRENZ is highly protein bound, dialysis is unlikely to significantly remove the drug from the blood. Treatment is symptomatic and supportive.