Efamat 50 mg, 100 mg, 200 mg FC tablet

EFAMAT, in combination with other antiretroviral medicines, is indicated for the treatment of HIV-1 infected adults, adolescents and children greater than 3 years of age and 13 kg in weight.

Posology
The therapy should be initiated by a doctor experienced in the management of HIV infection.
Dosage:
Adults: The recommended dosage of EFAMAT 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, bedtime 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: EFAMAT must be given in combination with other antiretroviral medications (see section 4.5).
Special populations
Adolescents and children (17 years and under):
u2022 The recommended dosage of EFAMAT in combination with a protease inhibitor, and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs) for patients 17 years of age and under is described in Table 1.
u2022 EFAMAT should only be administered to children who are able to reliably swallow tablets.
u2022 EFAMAT has not been studied in children under the age of 3 years or children weighing less than 13 kg. EFAMAT must not be used in children less than 3 years of age or less than 13 kg in weight.
Table 1 Paediatric Dose to be Administered Once Daily
Body Weight (kg)
EFAMAT 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
Method of administration
For oral use. EFAMAT should be taken on an empty stomach, preferably at bedtime (see section 4.4).

• EFAMAT is contraindicated in patients with hypersensitivity to efavirenz or any of the excipients of EFAMAT.
• EFAMAT should not be administered concurrently with cisapride, midazolam, triazolam 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).
• Pregnancy and lactation (see section 4.6).
• A history of previous liver injury/ failure with efavirenz containing antiretroviral treatment (ART).
• Patients with severe hepatic impairment (Child Pugh Grade C) (see section 5.2).
• Co-administration with elbasvir (EBR) and grazoprevir (GZR) due to the potential for significant decreases in plasma concentrations of EBR and GZR (see section 4.5).
• Herbal preparations containing St. John's wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz (see section 4.5).
• Patients with:
• a family history of sudden death or of congenital prolongation of the QTc interval on electrocardiograms, or with any other clinical condition known to prolong the QTc interval.
• a history of symptomatic cardiac dysrhythmia or with clinically relevant bradycardia or with congestive cardiac failure accompanied by reduced left ventricle ejection fraction.
• severe disturbances of electrolyte balance e.g. hypokalemia or hypomagnesemia.
• Patients taking medicines that are known to prolong the QTc interval (proarrythmic dysrhythmic). These medicines include:
• dysrhythmia of classes IA and III,
• neuroleptics, antidepressant medicines,
• certain antibiotics including some medicines of the following classes: macrolides, fluoroquinolones, imidazole and triazole antifungal medicines,
• certain non-sedating antihistamines (terfenadine),
• cisapride,
• flecainide,
• certain antimalarials,
• methadone.

Resistant human immuno-virus (HIV) strains emerge rapidly when EFAMAT is administered as monotherapy, therefore, EFAMAT must not be used as a single medicine to treat HIV or added on as a sole medicine to a failing regimen. When prescribing other medicines concomitantly with EFAMAT, doctors should refer to the corresponding manufactureru2019s medicine package insert. If any antiretroviral medication in a combination regimen is interrupted because of e.g suspected intolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviral medications. The antiretroviral medications 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 medicine-resistant mutant viruses. Co-administration of efavirenz as contained in EFAMAT with the fixed combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil 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 EFAMAT 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). While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken. Skin Rash: Mild-to-moderate rash has been reported with EFAMAT use and usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. EFAMAT should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. If therapy with EFAMAT is discontinued, consideration should also be given to interrupt therapy with other antiretroviral medicines to avoid development of resistant viruses (see section 4.8). Prophylaxis with appropriate antihistamines prior to initiating therapy with EFAMAT in children may be considered. EFAMAT is not recommended for patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome) while taking another NNRTI.
Psychiatric symptoms: Psychiatric adverse reactions have been reported in patients treated with EFAMAT. Patients with a 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, 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 EFAMAT, and if so, to determine whether the risks of continued therapy outweigh the benefits (see section 4.8).
Nervous System Symptoms: Nervous system symptoms have been reported with EFAMAT use (see section 4.8). In addition, there have been reports of inappropriate behaviour (including aggressive reactions), predominantly in patients with a history of mental illness or substance abuse.
Seizures: Convulsions have been observed in adult and paediatric patients receiving EFAMAT, 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 medicine interaction study, carbamazepine plasma concentrations were decreased when carbamazepine was coadministered with efavirenz as contained in EFAMAT (see section 4.5). Caution must be taken in any patient with a history of seizures.

EFAMAT is an inducer of CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when co-administered with EFAMAT. EFAMAT exposure may be increased when given with medicines (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 EFAMAT. 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).
QT Prolonging Medicines: EFAMAT is contraindicated with concomitant use of medicines (they may cause prolonged QTc interval and Torsade de Pointes) such as: antidysrhythmic of classes IA and III, neuroleptics and antidepressant medicines, certain antibiotics including some medicines of the following classes: macrolides, fluoroquinolones, imidazole, and triazole antifungal medicines, certain non-sedating antihistaminics (terfenadine), cisapride, flecainide, certain antimalarials and methadone (see section 4.3).
Saquinavir: When saquinavir (1,200 mg given 3 times a day, soft capsule formulation) was given with efavirenz the saquinavir AUC and C max were decreased by 62 % and 50 % respectively. Use of EFAMAT in combination with saquinavir as the sole protease inhibitor is not recommended.
Oral contraceptives: Only the ethinyl oestradiol component of oral contraceptives has been studied. The AUC following a single dose of ethinyl oestradiol was increased (37 %) after multiple dosing of efavirenz. No significant changes were observed in Cmax of ethinyl oestradiol. The clinical significance of these effects is not known. No effect of a single dose of ethinyl oestradiol on efavirenz Cmax or AUC was observed. Because the potential interaction of EFAMAT with oral contraceptives has not been fully characterised, a reliable method of barrier contraception must be used in addition to oral contraceptives (see section 4.6).
Contraindications of concomitant use: EFAMAT must not be administered concurrently with terfenadine, 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 EFAMAT 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 EFAMAT should not concomitantly use products containing St. Johnu2019s Wort (Hypericum perforatum) since it may be expected to result in reduced plasma concentrations of EFAMAT. This effect is due to an induction of CYP3A4 and may result in loss of therapeutic effect and development of resistance.
Metamizole: Co-administration of EFAMAT with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of EFAMAT with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and EFAMAT are administered concurrently; clinical response and/or medicine levels should be monitored as appropriate.
Cannabinoid Test interaction: Efavirenz does not bind to cannabinoid receptors. False positive urine cannabinoid test results have been reported in uninfected volunteers who received EFAMAT. False positive test results have only been observed with the CEDIA DAU Multi-Level THC assay, which is used for screening, and have not been observed with other cannabinoid assays tested including tests used for confirmation of positive results.

Women of childbearing potential/ Contraception in males and females
Women of childbearing potential should undergo pregnancy testing prior to initiation of EFAMAT (see section 4.3). Barrier contraception should always be used in combination with other methods of contraception (oral or other hormonal contraceptives e.g. injectable or implant contraception). (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
The use of EFAMAT during pregnancy is contraindicated as teratogenicity has been noted. 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 EFAMAT.
Breastfeeding
The safety in lactation has not been established. Since animal data suggest that the substance may be passed into breast milk, it is recommended that mothers taking EFAMAT do not breastfeed their infants.

EFAMAT 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.

a. Summary of the safety profile
The most frequently reported adverse reactions of EFAMAT of at least moderate severity reported were rashes, dizziness, nausea, headaches and fatigue. The most notable adverse reactions associated with EFAMAT are rashes and nervous system symptoms. Nervous system symptoms usually begin soon after therapy onset and generally resolve after the first 2 - 4 weeks. Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; psychiatric adverse reactions including severe depression, death by suicide, and psychosis like behaviour; and seizures have been reported in patients treated with EFAMAT. The administration of EFAMAT with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (see section 4.4).
Tabulated list of adverse reactions
Body System Undesirable effect
Frequent Less frequent Frequency not known
Immune system disorders: allergic reaction, erythema multiforme, Stevens-Johnson syndrome immuno-allergic reaction liver injury/failure
Endocrine disorders: pancreatitis
Metabolism and nutrition disorders: Hypertriglyceridaemia anorexia hypercholesterolaemia increased appetite; redistribution/accumulation of body fat; weight gain and weight loss
Psychiatric disorders: insomnia abnormal dreams, anxiety, depression abnormal thinking; agitation; aggravated depression; amnesia; anxiety; apathy; confusion; delirium; emotional lability; euphoria; hallucinations; psychosis; stupor; mania; suicide attempt; suicide ideation; catatonia 2 neurosis; paranoid reactions; completed suicide
Nervous system disorders: dizziness; fatigue; headache; impaired concentration; somnolence ataxia; convulsions; impaired coordination; malaise; neuralgia; peripheral neuropathy abnormal coordination; hypo-aesthesia; neuropathy and pain; paraesthesia; speech disorder; tremor
Eye disorders: abnormal vision
Ear and labyrinth disorders: tinnitus, vertigo
Cardiac disorders: palpitations and tachycardia
Vascular disorders: flushing hot flushes
Respiratory, thoracic and mediastinal disorders: asthma dyspnoea; sinusitis; upper respiratory tract infections
Gastrointestinal disorders: nausea; vomiting; taste perversion abdominal pain and gastroesophageal reflux constipation; diarrhoea; dyspepsia; gastritis; gastroenteritis; malabsorption pancreatitis 2
Hepato-biliary disorders: aspartate amino transferase (AST) increased, alanine aminotransferase (ALT) increased, gammaglutamyltransferase (GGT) increased hepatitis and hepatic enzyme increase hepatic failure
Skin and subcutaneous tissue disorders: pruritus; rash alopecia; eczema; folliculitis; skin exfoliation and urticarial; Stevens-Johnson syndrome 2 acne; increased sweating; nail disorders; seborrhoea; skin discolouration
Musculoskeletal, connective tissue and bone disorders: arthralgia and myalgia Myopathy, osteonecrosis
Reproductive system and breast disorders: gynaecomastia 2 decreased libido; increased libido; impotence
Congenital and familial/genetic disorders: General disorders and administrative site conditions: fatigue asthenia alcohol intolerance; influenza-like symptoms
Description of selected adverse reactions
Rashes are usually mild to moderate maculopapular skin eruptions that occur within the first two weeks of initiating therapy with EFAMAT. In most patients, rash resolves with continuing therapy with EFAMAT within one month. EFAMAT can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when EFAMAT is restarted. Experience with EFAMAT in patients who discontinued other antiretroviral medicines of the NNRTI class is limited. Reported rates of recurrent rash following a switch from nevirapine to efavirenz therapy, primarily based on retrospective cohort data from published literature, range from 13 to 18 %.
Psychiatric symptoms: Serious psychiatric adverse reactions have been reported in patients treated with EFAMAT. Specific serious psychiatric events: - severe depression - suicidal ideation - non-fatal suicide attempts - aggressive behaviour - paranoid reactions - manic reactions Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse reactions with frequencies ranging from 0.3 % for manic reactions to 2.0 % for both severe depression and suicidal ideation. There have also been post-marketing reports of death by suicide, delusions, psychosis-like behaviour and catatonia.
Nervous system symptoms: in clinical controlled trials, frequently reported adverse reactions included, but were not limited to dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming. Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2 - 4 weeks. In a study of uninfected volunteers, a representative nervous system symptom had a median time to onset of 1 hour post-dose and a median duration of 3 hours. Nervous system symptoms may occur more frequently when efavirenz is taken concomitantly with meals possibly due to increased efavirenz plasma levels (see section 5.2). Dosing at bedtime seems to improve the tolerability of these symptoms and can be recommended during the first weeks of therapy and in patients who continue to experience these symptoms (see section 4.2). Dose reduction or splitting the daily dose has not been shown to provide benefits.
Laboratory abnormalities: Liver enzymes: Raised liver enzyme values have occurred, particularly in patients with viral hepatitis. Raised serum-cholesterol and triglyceride concentrations have been reported. Elevations of AST and ALT were seen in patients treated with 600 mg of EFAMAT. Elevations of GGT to greater than 5 times the upper limit of the normal range were observed in patients treated with 600 mg EFAMAT and in a greater percentage in patients seropositive for Hepatitis B or C. Lipids: An increase in total cholesterol of 10 to 20 % has been observed in uninfected volunteers receiving 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 efavirenz+IDV. The effects of efavirenz on triglycerides and LDL were not well-characterised. The clinical significance of these findings is unknown (see section 4.4).
Metabolic parameters: Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).
Paediatric population: Undesirable effects in children were generally similar to those of adult patients. Rash was reported more frequently in children treated with EFAMAT and was more often of higher grade than in adults. Prophylaxis with appropriate antihistamines prior to initiating therapy with EFAMAT in children may be considered.
Other special populations: Liver enzymes in hepatitis B or C co-infected patients: Patients treated with efavirenz-containing regimens, as contained in EFAMAT, were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive).
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

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8). Some patients who have accidentally taken 600 mg twice daily have reported increased nervous system symptoms and involuntary muscle contractions. Administration of activated charcoal may be used to aid removal of unabsorbed substance. There is no specific antidote for overdose with EFAMAT. Since EFAMAT is highly protein bound, dialysis is unlikely to significantly remove the medicine from blood.