Quadrimune 10 mg, 15mg, 30mg, 40mg Oral Granules

QUADRIMUNE is a fixed dose combination medicine containing two nucleoside analogues (abacavir and lamivudine) and two protease inhibitors (lopinavir and ritonavir), indicated for the treatment of HIV-1 infection in children aged u2265 3 months, weighing u2265 3 to u2264 19,9 kg (WHO weight band 1 (WB1), WB 2, WB 3 and WB 4), and stabilised on concomitant use of the actives as separate formulations before switching to the fixed dose combination if similar doses of the actives can be achieved with QUADRIMUNE.

Patients should be screened for the HLA-B*5701 allele prior to initiating therapy with QUADRIMUNE (see boxed warning).

Posology:

Table 1: QUADRIMUNE should be administered twice daily with food according to weight band as follows:

• Weight (in kg) Number of capsules to be administered In the morning In the evening
• 3,0 to 5,9 2 2
• 6,0 to 9,9 3 3
• 10, 0 to 13,9 4 4
• 14,0 to 19,9 5 5

QUADRIMUNE should not be administered to neonates before a postmenstrual age (first day of the motheru2019s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained.

Dose adjustment: In case of concomitant therapy with efavirenz or nevirapine, a dose increase of lopinavir and ritonavir may be required. However, precise dose titration will not be possible with QUADRIMUNE. Thus, it is recommended that other formulation of individual components be used in this situation.

Method of administration:

Caution: Capsules should not be swallowed whole. Contents of QUADRIMUNE capsules should be administered with age-appropriate soft food/liquid, as described below.

Method of administration with milk/drinking water:

• Obtain the prescribed number of capsules needed for a dose.
• Dose the required number of capsules one by one.
• Hold one capsule vertically with the brown cap at the top and white body at the bottom and then gently tap on top of the capsule. Open the capsule by gently twisting and pulling up the cap.
• Pour the contents of capsule into a spoon.
• Add milk/drinking water to the spoon till the spoon fills and feed to the child immediately.
• Repeat this step for the prescribed number of capsules. Additional milk/drinking water can be taken after each dose if required.

Method of administration with soft food (e.g. porridge or mashed fruit):

• Prepare porridge/ fruit and cool to room temperature.
• Obtain the prescribed number of capsules needed for a dose.
• Dose the required number of capsules one by one.
• Take a small amount of porridge or fruit on the spoon.
• Hold one capsule vertically with the brown cap at the top and white body at the bottom and then gently tap on top of the capsule. Open the capsule by gently twisting and pulling up the cap.
• Pour the contents of capsule on the spoon containing porridge / fruit and feed to the child immediately. The porridge/ fruit with the drug sprinkled on top should be swallowed immediately and should not be stored for future use.
• Repeat this step for the prescribed number of capsules.
• Administration of the required dose should be followed by more food or drinking water/ milk, to ensure that no granules remain in the mouth.

QUADRIMUNE is contraindicated in:

• Patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to abacavir, lamivudine, lopinavir, ritonavir or any of the ingredients of QUADRIMUNE listed on section 6.1.
• Patients with moderate (Child-Pugh class B) or severe hepatic impairment (Child-Pugh class C) (see section 4.4).
• Combination with medicines that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions (see sections 4.5 and 5.2).
• Combination with medicines that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance (see sections 4.5 and 5.2).
• Pregnancy and lactation (see section 4.6).

Hypersensitivity to abacavir Refer to section boxed warning included under section 1 and side effects described in section 4.8. Some patients with the HLA-B*5701 allele developed abacavir-associated hypersensitivity reactions, which were fatal in some cases. Hypersensitivity is characterised by the appearance of symptoms indicating multi-organ/body-system involvement. Patients who develop a hypersensitivity reaction must discontinue QUADRIMUNE and must not be rechallenged with QUADRIMUNE, or any other product containing abacavir.

Medicine interactions:

Anti-mycobaterials: Rifampicin: QUADRIMUNE should not be co-administered with rifampicin because large decreases in lopinavir concentrations may significantly decrease the therapeutic effect (see section 4.5).

Bedaquiline: co-administration of bedaquiline with strong CYP3A4 inhibitors (e.g.: Lopinavir and ritonavir contained in QUADRIMUNE) may increase the systemic exposure of bedaquiline, which could potentially increase the risk of bedaquiline-related adverse reactions (see section 4.5). Bedaquiline must be used cautiously with QUADRIMUNE, only if the benefit of co-administration outweighs the risk.

Delamanid: co-administration of delamanid with a strong inhibitor of CYP3A4 (lopinavir/ritonavir contained in QUADRIMUNE) may slightly increase exposure to delamanid metabolite, which has been associated with QTc prolongation. Therefore, if co-administration of delamanid with QUADRIMUNE is considered necessary, frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 4.5).

Corticosteroids: Concomitant use of lopinavir/ritonavir as contained in QUADRIMUNE and inhaled, injectable, or intranasal fluticasone, budesonide, triamcinolone, or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushingu2019s syndrome and adrenal suppression.

PDE5 inhibitors: Co-administration of QUADRIMUNE with avanafil is not recommended. Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil for the treatment of erectile dysfunction in patients receiving QUADRIMUNE. Co-administration of QUADRIMUNE with these medicines is expected to substantially increase their concentrations and may result in increased associated adverse events such as hypotension, and prolonged erection.

Lactic acidosis / hyperlactataemia: Long-term use of QUADRIMUNE can result in potentially fatal lactic acidosis because of mitochondrial dysfunction. Symptomatic hyperlactataemia and lactic acidosis are not frequent. Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea and tachypnoea, fatigue and weight loss.

Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased anion gap and raised serum lactate level. Antiretroviral therapy should be stopped in any patient with a raised serum lactate level.

Abacavir: Based on the results of in vitro experiments and the known major metabolic pathways of abacavir, the potential for medicine interactions involving abacavir is low. Abacavir shows no potential to inhibit metabolism mediated by the cytochrome P450 3A4 enzyme.

Lamivudine: 3TC is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicines administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic transport system e.g., trimethoprim.

Lopinavir/ritonavir component of QUADRIMUNE: Lopinavir/ritonavir is a potent inhibitor of CYP3A (cytochrome P450 3A) both in vitro and in vivo. Co-administration of QUADRIMUNE and medicines primarily metabolised by CYP3A (e.g. dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and PDE5 inhibitors may result in increased plasma concentrations of the other medicines that could increase or prolong their therapeutic and adverse effects.

Pregnancy: QUADRIMUNE is contraindicated during pregnancy. Abacavir: Safety in human pregnancy has not been established. Abacavir should not be used during pregnancy and lactation since teratogenicity and/or foetal toxicity cannot be excluded (see section 4.3).

Breastfeeding: Studies have indicated that components of QUADRIMUNE (abacavir, lamivudine and lopinavir) are excreted in breast milk. Therefore, nursing mothers should not breastfeed their children while on QUADRIMUNE therapy.

Fertility: There are no data on fertility.

There are less frequent reports of visual impairment due to use of QUADRIMUNE. Patients need to be aware of how QUADRIMUNE affects them before engaging in potentially dangerous activities such as driving or operating machinery.

Summary of the safety profile: Some patients with hypersensitivity reactions were initially thought to have gastroenteritis, respiratory disease (pneumonia, bronchitis, pharyngitis) or a flu-like illness. This delay in diagnosis of hypersensitivity has resulted in abacavir being continued or re-introduced, leading to more severe hypersensitivity reactions or death.

Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of treatment with abacavir, as contained in QUADRIMUNE, although these reactions may occur at any time during therapy. Close medical supervision is necessary during the first two months, with consultations every two weeks.

Regardless of their HLA-B*5701 status, patients who develop this hypersensitivity reaction must discontinue QUADRIMUNE and must never be rechallenged with QUADRIMUNE, or any other medicine containing abacavir.

Abacavir/ lamivudine component: Symptoms and signs: In overdose, side effects can be precipitated and/or be of increased severity. No specific symptoms or signs have been identified following acute overdose with abacavir or lamivudine, apart from those listed as side effects.

Treatment: If overdose occurs the patient should be monitored for evidence of toxicity. Treatment is symptomatic and supportive. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied.

Lopinavir / ritonavir component: Treatment of overdose with lopinavir / ritonavir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with lopinavir / ritonavir.